Experimental Cell Line Models for Nephrotoxicity Screening

The aim of the study was to review literature data on cell models for experimental assessment of drug nephrotoxicity in vitro. Because of nephrotoxicity, 2% of new investigational medicinal products are discarded at the stage of preclinical in vivo studies in laboratory animals, and 19%—after phase 3 clinical trials. Prediction of toxicity in cell models could make drug development more cost-effective and help to reduce/avoid animal testing. At present, there are no official international guidelines for assessment of nephrotoxicity in vitro, but there is a lot of research underway. The main toxicity target in kidneys is renal proximal tubule epithelial cells, therefore the main research is focused on the development of renal proximal tubule epithelial cell lines with stable functional characteristics. Another important aspect in nephrotoxicity modeling is the choice of relevant test methods and end points which would reflect potential toxicity mechanisms. The paper reviews existing human renal proximal tubule epithelial cell lines and current test methods for assessing cytotoxicity. Promising areas for future development of cell models for nephrotoxicity assessment— are optimisation and standardisation of in vitro systems that would help to make preclinical predictions of drug nephrotoxicity in vivo

Preparation of Hydrophobic PET Track-Etched Membranes for Separation of Oil–Water Emulsion

The paper describes the separation of an oil–water emulsion by filtration using poly(ethylene terephthalate) track-etched membranes (PET TeMs) with regular pore geometry and narrow pore size distribution. PET TeMs were modified with trichloro(octyl)silane to increase their hydrophobic properties. Conditions for the modification of PET TeMs with trichloro(octyl)silane were investigated. The results of changes in the pore diameters and the contact angle depend on the concentration of trichloro(octyl)silane and the soaking time are presented. The obtained samples were characterized by FTIR, AFM, SEM-EDX and gas-permeability test. Chloroform–water and cetane–water emulsions have been used as a test liquid for oil–water separation. © 2021 by the authors.Funding: This research was funded by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan (Grant No. AP09057934) and Belarusian Republican Foundation for Basic Research (contr. F20MS-025 of 04.06.2020)

Graft Polymerization of Stearyl Methacrylate on PET Track-Etched Membranes for Oil–Water Separation

In this article, results of PET track-etched membranes (PET TeMs) hydrophobized by photo-induced graft polymerization of stearyl methacrylate (SM) inside the pores were presented. The effects of monomer concentration, time of irradiation and the nature of the solvent on the degree of grafting and membrane morphology were investigated. The PET TeMs with pore diameters ranging from 350 nm (pore density of 1 × 108 pore/cm2) to 3.05 µm (pore density of 1 × 106 pore/cm2) were hydrophobized and tested for oil–water separation by using hexadecane–water and chloroform–water emulsions. Studies have shown high separation performance for membranes (up to 1100 mL/m2·s) with large pore diameters while achieving a high degree of purification. © 2022 by the authors.Belarusian Republican Foundation for Fundamental Research, BRFFR: F20MS-025; Ministry of Education and Science of the Republic of Kazakhstan: AP09057934This research was funded by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan (Grant No. AP09057934) and the grant of the Belarusian Republican Foundation for Fundamental Research (BRFFR) No. F20MS-025 of 04.06.2020

Гидрофобизация пэтф-поверхностей для разделения эмульсий типа «вода в масле»

