Pharmacogenetics of Direct Oral Anticoagulants

For more than 50 years, oral vitamin K antagonists were the choice of anticoagulant for the long-term treatment and prevention of arterial and venous thromboembolic events. In recent years, four direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban have been compared with warfarin for thromboembolism prevention. These anticoagulants directly inhibit specific proteins within the coagulation cascade; in contrast, oral vitamin K antagonists inhibit the synthesis of vitamin K-dependent clotting factors. Dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, the factor Xa inhibitors, produce a more predictable, less labile anticoagulant effect. DOACs do not have limitations inherent vitamin K antagonists. DOACs have a predictable pharmacokinetic profile and are free of advers drugs reactions inherent in vitamin K antagonists. However, it is necessary to take into account the pharmacogenetic characteristics of the individual that can affect effectiveness and safety of use of DOACs. The results carried out to the present fundamental and clinical studies of DOACs studies demonstrate an undeniable the influence of genome changes on the pharmacokinetics and pharmacodynamics of DOACs. However, the studies need to be continued. There is a need to plan and conduct larger studies in various ethnic groups with the inclusion of sufficient associative genetic studies of the number of patients in each of the documented groups treatments with well-defined phenotypes

Process of Personalized Prescription of Valproic Acid as the Main Element of the Management of Epilepsy

The purpose of this study was to develop a sequential process of personalized valproic acid (VPA) prescription in patients with epilepsy. Materials and Methods: We randomly selected 167 patients with epilepsy receiving VPA, based on carriage of CYP2C9*2 and/or CYP2C9*3 and therapeutic drug monitoring. The patients’ CYP2C9 status was determined by CYP2C9 genotyping before the beginning of anticonvulsant therapy. Results: The sequence of personalized valproic acid prescription has been developed. Conclusion: Using the sequential process of personalized VPA prescription will allow neurologists, psychiatrists and general practitioners to select starting and maintenance dosages of VPA with respect to the individual patient’s pharmacogenetic profile and thereby, significantly improve the safety of pharmacotherapy in epilepsy patients

Candidate Genes Encoding Dopamine Receptors as Predictors of the Risk of Antipsychotic-Induced Parkinsonism and Tardive Dyskinesia in Schizophrenic Patients

(1) Introduction: Extrapyramidal disorders form the so-called extrapyramidal syndrome (EPS), which is characterized by the occurrence of motor disorders as a result of damage to the basal ganglia and the subcortical-thalamic connections. Often, this syndrome develops while taking medications, in particular antipsychotics (APs). (2) Purpose: To review studies of candidate genes encoding dopamine receptors as genetic predictors of development of AP-induced parkinsonism (AIP) and AP-induced tardive dyskinesia (AITD) in patients with schizophrenia. (3) Materials and Methods: A search was carried out for publications of PubMed, Web of Science, Springer, and e-Library databases by keywords and their combinations over the last 10 years. In addition, the review includes earlier publications of historical interest. Despite extensive searches of these commonly used databases and search terms, it cannot be ruled out that some publications were possibly missed. (4) Results: The review considers candidate genes encoding dopamine receptors involved in pharmacodynamics, including genes DRD1, DRD2, DRD3, and DRD4. We analyzed 18 genome-wide studies examining 37 genetic variations, including single nucleotide variants (SNVs)/polymorphisms of four candidate genes involved in the development of AIP and AITD in patients with schizophrenia. Among such a set of obtained results, only 14 positive associations were revealed: rs1799732 (141CIns/Del), rs1800497 (C/T), rs6275 (C/T), rs6275 (C/T) DRD2; rs167771 (G/A) DRD3 with AIP and rs4532 (A/G) DRD1, rs6277 (C/T), rs6275 (C/T), rs1800497 (C/T), rs1079597 (A/G), rs1799732 (141CIns/Del), rs1045280 (C/G) DRD2, rs6280 (C/T), rs905568 (C/G) DRD3 with AITD. However, at present, it should be recognized that there is no final or unique decision on the leading role of any particular SNVs/polymorphisms in the development of AIP and AITD. (5) Conclusion: Disclosure of genetic predictors of the development of AIP and AITD, as the most common neurological adverse drug reactions (ADRs) in the treatment of patients with psychiatric disorders, may provide a key to the development of a strategy for personalized prevention and treatment of the considered complication of AP therapy for schizophrenia in real clinical practice

