Репозиторий Университета

© 2019 Elsevier B.V. A new sample extraction protocol was developed for pharmacokinetic studies of dabigatran with high-performance liquid chromatography separation - electrospray ionization time-of-flight mass spectrometry analysis. After protein precipitation with acetonitrile, free dabigatran and its metabolites are separated into water phase by water-dichloromethane liquid-liquid extraction to purify the sample from proteins and endogenous lipophilic compounds. Chromatographic separation was achieved on an Agilent Zorbax SB-CN column (150 × 4.6 mm, 5 µm)) using 0.1% aqueous solution of formic acid and acetonitrile (80:20) as the mobile phase. Agilent Zorbax SB-CN column was selected to improve sample resolution and to avoided early elution of dabigatran previously seen when using a C18 column. The extended calibration curve was constructed from 5 to 1000 ng/L while precision and accuracy were assessed at four levels across the linear dynamic ranges. Within-run precision was <5.6% and the between-run precision was <3.9%. The method accuracy ranged from 89.8% to 104.4%. The developed method was successfully applied to 30 patient samples to evaluate antithrombotic efficacy and anticoagulant activity of dabigatran following knee endoprosthesis surgery.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Low-molecular-weight heparins (LMWHs) are widely used in medical practice. LMWHs are produced using various methods of controlled depolymerization of unfractionated heparin (UFH). Herein, a method for radiation-induced destruction of aqueous heparin solutions using a 60Co gamma-irradiation source is presented. The optimal conditions for depolymerization of starting heparin were found. The anticoagulant activity of LMWHs was studied as a function of irradiation dose. The results allowed this LMWH production method to be recommended for development of new anticoagulants.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. An HPLC-MS/MS method for determining dabigatran in human blood serum was developed. Samples were prepared by precipitation of proteins using MeOH followed by centrifugation and dilution with deionized H2O. The developed method had a simple sample-preparation procedure, short analysis time, and wide analytical range (from 1 to 1,000 ng/mL). This method was suitable for routine bioanalytical studies, in particular, therapeutic drug monitoring.

© 2018 Limited Liability Company KlinMed Consulting. All Rights Reserved. In the clinical practice a physician quite often is at a loss due to “freedom of choice” granted by availability of direct oral anticoagulants (DOAC). If a patient with nonvalvular atrial fibrillation (AF) has indications for therapy with anticoagulants which DOAC should be preferred? What are benefits for a patient with ischemic heart disease and AF when definite NOAC is chosen and what are risks inherent of this choice? Answers to such questions are given in this paper.

© 2018 Limited Liability Company KlinMed Consulting. All Rights Reserved. Is this paper discuss problems of selection of anticoagulant therapy in elderly patients with atrial fibrillation, use of unreasonably low doses of anticoagulants, their risks and adherence to therapy is discussed in the paper.

© 2018 Stolichnaya Izdatelskaya Kompaniya. The article presents a clinical observation of the left atrial appendage thrombosis in a 51-year-old female patient with a paroxysmal form of nonvalvular atrial fibrillation which occurred despite long-term anticoagulant therapy with apixaban in a full dose (5 mg b.i.d.), and the patient's management. The patient was admitted with recurrent symptomatic paroxysm for more than 48 hours, because of which, in accordance with the recommendations, transesophageal echocardiography was performed before an emergency rhythm restoration. Thrombus in the left atrial appendage 0.5×1.03 cm in size was detected. It was decided to refrain from the immediate restoration of the rhythm due to the very high risk of thromboembolic complications. In connection with the categorical refusal of the patient from warfarin, it was decided to replace apixaban with another direct oral anticoagulant - dabigatran 150 mg bid for a period of 4 weeks followed by performing a control transesophageal echocardiographic study. As a result, no thrombus was found on control echocardiography. The particularity of this observation is concomitant hypertrophic cardiomyopathy and diabetes mellitus type 1 in this patient..

