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.

Background: Information about the distribution of clinically significant genetic markers in different populations may be helpful in elaborating personalized approaches to the clinical management of COVID-19 in the absence of consensus guidelines. Aim: Analyze frequencies and distribution patterns of two markers associated with severe COVID-19 (rs11385942 and rs657152) and look for potential correlations between these markers and deaths from COVID-19 among populations in Russia and across the world. Methods: We genotyped 1883 samples from 91 ethnic groups pooled into 28 populations representing Russia and its neighbor states. We also compiled a dataset on 32 populations from other regions using genotypes extracted or imputed from the available databases. Geographic maps showing the frequency distribution of the analyzed markers were constructed using the obtained data. Results: The cartographic analysis revealed that rs11385942 distribution follows the West Eurasian pattern: the marker is frequent among the populations of Europe, West Asia and South Asia but rare or absent in all other parts of the globe. Notably, the transition from high to low rs11385942 frequencies across Eurasia is not abrupt but follows the clinal variation pattern instead. The distribution of rs657152 is more homogeneous. The analysis of correlations between the frequencies of the studied markers and the epidemiological characteristics of COVID-19 in a population revealed that higher frequencies of both risk alleles correlated positively with mortality from this disease. For rs657152, the correlation was especially strong (r = 0.59, p = 0.02). These reasonable correlations were observed for the “Russian” dataset only: no such correlations were established for the “world” dataset. This could be attributed to the differences in methodology used to collect COVID-19 statistics in different countries. Conclusion: Our findings suggest that genetic differences between populations make a small yet tangible contribution to the heterogeneity of the pandemic worldwide.

PHARMACOGENETIC ASPECTS OF NEW ORAL ANTICOAGULANTS APPLICATION

INTRODUCTION. The variability in patient response to non-steroidal anti-inflammatory drugs (NSAIDs) may be due to genetic polymorphisms. Decreased-function or non-functional CYP2C9 alleles are known to be significant contributors to response variability, and research is being conducted on the potential contribution of polymorphisms in the PTGS1 and PTGS2 genes that encode for the NSAID targets, cyclooxygenases 1 and 2.AIM. This study aimed to demonstrate the contribution of pharmacogenetic characteristics to the development of adverse reactions to NSAIDs in clinical cases.MATERIALS AND METHODS. This study reports two clinical cases observed in a multidisciplinary hospital in Moscow. The first case report demonstrates a neurosurgical patient with spondylodiscitis who showed signs of renal failure associated with ketorolac administration during 13 days of inpatient treatment. The second case report presents a patient with gastrointestinal bleeding that developed after 3 weeks of ketorolac self-administration and ultimately required gastric resection surgery. According to real-time polymerase chain reaction results, these patients have single-nucleotide polymorphisms, including rs179985 (CYP2C9*2) and rs1057910 (CYP2C9*3) in the CYP2C9 gene, rs10306135 and rs12353214 in the PTGS1 gene, and rs20417 in the PTGS2 gene.RESULTS. The described adverse reactions to ketorolac are attributable to the patients’ pharmacogenetic characteristics and other factors (exceeding the recommended duration of ketorolac therapy, concomitant conditions, drug interactions, and older age). In the case of nephrotoxicity, the patient has the CYP2C9*1/*2 genotype, which is associated with decreased NSAID metabolism. Additionally, this patient has the PTGS1 (C>T) rs12353214 genotype, which may be associated with variations in the activity of cyclooxygenase 1 and may lead to an increased risk of adverse reactions to NSAIDs. In the case of gastrointestinal bleeding, the patient also has genetic characteristics that affect the response to NSAIDs, as the CYP2C9*1/*3 genotype is associated with significantly decreased NSAID metabolism. Patients with this genotype should take the lowest doses or switch to alternatively metabolised NSAIDs.CONCLUSIONS. To reduce the risk of nephrotoxicity and gastrointestinal bleeding in patients when prescribing ketorolac, healthcare providers should strictly follow the recommended dosing regimen and consider individual comorbidities and potential drug interactions that may potentiate adverse drug reactions. Additionally, patient risk management requires pharmacogenetic testing, including the determination of decreased-function or non-functional CYP2C9 alleles and the rs12353214 polymorphism in the PTGS1 gene.

Aim. To study pharmacokinetics of apixaban in patients with atrial fibrillation and cardioembolic stroke in acute phase. Material and methods. 17 patients (14 women and 3 men), aged 76.6±9.5 years with atrial fibrillation and cardioembolic stroke in acute phase were enrolled into the study. High performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Results. Intake of a single dose of apixaban 5 mg is described by the following pharmacokinetic parameters: geometric mean of Cmax 124.5 ng/mL (CV%=48), AUC (0, τ) 1008.0 ng•h/mL (CV%=48), AUC (0, ∞) 2751.6 ng•h/mL (CV%=82), median Tmax 3 hours (min 1, max 4), mean t½ 16.9 h (SD 13.6). Negative correlation between NIHSS stroke severity score and Tmax was found (r=-0.628, p=0.007) as well as positive correlation between apixaban t½ and patient age (r=0.638, p=0.01). A tendency to increase in AUC (0, ∞) was observed according to CHA2DS2-VASc points amount but it did not reach the statistical significance (r=0.620, p=0.14). Conclusion. For the first time in Russia pharmacokinetic data of apixaban were obtained in patients with cardioembolic stroke in acute phase. It could be the basis for the development of new personalized approaches to anticoagulation therapy in these patients. Keywords: new oral anticoagulants, apixaban, pharmacokinetics, atrial fibrillation, cardioembolic stroke

The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disor ders; gastrointestinal disorders, neurological disorders, and allergic reactions; and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia; neutropenia is also characteristic of a number of interleukin inhibitors. Haemo static adverse reactions to anticoagulants depend on the patient’s dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.