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

Comparative Dissolution Kinetics of Several Multisource Thioctic Acid Products

The relationship between dissolution and bioavailability is an example of the interdependency between the quality of a medicinal product and its safety and efficacy. The uniqueness of thioctic acid is that it can exist in an oxidised and a reduced form, showing lipophilic (lipoic acid) and hydrophilic (dihydrolipoic acid) properties. Bioavailability studies of thioctic acid are necessary to evaluate the expected therapeutic effect and mitigate side effects of the medicinal product.The aim of the study was to carry out equivalence dissolution testing to compare the release of thioctic acid from medicinal products produced by several manufacturers.Materials and methods: the study used a reference medicinal product and three multisource medicinal products by different manufacturers; more specifically, film-coated tablets containing 600 mg of thioctic acid. The experiment was carried out in dissolution media at pH of 6.8±0.05 and 1.2±0.05. Statistical analysis was performed by calculating the average amounts of the substance dissolved, the standard deviation (SD), and the relative standard deviation (RSD, %) using Microsoft Office Excel 2007.Results: The authors chose the testing conditions (dissolution media pH values of 6.8±0.05 and 1.2±0.05) taking into account the nature and characteristics of thioctic acid. The comparison of thioctic acid release profiles based on the calculation of the similarity factor (f2) showed that the dissolution profiles of multisource medicinal products 2 and 3 at pH 6.8 were equivalent to that of the reference medicinal product (more than 85% of the active pharmaceutical ingredient released within 15 minutes) and the dissolution profile of multisource medicinal product 1 was not equivalent to it (with f2 of 28).Conclusions: the established differences in the rate and degree of active ingredient release from the studied medicinal products may indicate possible differences in their pharmacological effectiveness in vivo

Терапевтический лекарственный мониторинг, гено- и фенотипирование CYP2C9 при применении препаратов глибенкламида у больных сахарным диабетом

Rational use of glybenclamide products in the treatment of patients with type 2 diabetes remains a high-priority task. The paper offers a summary of the main groups of glibenclamide drugs and describes pharmacogenetics of glybenclamide. Glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9). Individuals with genetically determined low CYP2C9 activity are at an increased risk of hypoglycaemia. Carriers of CYP2C9*3 and CYP2C9*2 alleles tend to have higher concentrations of glybenclamide in blood and increased insulin secretion. Pharmacogenetic testing of patients and drug concentration monitoring using HPLC-MS can help reduce the risk of hypoglycemia during glibenclamide treatment. Based on literature review the authors selected the method characterised by a simple sample preparation procedure, short analysis time, and a wide analytical range for the substances being determined. This method can be useful both for bioequivalence studies and evaluation of glibenclamide products interchangeability. Glibenclamide pharmacokinetics is characterised by high interindividual variability. This may lead to both an increased risk of hypoglycemia and drug inefficacy, therefore, when prescribing glibenclamide, a physician should carefully control the efficacy and safety of drug therapy.Вопросы рационального применения препаратов глибенкламида при лечении больных сахарным диабетом 2 типа продолжают оставаться актуальными. В статье представлена обобщенная характеристика основных групп препаратов глибенкламида, рассмотрены особенности его фармакогенетики. Глибенкламид метаболизируется ферментом цитохрома P450 2C9 (CYP2C9), лица с генетически обусловленной низкой активностью CYP2C9 подвержены повышенному риску гипогликемии. Носители аллелей CYP2C9*3 и CYP2C9*2 склонны к более высокой концентрации глибенкламида в крови и повышенной секреции инсулина. Для снижения риска гипогликемии при терапии глибен-кламидом могут быть использованы фармакогенетическое тестирование и мониторинг концентрации лекарственных препаратов у пациентов с помощью ВЭЖХ-МС. На основании анализа данных литературы выбрана методика, которая отличается простотой пробоподготовки, коротким временем анализа и широким аналитическим диапазоном для определяемых веществ. Данная методика может быть полезной как для изучения биоэквивалентности, так и для оценки взаимозаменяемости препаратов глибенкламида. Фармакокинетика глибенкламида характеризуется высокой межиндивидуальной вариабельностью. Это является фактором как повышенного риска гипогликемии, так и неэффективности препарата, поэтому при назначении глибенкламида врач должен внимательно следить за эффективностью и безопасностью терапии