Blood and Urinary Biomarkers of Antipsychotic-Induced Metabolic Syndrome

Metabolic syndrome (MetS) is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Antipsychotic (AP)-induced MetS (AIMetS) is the most common adverse drug reaction (ADR) of psychiatric pharmacotherapy. Herein, we review the results of studies of blood (serum and plasma) and urinary biomarkers as predictors of AIMetS in patients with schizophrenia (Sch). We reviewed 1440 studies examining 38 blood and 19 urinary metabolic biomarkers, including urinary indicators involved in the development of AIMetS. Among the results, only positive associations were revealed. However, at present, it should be recognized that there is no consensus on the role of any particular urinary biomarker of AIMetS. Evaluation of urinary biomarkers of the development of MetS and AIMetS, as one of the most common concomitant pathological conditions in the treatment of patients with psychiatric disorders, may provide a key to the development of strategies for personalized prevention and treatment of the condition, which is considered a complication of AP therapy for Sch in clinical practice

Pharmacotherapy and other aspects of senior medical students’ knowledge in community-acquired pneumonia: the final results of the KNOCAP II project

Introduction: Community-acquired pneumonia (CAP) remains an extensive medical and social problem. It is the most common human disease and one of the leading causes of death from infectious diseases. Increasing the level of senior medical students’ knowledge of the diagnosis, treatment and prevention of CAP will improve the level of medical care to the population. The aim of the study: to determine the level of senior medical students’ basic knowledge of CAP prevention, diagnosis and treatment with the help of a pharmacoepidemiological study. Materials and methods: The multicenter study “KNOCAP” (the full name of the project “The Assessment of Physicians’ and Students’ Knowledge of Community-acquired Pneumonia Basics”) presents the results of an anonymous prospective survey aimed at assessing the knowledge and preferences of senior medical students in terms of the CAP pharmacotherapy. In the second stage of the project (2017–2019). The results from 394 senior students from 8 centers of Russia, Ukraine and Kyrgyzstan were received and analyzed. An original questionnaire was developed for this study on the basis of the current clinical guidelines. Conclusion: The final results of a prospective survey revealed an insufficient level of students’ basic knowledge of diagnosis, treatment and prevention of CAP. The study revealed a statistically significant heterogeneity of knowledge levels in different centers, which indicates the need for the introduction of unified and in-depth training programs in this area

Rational antimicrobial chemotherapy: assessment of the level of basic knowledge of general practitioners. Final results of the KANT project

Introduction: The irrational use of medicines leads to a decrease in the quality of care, an increase in treatment costs and side effects. In the case of antibacterial drugs, in addition to all the above-mentioned consequences, their improper use can lead to an aggravation of the existing and quite challenging problem of our time – the growth of antibiotic resistance among pathogenic microorganisms. The aim of the study: to determine the level of basic knowledge of medical specialists in the field of a rational use of antimicrobial drugs (AMD). Materials and methods: The study was based on an analysis of an anonymous multicenter survey in the framework of the KANT project (the full name of the project is “Physicians’ (Students’) Knowledge of Antimicrobials Usage”). It was conducted in 2018–2019 in 10 major centers of Russia. Results and iscussion: According to the results of the study, the respondents showed a low level of knowledge of the rational use of antibacterial drugs. The best results are obtained for questions No.1 (time interval for evaluating the effectiveness of the initial antimicrobial therapy (AMT)), No.2 (rationality and period of AMD change with a positive clinical effect), and No.9 (determining the mode of using the proposed drugs), whereas the worst results were obtained for questions No.3 (determining irrational combinations of AMD), No.4 (determining a situation requiring a long course of AMT), and No.7 (choosing auxiliary drugs for bacterial respiratory infections). Conclusion: The results obtained in the study indicate the need for additional educational activities among health professionals

Assessment of physicians’ and medical majors’ knowledge of asthma basics: Current results of the ASSA-II study

