Experience in Using Antiviral Agents for the Treatment of Novel Coronavirus Infection (COVID-19) in Kyrgyzstan

The national clinical guidelines for the treatment of novel coronavirus infection (COVID-19) are the main source of information and the reference point for clinical decision-making by healthcare professionals in the Kyrgyz Republic. The recommendations presented in these documents are largely based on data from real clinical practice, but the efficacy and safety of a number of antiviral agents, the indications for which have been expanded to include COVID-19 treatment, remain unclear.The aim of the study was to conduct a retrospective pharmacoepidemiological analysis of lopinavir+ritonavir use in hospitals in the Kyrgyz Republic for the treatment of COVID-19 during the period from March until April 2020.Materials and methods: the paper describes a retrospective study of 145 medical records of patients with confirmed COVID-19 who were hospitalized in infectious disease departments/hospitals of the Kyrgyz Republic. Statistical processing was performed using Microsoft Excel 2017.Results: between 16 March 2020 and 25 April 2020, 145 patients were prescribed lopinavir+ritonavir at a dose of 200 mg + 50 mg, 2 tablets twice a day—in line with the dosage regimen recommended by the national guideline. The national guideline recommended the treatment duration of 10 days, while the actual treatment duration was 1–12 days (5.5 days on average) depending on the tolerability of the drug. The use of the drug was accompanied by adverse drug reactions (ADRs) in 78 patients (53.8%), and caused deterioration in the general condition of 73 of these patients (94.8%) which resulted in discontinuation of the drug. The most common ADRs were nausea, vomiting, diarrhoea, decreased appetite, yellowness of the skin, and, according to laboratory studies, an increase in serum levels of bilirubin, creatinine, glucose, aspartate aminotransferase and amylase activity. A retrospective assessment of the causal relationship probability according to the Naranjo scale showed an interrelation between the use of lopinavir+ritonavir and ADR development.Conclusions: the use of the lopinavir+ritonavir drug in COVID-19 patients led to deterioration of their general condition, which was severe in some cases. The data obtained indicate that the use of this drug for COVID-19 treatment is clinically unreasonable and irrational. Lopinavir+ritonavir was excluded from subsequent revisions of the clinical guidelines for the diagnosis and treatment of COVID-19 in the Kyrgyz Republic.

Analysis of Pharmacokinetic Parameters of Acetylsalicylic Acid for Prediction of Potential Nephrotoxic Effects

Nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid, can have a dose-dependent nephrotoxic effect. The study of the pharmacokinetics of acetylsalicylic acid products will contribute to timely detection and correction of side effects caused by this medicinal product.The aim of the study was to evaluate potential nephrotoxic effects following a single oral administration of 75 mg of acetylsalicylic acid, based on the analysis of the pharmacokinetic parameters.Materials and methods: the study involved 24 healthy volunteers who received 75 mg of acetylsalicylic acid (tablets) once orally. The measurement of the active metabolite of acetylsalicylic acid—salicylic acid—in blood plasma was performed by HPLC/MS using an Agilent 1200 liquid chromatography system coupled to an Agilent 6140 tandem mass spectrometer. Agilent Eclipse XDB-C18 column (4.6 mm×150 mm; 5.0 μm) was used for chromatographic separation. The test procedure used in the study was validated. The results obtained were used to calculate the pharmacokinetic parameters: Cmax (maximum concentration), Tmax (time to maximum concentration), T1/2 (half-life of the drug), AUC0-t (area under the pharmacokinetic curve from 0 to the last time point of the curve), AUC0-∞ (total area under the pharmacokinetic curve from 0 to ∞), MRT (mean residence time of the drug in the blood), Kel (elimination rate constant), Cl/F (total clearance), Vd/F (apparent volume of distribution). The Statistics (22.0.0.0) software was used for statistical processing of the results.Results: T1/2 of salicylic acid in blood plasma was determined to be 1.6 ± 0.5 h, Cmax was 4523.0 ± 725.0 ng/mL, and Tmax was 0.98 ± 0.4 h. AUC0–t was equal to 16183.0 ± 3823.0 ng×h/m, Vd/F was 12.0 ± 3.1 L/kg, and MRT was 2.9 ± 0.6 h.Conclusions: the analysis of the pharmacokinetic parameters demonstrated a high absorption rate, intensive distribution, and moderate elimination rate of salicylic acid (the main metabolite of acetylsalicylic acid), indicating a low risk of nephrotoxic effects associated with the studied dose of the drug.