Features of Toxic Nephropathy Development during Antibiotic Therapy

Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys. The aim of the study was to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug-drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy

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

Evaluation of the Efficacy and Safety of Initial Empirical Antibiotic Therapy for Community-Acquired Pneumonia in Middle-Aged People

β-lactam antibiotics, including cephalosporins, are the drugs of choice for empirical antibiotic therapy (ABT) in patients with community-acquired pneumonia. Unreasonable and irrational use of antibiotics leads to an increased risk of adverse reactions, contributes to the growth of antibiotic resistance.The aim of the study was to analyse data on the efficacy and safety of initial empirical ABT using cephalosporins for community-acquired pneumonia in middle-aged patients of multidisciplinary hospitals in Moscow.Materials and methods: the authors analysed 177 archived medical records of the patients admitted to three multidisciplinary hospitals (I.V. Davydovsky City Clinical Hospital, City Clinical Hospital 52 and City Clinical Hospital 4) in Moscow from 2017 to 2019 and prescribed mono- and/or combination therapy including a cephalosporin antibiotic as a starting therapy for community-acquired pneumonia. The initial ABT was considered effective if a patient’s body temperature normalised within 48–72 h following initiation of treatment and safe if no adverse reactions developed during the period of inpatient treatment.Results: the combination of ceftriaxone and azithromycin was the most frequently prescribed ABT regimen; its effectiveness was 71.9%. Ceftriaxone monotherapy was the second in frequency of prescription; its effectiveness amounted to 77.2%. The third regimen included cefotaxime and azithromycin and was effective in 70% of cases. The patients who needed a change in initial ABT had a significantly higher incidence of developing severe community-acquired pneumonia and complications. The study results indicate that the structure of comorbidity did not affect the effectiveness of initial empirical ABT. Streptococcus pneumoniae was found to be the most common causative agent of community-acquired pneumonia in the studied population (44.8% of cases). Only 13% of the patients faced adverse reactions associated with the use of antibiotics as part of the initial empirical ABT; the most common were leukopenia and diarrhoea.Сonclusions: the results of the study indicate the feasibility of mono- and/or combination ABT including a cephalosporin antibiotic as a starting empirical therapy for community-acquired pneumonia due to its effectiveness and favourable safety profile

Новые антиконвульсанты: проблемы взаимозаменяемости и применения воспроизведенных лекарственных препаратов в клинической практике