© 2018 Media Sphera Publishing Group.All rights reserved. Purpose: To assess the prevalence of atrial fibrillation (AF) and use of antithrombotic agents in adult patients with acute coronary syndrome (ACS). Materials and Methods. We consecutively enrolled all ACS patients (n=1155) who were hospitalized in two Moscowbased percutaneous coronary intervention centers (each center performs over 500 PCIs a year) between October 2017 and February 2018. AF was diagnosed in 204 patients (17.7%). The risk of thromboembolic complications was assessed using the CHA2DS2-VASc Score. The risk of hemorrhagic complications was assessed using the HAS-BLED Score. The data were processed using StatSoft Statistica 10.0 and IBM SPSS Statistics v.23 software. Results. The prevalence of diagnosed AF was 13.6%, while the prevalence of undiagnosed AF was 4.1%. Of the 179 discharged patients with AF, only 2 had a low risk of ischemic stroke (IS). One hundred and fifty patients (83.8%) eligible for oral anticoagulant therapy received oral anticoagulants. Patients with diagnosed AF were administered oral anticoagulants (OACs) significantly more often than patients with undiagnosed AF [125 (91.9%) vs. 25 (58.1%), р 0.001]. Novel oral anticoagulants (NOACs) were administered four times more often than vitamin K antagonists [120 (80.0%) vs. 29 (19.3%), р0.001]. Rivaroxaban was used in 51.3% of cases. Of the 29 patients treated with warfarin, only 3 (10.3%) achieved the target international normalized ratio (INR) at discharge. Of the 107 patients who underwent percutaneous coronary intervention (PCI), 77 patients (80%) received an OAC and two antiplatelet agents (with 74% receiving this three-agent therapy for one month), 11 patients (10.3%) received an OAC and an antiplatelet agent, and 18 patients (16.8%) received two antiplatelet agents. The only antiplatelet agent used as part of the three-agent therapy was clopidogrel. The three-agent therapy without PCI was administered in 43.1% of cases. Conclusion. We found that the prevalence of AF in patients with ACS was high. The fact that doctors administered NOACs suggests that they are aware of the need to use these agents to prevent thromboembolic complications in AF patients.

© 2018 Stolichnaya Izdatelskaya Kompaniya. The choice of anticoagulant therapy in patients with atrial fibrillation (AF) and concomitant diseases - coronary heart disease (CHD), including acute coronary syndrome (ACS) in history, peripheral arterial disease (PAD), is discussed in the article. The overall mortality and incidence of myocardial infarction in patients with CHD and AF is higher than in patients with AF without CHD. Patients with AF and PAD compared to patients with AF without PAD have higher risks both stroke and systemic embolism. The prescription of triple antithrombotic therapy is necessary for patients with a combination of AF and CHD who underwent percutaneous coronary interventions (in ACS or elective surgery). The possibility of prescription and duration, the choice of specific drugs and their doses should be determined individually, based on the risks of ischemic events associated with stenting, the risk of ischemic stroke and bleeding. Use of new oral anticoagulants (NOAC) instead of vitamin K antagonists (eg, warfarin), low doses of NOAC, studied in trials and proven efficacy in the prevention of stroke/systemic embolism, the use of clopidogrel as a drug of choice from the P2Y12 inhibitor group, the use of low doses of acetylsalicylic acid (ASA), the routine administration of drugs from the proton pump inhibitor group is recommended to minimize the risk of bleeding. The data of subanalysis of the ARISTOTEL randomized clinical trial, indicating a high profile of efficacy and safety of apixaban in patients with AF, depending on the presence of CHD, PAD, concomitant use of ASA, are also presented in the article. The benefits of apixaban over warfarin for reducing the risk of stroke/systemic embolism, total mortality and the risk of bleeding in a subgroup of CHD patients are just as obvious as in the general population of the ARISTOTLE study, and in the subgroup of patients without CHD. Treatment with apixaban, both in the subgroup of patients taking ASA, and a subgroup of patients without ASA, is accompanied by a lower risk of strokes and systemic embolism and a lower incidence of major bleeding. The risk of stroke or systemic embolism was similar in patients with AF and PAD randomized to the apixaban group or to the warfarin group, as well as in patients with AF without PAD. Patients with AF and PAD who received apixaban or warfarin had a similar incidence of major bleeding or clinically significant minor bleeding..