Erratum: E. A. Sokova et al., Risk factors and characteristics of adverse reactions associated with the use of beta-lactam antibiotics in older patients

Sоkоvа Е.А., Arkhipov V.V., Demidova O.A., Mazerkina I.A., Alexandrova T.V., Zhuravleva M.V. Risk factors and characteristics of adverse reactions associated with the use of beta-lactam antibiotics in older patients. Bezopasnost’ i risk farma koterapii = Safety and Risk of Pharmacotherapy. 2021;9(3):128–135. https://doi.org/10.30895/2312-7821-2021-9-3-128-135Dear readers, a technical error was made on page 134, issue 3 of the Safety and Risk of Pharmacotherapy, 2021 (2021;9(3):128–135). The following statement:“Acknowledgements. The study reported in this publication was carried out as part of a publicly funded research project No. 056-00005-21-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121021800098-4)”should read:“Acknowledgements. The study reported in this publication was carried out as part of a publicly funded research project No. 056-00005-21-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121022000154-2)”.The correction did not have any effect on the conclusions made by the authors.The text of the online version of the journal was corrected accordingly.

Cardiotoxic Effects of Yew Tree and Pink Periwinkle Alkaloids

Antitumour herbal medicines based on pink periwinkle and yew tree alkaloids are included in combination therapies for many types of cancer. The use of these classes of products may entail cardiotoxic effects leading to life-threatening conditions. The aim of the study was to analyse scientific literature on cardiotoxic effects of anticancer drugs based on yew tree alkaloids (taxanes) and pink periwinkle alkaloids (vinca alkaloids). The results of the analysis demonstrated that the main manifestations of taxane-induced cardiotoxicity were bradycardia, atrioventricular block, atrial and ventricular arrhythmias. Concomitant use of taxanes and anthracycline antibiotics exacerbated cardiotoxic effects of both drug classes. The use of vinca alkaloids was associated with haematological toxicity in the form of neutropenia, while cardiotoxic effect was rarely observed during monotherapy. Raising awareness among oncologists, cardiologists, and other specialists involved in the management of cancer patients about potential cardiac complications of antitumour therapy contributes to early detection of adverse reactions and allows for individual correction of treatment regimens, especially in patients with predisposition to cardiovascular disease.

Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

Drug-induced kidney injury (DIKI) accounts for 8 to 60% of episodes of acute kidney injury (AKI) among hospital patients. Early DIKI detection and timely adjustment of therapy will help reduce the kidney injury incidence and mortality. The aim of the study was to analyse scientific literature on the biomarkers used in DIKI diagnosis. The study revealed that the use of such kidney damage markers as serum creatinine, urinary output, urea nitrogen, sodium excretion, urinary sediment microscopy is limited because they do not give a full picture of the kidney injury degree and progression and do not allow for early AKI diagnosis. It was demonstrated that some of the most promising biomarkers are KIM-1, L-FABP, NAG, NGAL, cystatin C, clusterin, β2-microglobulin, МСР-1, IGFBP7, and TIMP-2. However, recommendations for determination of these biomarkers’ urine or blood concentrations for AKI diagnosis are somewhat preliminary, because there have been insufficient clinical and preclinical studies to establish validity of such tests. No precise algorithms based on determination of the biomarkers levels in urea and/or blood serum have been developed for AKI risk assessment, diagnosis, monitoring, and treatment. Thus, further research is necessary to investigate different AKI biomarkers and improve experimental models (both in vivo and in vitro), which will support assessment of potential nephrotoxic properties of existing and new medicinal products.

Investigation of Cytotoxic Effects of Recombinant Human Interferon Lambda-1 and Its Pegylated Form on Human Conjunctival Epithelial Cells