This article looks into interchangeability and therapeutic equivalence of innovator and generic anticonvulsants — the first-generation and new antiepileptic drugs (AEDs). The results of a number of clinical trials assessing therapeutic equivalence of generic AEDs support the opinion that these medicines could only be substituted provided an ultra-cautious approach is used, even if the case involves only one International Nonproprietary Name, including, but not limited to different dosage forms of one and the same product. The aim of the study was to analyse factors leading to incorrect assessment of therapeutic equivalence of new and generic anticonvulsant drugs, and to improve methodological approaches to conducting clinical trials of these products. The paper cites data from Russian and foreign sources which state that the substitution of AEDs in some patients in full remission may result in adverse reactions or relapse of seizures. The analysis of the experience of scientific, expert, and regulatory institutions made it possible to develop a course of actions to be used when substituting AEDs and conducting clinical trials that assess therapeutic equivalence of new and generic anticonvulsants. The proposed methodology will help minimise potential health risks brought about by various factors that result in incorrect assessment of AEDs therapeutic equivalence and interchangeability.Статья посвящена проблеме взаимозаменяемости и терапевтической эквивалентности оригинальных и воспроизведенных антиконвульсантов — противоэпилептических препаратов (ПЭП) первого поколения и новых. В ряде клинических исследований по изучению терапевтической эквивалентности воспроизведенных ПЭП подтверждается вывод о необходимости крайне осторожного подхода к осуществлению их замены даже в рамках одного международного непатентованного наименования, в том числе между разными лекарственными формами одного препарата. Цель работы — анализ факторов, приводящих к неправильной оценке терапевтической эквивалентности новых и воспроизведенных противосудорожных препаратов и совершенствование методологических подходов к проведению клинических исследований этих препаратов. Представлены данные из отечественных и зарубежных источников, в которых отмечается, что замена ПЭП у отдельных пациентов с полной ремиссией может привести к развитию нежелательных реакций или возобновлению судорожных припадков. На основании изученного опыта работы научных, экспертных и регуляторных организаций авторы предлагают комплекс мероприятий при замене ПЭП и проведении клинических исследований терапевтической эквивалентности новых и воспроизведенных противосудорожных препаратов. Применение предложенной методологии будет способствовать минимизации потенциальных рисков для здоровья пациентов, обусловленных различными факторами, приводящими к неправильной оценке терапевтической эквивалентности ПЭП и их взаимозаменяемости

Сравнительная кинетика растворения тиоктовой кислоты для ряда воспроизведенных препаратов

The relationship between dissolution and bioavailability is an example of the interdependency between the quality of a medicinal product and its safety and efficacy. The uniqueness of thioctic acid is that it can exist in an oxidised and a reduced form, showing lipophilic (lipoic acid) and hydrophilic (dihydrolipoic acid) properties. Bioavailability studies of thioctic acid are necessary to evaluate the expected therapeutic effect and mitigate side effects of the medicinal product.The aim of the study was to carry out equivalence dissolution testing to compare the release of thioctic acid from medicinal products produced by several manufacturers.Materials and methods: the study used a reference medicinal product and three multisource medicinal products by different manufacturers; more specifically, film-coated tablets containing 600 mg of thioctic acid. The experiment was carried out in dissolution media at pH of 6.8±0.05 and 1.2±0.05. Statistical analysis was performed by calculating the average amounts of the substance dissolved, the standard deviation (SD), and the relative standard deviation (RSD, %) using Microsoft Office Excel 2007.Results: The authors chose the testing conditions (dissolution media pH values of 6.8±0.05 and 1.2±0.05) taking into account the nature and characteristics of thioctic acid. The comparison of thioctic acid release profiles based on the calculation of the similarity factor (f2) showed that the dissolution profiles of multisource medicinal products 2 and 3 at pH 6.8 were equivalent to that of the reference medicinal product (more than 85% of the active pharmaceutical ingredient released within 15 minutes) and the dissolution profile of multisource medicinal product 1 was not equivalent to it (with f2 of 28).Conclusions: the established differences in the rate and degree of active ingredient release from the studied medicinal products may indicate possible differences in their pharmacological effectiveness in vivo.Взаимосвязь между растворением и биодоступностью является одним из примеров взаимосвязи между качеством лекарственного препарата, его безопасностью и эффективностью. Уникальность тиоктовой кислоты в том, что она может существовать как в окисленной, так и в восстановленной форме, проявляя как липофильные (липоевая кислота), так и гидрофильные (дигидролипоевая кислота) свойства. Изучение биодоступности данного лекарственного средства необходимо для оценки ожидаемого терапевтического эффекта и уменьшения побочного действия препарата на организм.Цель работы: изучение процесса высвобождения тиоктовой кислоты из препаратов разных производителей с помощью теста сравнительной кинетики растворения.Материалы и методы: объектами исследования являлись референтный (РП) и три воспроизведенных препарата (ВЛС1, ВЛС2 и ВЛС3) различных производителей – таблетки, покрытые пленочной оболочкой, содержащие тиоктовую кислоту в дозе 600 мг. Эксперимент проводили в средах растворения c рН 6,8±0,05 и рН 1,2±0,05. Статистическую обработку проводили с помощью пакета Microsoft Office Excel 2007 путем расчета среднего значения количества растворившейся субстанции, стандартного отклонения (SD) и относительного стандартного отклонения (RSD, %).Результаты: на основании особенностей и характеристик тиоктовой кислоты выбраны условия проведения испытания (рН среды растворения 6,8±0,05 и 1,2±0,05). При сравнении профилей высвобождения  тиоктовой кислоты на основании расчета фактора сходимости (f2) был отмечен эквивалентный профиль растворения препаратов ВЛС2 и ВЛС3 при рН 6,8 (высвобождение субстанции более 85% через 15 мин) и неэквивалентный профиль растворения препарата ВЛС1 (f2 составил 28).Выводы: установленные различия в скорости и степени высвобождения действующего вещества из изучаемых препаратов могут свидетельствовать о возможных различиях  их фармакологической эффективности в условиях in vivo