Introduction: Bronchial asthma is a disease characterized by chronic inflammation of the airways. At present, about 235-300 million people suffer from asthma, and this number continues to grow. This pathology is also common in children. It causes significant social and economic damage worldwide. Severe forms of asthma are difficult to treat. Thus, a continuous improvement of doctors’ knowledge in this field is of great importance. Methods: The analysis of an anonymous survey of physicians and senior medical students was used in the research. Results: The study revealed both an average level of basic knowledge in asthma etiology and pathogenesis among the physicians and senior medical students and the significant differences in their knowledge regarding clinical picture and treatment of asthma. Only 49.2% of students and 56.0% of doctors were able to choose the correct definition of asthma from the suggested answers; 65.7% of students and 69.9% of doctors correctly indicated the main clinical and laboratory markers of asthma; 60.2% of students and 91.0% of doctors determined the correct combination of drugs in one delivery device; and 75.9% of students and 91.2% of doctors selected the correct basic asthma therapy depending on the severity. Conclusion: Basing on the results obtained it was recommended to introduce additional educational activities on the diagnosis and therapy of asthma among medical majors and physicians

Antimicrobial prescribing patterns in patients with COVID-19 in Russian multi-field hospitals in 2021 : results of the Global-PPS Project

The COVID-19 pandemic is a global public health challenge with understudied effects on antimicrobial usage. We aimed to analyze antimicrobial prescribing patterns in COVID-19 patients in Russian multi-field hospitals by means of the Global-PPS Project developed by the University of Antwerp. Out of 999 patients in COVID-19 wards in six hospitals surveyed in 2021, 51.3% received antimicrobials (79% in intensive care, 47.5% in medical wards). Systemic antivirals and antibiotics were prescribed to 31% and 35.1% of patients, respectively, and a combination of both to 14.1% of patients. The top antivirals administered were favipiravir (65%), remdesivir (19.2%), and umifenovir (15.8%); the top antibiotics were ceftriaxone (29.7%), levofloxacin (18%), and cefoperazone/sulbactam (10.4%). The vast majority of antibiotics was prescribed for treatment of pneumonia or COVID-19 infection (59.3% and 25.1%, respectively). Treatment was based on biomarker data in 42.7% of patients but was targeted only in 29.6% (6.7% for antibiotics). The rate of non-compliance with guidelines reached 16.6%. Antimicrobial prescribing patterns varied considerably in COVID-19 wards in Russian hospitals with groundlessly high rates of systemic antibiotics. Antimicrobial usage surveillance and stewardship should be applied to inpatient care during the COVID-19 pandemic

Therapeutic and Toxic Effects of Valproic Acid Metabolites

Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington’s disease, Parkinson’s disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: β-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects. It is known that some active metabolites of VPA may have a stronger clinical effect than VPA itself. These reasons explain the relevance of this narrative review, which summarizes the results of studies of blood (serum, plasma) and urinary metabolites of VPA from the standpoint of the pharmacogenomics and pharmacometabolomics. In addition, a new personalized approach to assessing the cumulative risk of developing VPA-induced adverse reactions is presented and ways for their correction are proposed depending on the patient’s pharmacogenetic profile and the level of therapeutic and toxic VPA metabolites in the human body fluids (blood, urine)

Antimicrobial Prescribing Patterns in Patients with COVID-19 in Russian Multi-Field Hospitals in 2021: Results of the Global-PPS Project

The COVID-19 pandemic is a global public health challenge with understudied effects on antimicrobial usage. We aimed to analyze antimicrobial prescribing patterns in COVID-19 patients in Russian multi-field hospitals by means of the Global-PPS Project developed by the University of Antwerp. Out of 999 patients in COVID-19 wards in six hospitals surveyed in 2021, 51.3% received antimicrobials (79% in intensive care, 47.5% in medical wards). Systemic antivirals and antibiotics were prescribed to 31% and 35.1% of patients, respectively, and a combination of both to 14.1% of patients. The top antivirals administered were favipiravir (65%), remdesivir (19.2%), and umifenovir (15.8%); the top antibiotics were ceftriaxone (29.7%), levofloxacin (18%), and cefoperazone/sulbactam (10.4%). The vast majority of antibiotics was prescribed for treatment of pneumonia or COVID-19 infection (59.3% and 25.1%, respectively). Treatment was based on biomarker data in 42.7% of patients but was targeted only in 29.6% (6.7% for antibiotics). The rate of non-compliance with guidelines reached 16.6%. Antimicrobial prescribing patterns varied considerably in COVID-19 wards in Russian hospitals with groundlessly high rates of systemic antibiotics. Antimicrobial usage surveillance and stewardship should be applied to inpatient care during the COVID-19 pandemic