The technique of poly(ethylene terephthalate) track-etched membranes (PETF TMs) modification to increase of water-in-oil emulsions separations is developed. The water-in-oil emulsions separations by using PETF TMs with regular pore geometry and pore sizes 200 and 350 nm is described in the article. PETF TMs were modified with octadecyltrichlorosilane by spin-coating method to increase their hydrophobic properties. The results of changes in the pore diameters and the contact angle after PETF TMs modification are presented. The obtained samples were characterized by AFM, SEM and gas permeability test. Chloroform–water and n-hexadecane–water emulsions have been used as a test liquid for water-in-oil emulsions separations. At an operating vacuum of 700 mbar, the specific filtration performance of chloroform: water emulsions were 51.5 and 932.0 l/(m2 ⋅ h), hexadecane: water were 46.1 and 203.4 l/(m2 ⋅ h) for PETF-200 / OTS and PETF-350 / OTS, respectively. The degree of purification of emulsions by modified membranes according to the refractive index is of 100 %. Obtained membranes can be used to separate oil-water emulsions in order to prevent the corrosion of pipelines and changes of crude oil viscosity, as well as the treatment of water purification from oil industry waste.Разработана модификация поли(этилентерефталатных) трековых мембран (ПЭТФ ТМ) для увеличения разделения водомасляных эмульсий. Описано разделение эмульсий типа «вода в масле» с использованием ПЭТФ ТМ с правильной геометрией пор и размером пор 200 и 350 нм. Мембраны модифицированы октадецилтрихлорсиланом методом спин-коатинга для повышения их гидрофобных свойств. Представлены результаты изменения диаметров пор и угла смачивания после модификации ПЭТФ ТМ. Структура образцов изучена методами атомносиловой и сканирующей электронной микроскопии. Методом газопроницаемости определен размер пор мембран. Эмульсии хлороформ–вода и н-гексадекан–вода использовали в качестве тестовой жидкости для разделения эмульсий типа «вода в масле». При вакууме 700 мбар удельные показатели фильтрации эмульсий хлороформ : вода составляли 51,5 и 932,0 л/(м2⋅ч), гексадекан : вода – 46,1 и 203,4 л/(м2⋅ч) для ПЭТФ-200/ОТС и ПЭТФ-350/ОТС соответственно. Степень очистки эмульсий модифицированными мембранами по показателю преломления составила 100 %. Полученные трековые мембраны могут применяться для разделения водонефтяных эмульсий с целью предотвращения коррозии трубопроводов и изменения вязкости нефти, а также при очистке воды от отходов нефтяной промышленности

Retrospective Analysis of the Safety of Antibacterial Medicinal Products for Elderly Patients with Community-Acquired Lower Respiratory Tract Infections

Cephalosporins are the empirical antibiotic therapy (ABT) of choice for patients with community-acquired pneumonia (CAP). When treated with antibiotics, elderly patients, especially those with comorbidities, are at higher risk of developing adverse drug reactions (ADRs).The aim of the study was to analyse data on the safety and efficacy of initial empirical ABT with cephalosporins in elderly patients over 75 years old with CAP admitted to multidisciplinary hospitals in Moscow.Materials and methods. The retrospective study included 305 medical records of patients with CAP admitted to three multidisciplinary hospitals in Moscow in 2017–2019 and prescribed initial mono- and/or combination ABT including a cephalosporin. Initial ABT was considered effective if the body temperature normalised within 48–72 h from the start of treatment. It was considered safe if there were no ADRs during hospital stay.Results. Mostly, patients were prescribed ceftriaxone monotherapy or ceftriaxone and azithromycin combination therapy. These ABT regimens were effective in 69.07% and 78.10% of the cases, respectively. Patients with severe CAP needed their initial ABT adjusted significantly more often than those with non-severe CAP. The initial ABT was changed for a number of reasons, including ineffectiveness, ADRs, abscesses formed as a complication of CAP, sputum culture results enabling causal ABT, secondary hospital-acquired infections, and exacerbated chronic infections. All patients had comorbidities, and the most prevalent were arterial hypertension (83.9%), coronary heart disease (45.6%), chronic heart failure (44.9%), cerebrovascular disease (40.9%), atrial fibrillation (26.9%), diabetes mellitus (21.3%), and chronic obstructive pulmonary disease (19.0%). Initial ABT was significantly more often considered ineffective in patients with chronic heart failure and cerebrovascular disease. The most common causative agent of CAP in the study population was Streptococcus pneumoniae (31.9%). In 16% of patients, the authors identified ADRs associated with the antibiotics used as initial therapy. The most common were diarrhoea, anaemia, leucopenia, and hepatopathy. Ceftriaxone was associated with ADRs in 11% of patients.Conclusions. The study results suggest that initial mono- and/or combination ABT including a cephalosporin is effective and relatively safe; therefore, this treatment option is expedient for elderly patients with CAP. For this population, the safety of ABT may be improved through the wider use of existing markers of ADRs and the identification of new ones

β-лактамные антибиотики – межлекарственное взаимодействие на уровне транспортеров органических анионов ОАТ1 и ОАТ3