FORMATION OF NANOCRYSTALLINE COMPOSITIONS TiC–Co AND TiN–Co IN THE PRESENCE OF MOLYBDENUM AND ITS REFRACTORY COMPOUNDS DURING PLASMA RECONDENSATION

Методом плазменной переконденсации в низкотемпературной азотной плазме были переработаны механические смеси микрокристаллических порошков TiC–Co и TiN–Co. В ходе рентгенографических и электронно-микроскопических исследований, в том числе с использованием методик EDX-анализа, было установлено, что нанокристаллические композиции имеют радиально-слоевую структуру, состоящую из тугоплавкого ядра и металлической оболочки, содержащей кобальт, молибден или их взаимные твердые растворы.Mechanical mixtures of microcrystalline TiC–Co and TiN–Co powders were processed by plasma recondensation in a low-temperature nitrogen plasma. It was found that during radiographic and electron microscopic studies, including using EDX analysis techniques, nanocrystalline compositions have a radial layer structure consisting of a refractory core and a metallic shell containing cobalt, molybdenum or their mutual solid solutions.Авторы выражают благодарность канд. техн. наук Э. К. Добринскому (ФГУП ГНИИХТЭОС) за помощь в проведении экспериментов по плазменной переконденсации механической смеси TiN–Co и TiC–Co

Meteorological conditions during the ACLOUD/PASCAL field campaign near Svalbard in early summer 2017

The two concerted field campaigns, Arctic CLoud Observations Using airborne measurements during polar Day (ACLOUD) and the Physical feedbacks of Arctic planetary boundary level Sea ice, Cloud and AerosoL (PASCAL), took place near Svalbard from 23 May to 26 June 2017. They were focused on studying Arctic mixed-phase clouds and involved observations from two airplanes (ACLOUD), an icebreaker (PASCAL) and a tethered balloon, as well as ground-based stations. Here, we present the synoptic development during the 35-day period of the campaigns, using near-surface and upper-air meteorological observations, as well as operational satellite, analysis, and reanalysis data. Over the campaign period, short-term synoptic variability was substantial, dominating over the seasonal cycle. During the first campaign week, cold and dry Arctic air from the north persisted, with a distinct but seasonally unusual cold air outbreak. Cloudy conditions with mostly low-level clouds prevailed. The subsequent 2 weeks were characterized by warm and moist maritime air from the south and east, which included two events of warm air advection. These synoptical disturbances caused lower cloud cover fractions and higher-reaching cloud systems. In the final 2 weeks, adiabatically warmed air from the west dominated, with cloud properties strongly varying within the range of the two other periods. Results presented here provide synoptic information needed to analyze and interpret data of upcoming studies from ACLOUD/PASCAL, while also offering unprecedented measurements in a sparsely observed region.</p