© Russian Association of Endocrinologists, 2018. BACKGROUND. Intensive glycaemic control in patients with type 1 diabetes may lead to hypoglycaemia and thus increase the risk of cardiovascular and cerebrovascular events. Platelet activation and/or decreased activity of physiological anticoagulants during hypoglycaemia may play a role in the development of cardiovascular or cerebrovascular complications. AIMS. To investigate induced platelet activity, the activity of physiological anticoagulants, and the von Wil-lebrand factor in patients with type 1 diabetes with the hyperinsulinaemic-hypoglycaemic clamp. MATERIALS AND METHODS. We examined 11 patients with type 1 diabetes without macro- and micro-vascular complications (6 males, 5 females, mean age 23.7 ± 5.6 years, A1C 9.7 ± 2.3%). Induced platelet aggregation, physiological anticoagulants (Protein S, Protein C, AT III) and the von Willebrand factor were studied at hyperglycaemic, euglycaemic, and hypoglycaemic stages during use of a hyperinsulinaemic (1 mU/kg/min) hypoglycaemic clamp. RESULTS. Platelet aggregation to all agonists increased significantly during the hypoglycaemic stage, compared with the euglycaemic or hyperglycaemic stages. There was no difference in platelet aggregation between the euglycaemic and hyperglycaemic stages. Platelet aggregation to all agonists increased during the hypoglycaemic stage compared with the hyperglycaemic period: thrombin-23.9%, ADP-30.6%, arachidonic acid-30.9%, collagen-69.4% and ristocetin-70.8%. During hypoglycaemia aggregation to ADP, arachidonic acid and collagen remained within normal limits (upper quartile); aggregation to thrombin was significantly above normal limits and aggregation to ristocetin remained significantly below lower limits. Protein S activity was significantly increased during hypoglycaemia compared with euglycaemia (p = 0.046) and hyperglycaemia (p = 0.046). Antithrombin-III activity decreased significantly at the euglycaemic and hypoglycaemic stages, compared with the hyperglycaemic period, but still remained significantly elevated above the upper threshold. Protein C and vWf activity did not change significantly. CONCLUSIONS. In patients with type 1 diabetes platelet aggregation and protein S activity increases significantly at the hypoglycaemic stage of the hyperinsulinaemic-hypoglycaemic clamp. Platelet activation is directly caused by hypoglycaemia and not by decreasing glucose levels. Increased protein S activity is a compensatory response to platelet activation.

© 2018 Sychev et al. Background: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods: A total of 60 patients, aged 37–81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p<0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. Conclusion: Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations.

© 2018 Media Sphera Publishing Group. All rights reserved. This article presents an overview of data of Russian and foreign literature on possible associations between cognitive impairment and atrial fibrillation (AF). It includes modern classification of cognitive impairment, mechanisms of the effect of AF on cognitive functions and development of dementia, recommendations for the prevention of cognitive impairment in patients with AF. Special attention is paid to the assessment of cognitive status, and safe anticoagulant therapy, which is a priority in the prevention of cognitive impairment in patients with AF. Analysis of literature showed greater efficacy and safety of drugs from the group of Non-Vitamin K Antagonist Oral Anticoagulants (NOAC), rivaroxaban in particular, in comparison with warfarin. Drugs from the NOAC group can be recommended for prevention stroke, cognitive impairment and dementia in elderly patients with AF.

© 2018 Kryukov et al. Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at —70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-β-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent. Results: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A. Conclusion: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class.