Organic anion transporters OAT1 and OAT3 play a key role in elimination of most β-lactam antibiotics. Since nonsteroidal anti-inflammatory drugs, antivirals, antitumor agents, and some other drugs are also substrates of OAT1/3, this enables drug-drug interaction (DDI). The aim of the study was to analyze scientific literature to determine the likelihood and significance of β-lactam antibiotic DDI mediated by organic anion transporters, as well as potential for predicting it. In clinical practice, inhibition of β-lactam antibiotic elimination is used to increase systemic exposition and reduce the cost of antibiotic therapy. OAT inhibitors (cilastatin, betamipron) are used in combination drugs to reduce nephrotoxicity of carbapenems. On the other hand, an increase in the concentration of β-lactams due to OAT inhibition may lead to adverse drug reactions. Therefore, the European Medicines Agency and the Food and Drug Administration recommendations for the development of new drugs state that in the case of significant renal excretion (≥25%) it is necessary to investigate OAT1/3 transport in vitro and calculate inhibition constant Ki and/or half maximal inhibitory concentration IC50 for predicting DDI. One of the main problems is the variability of Ki and IC50 values between laboratories, which requires the development of general recommendations for different transporters as regards methods of determination of these parameters.Транспортеры органических анионов (ОАТ1/3) играют ключевую роль в выведении большинства β-лактамных антибиотиков из организма. Поскольку субстратами ОАТ1/3 являются также нестероидные противовоспалительные средства, противовирусные, противоопухолевые и другие препараты, это создает условия для межлекарственного взаимодействия (МЛВ). Цель работы — определить на основании данных научной литературы вероятность и значимость, а также возможность прогнозирования МЛВ β-лактамных антибиотиков на уровне транспортеров органических анионов. Показано, что в клинической практике ингибирование выведения β-лактамных антибиотиков используют для повышения их системной экспозиции и снижения стоимости антибиотикотерапии. Ингибиторы ОАТ циластатин и бетамипрон используются в комбинированных препаратах для снижения нефротоксичности карбапенемов. С другой стороны, отмечено, что повышение концентрации β-лактамных антибиотиков вследствие ингибирования ОАТ может привести к появлению нежелательных реакций. В связи с этим Европейское агентство по лекарственным средствам и Управление по контролю за качеством продуктов питания и лекарственных средств рекомендуют при разработке новых лекарственных средств в случае значимого почечного выведения (≥25%) проводить исследования их транспорта ОАТ1/3 in vitro с вычислением константы ингибирования Ki и/или концентрации полумаксимального ингибирования IC50 для прогнозирования МЛВ. Выявлено, что одной из основных проблем при этом является вариабельность значений Ki и IC50 между лабораториями и необходима разработка единых общих рекомендаций по методикам определения данных показателей для различных транспортеров

Topical Issues of Drug Safety, Possibilities of Improving of Pharmacovigilance

Since 2010, Russia has been developing new drug legislation, internal quality control and safety of medical organizations, and has developed algorithms for submitting Individual Case Safety Reports (ICSR) using an automated information system. On April 1, 2019, Russia launched an updated national database of ICSR, which uses the international ICH E2B data standard, which may increase the amount of reporting to the Uppsala monitoring center. This publication covers the key aspects of pharmacovigilance system development in the Russian Federation. The analysis of pharmacovigilance structure in the Russian Federation is carried  out, its main problems are designated. Presents methods to identify causal relationships between adverse reaction and drug, evaluation of its degree of validity (questionnaires, algorithms, and scale), as already recommended by the WHO, and the new modifi ed versions. The expediency of using a scale for determining the degree of reliability of a causal relationship «an undesirable reaction — drug interaction» when analyzing spontaneous reports of undesirable reactions that may be caused by drug interactions is noted. An effective method of detection and prevention of adverse reactions is presented — the Global Trigger Tool (GTT). The question of the need for motivation and training of medical personnel in the correct design of spontaneous messages, as well as methods of identifying the causal relationship between adverse reactions of drugs. The directions of optimization of pharmacovigilance system are proposed, including methods of more effective active surveillance in the identifi cation and prevention of adverse reactions