Currently, there are no efficacious, all-purpose antiviral medicines for the treatment of ocular surface infections caused by viruses. At the same time, type III interferons demonstrate high potency for histological barriers, such as the conjunctiva. Modification of protein molecules in native products can significantly improve their pharmacodynamic properties. Thus, it seems reasonable to develop antiviral medicines based on interferon lambda (IFN-λ1) and its pegylated form (PEG IFN-λ1).The aim of the study was to evaluate the in vitro cytotoxic effect of recombinant human IFN-λ1 and its pegylated form on Chang conjunctiva clone 1-5c-4 human conjunctival cells.Materials and methods: PEG IFN-λ1 was obtained by the electron beam immobilisation method. A normal human conjunctival cell line Chang conjunctiva clone 1-5c-4 was used for cell cultivation. The MTT test was used to assess the cytotoxic effect. Cell proliferative activity was studied by measuring microelectrode impedance. Ultrastructural changes were assessed by electron microscopy. Statistical processing was performed using the Statistica 10.0 software package.Results: IFN-λ1 (37 μg/mL) and PEG IFN-λ1 (42 μg/mL) had no significant cytotoxic effect on the human conjunctiva cell culture and the cell proliferative activity. The analysis of ultrastructural changes demonstrated that IFN-λ1 activated metabolic processes in the cells, and PEG IFN-λ1 promoted differentiation and keratinisation of epithelial cells and led to modification of the cell membrane. A ten-fold increase in IFN-λ1 and PEG IFN-λ1 concentration (to 370 μg/mL and 420 μg/mL, respectively) reduced the cell viability by 15–20% as compared to the intact control.Conclusions: the study results demonstrated that IFN-λ1 and PEG IFN-λ1 could be used as active pharmaceutical ingredients in the development of medicines for the treatment of conjunctival viral infections.

Analysis of Noncompliances with Legislative Requirements in Pharmacovigilance Materials of Registration Dossiers

Since 1 January 2021 the authorisation of medicines in the Russian Federation has to be performed according to the Eurasian Economic Union (EAEU) procedure. The Pharmacovigilance System Master File (PSMF) is the main document describing the pharmacovigilance system of the marketing authorisation holder (MAH) or its authorised representative. The aim of the study was to analyse noncompliances with the EAEU requirements, which were revealed during PSMF assessment.Materials and methods: the authors analysed 687 pharmacovigilance documents included in registration dossiers that were submitted for assessment from 1 January to 30 June, 2021. Results: the authors identified and systematised the main noncompliances with the EAEU requirements in terms of presentation, content, completeness of each PSMF section. They analysed the frequency of noncompliances in PSMFs and identified the most frequent flaws of MAHs’ pharmacovigilance systems.Conclusions: the authors give recommendations for elimination of significant noncompliances identified during PSMF assessment, which may include: timely updating, maintenance, and revision of the documents in accordance with changes in legislation and any other significant changes, regular training of pharmacovigilance staff, etc. The results of this review will be useful for MAHs as the main participants of the marketing authorisation process who are directly involved in the pharmacovigilance system management at the pre- and post-authorisation stages, and will help them prevent potential mistakes when drawing up pharmacovigilance system documents.

Risk Factors and Characteristics of Adverse Reactions Associated with the Use of Beta-Lactam Antibiotics in Older Patients

The frequency of adverse drug reactions (ADRs) in older patients is approximately 11.0%, according to scientific literature. Antibiotics are the third largest group (19.5%) of medicinal products in terms of ADR frequency in geriatric patients. Beta-lactam antibiotics are the empiric treatment of choice for older outpatients and inpatients with community-acquired pneumonia. The mortality in this group of patients accounts for 85% of the overall mortality from community-acquired pneumonia. The aim of the study was to analyse scientific data on risk factors and characteristics of adverse drug reactions associated with the use of beta-lactam antibiotics in older patients. Specificity of ADRs to beta-lactam antibiotics in this group of patients is due to age-related changes in pharmacokinetics and pharmacodynamics as well as polymorbidity and polypharmacy. The analysis of scientific literature demonstrated that there have not been so many pharmacoepidemiological studies in this group of patients, and their results have been inconsistent. The frequency, causes, and clinical manifestations of ADRs in geriatric patients are diverse and differ considerably from those in younger patients. Of the most widely used antibiotics, ceftriaxone and cefaclor exhibited a statistically lower risk of ADRs in older patients than in younger patients. At the same time, ceftriaxone was associated with a relatively higher frequency of serious ADRs in older patients as compared to younger patients, whereas the frequency of serious ADRs was lower with cefaclor. The likelihood of nephrotoxic, neurotoxic, and hepatotoxic ADRs associated with the use of beta-lactam antibiotics is becoming more and more obvious but it is still underestimated in clinical and geriatric practice. Safety monitoring, therapeutic drug monitoring with due consideration of ADR risk factors in older patients, and inclusion of older patients in clinical trials of antimicrobial drugs, would improve efficacy and safety of antibiotic treatment.