Spontaneous and induced secretion of the pro-inflammatory and anti-inflammatory cytokines in patients with type 2 diabetes mellitus and diabetic foot syndrome

AIMS: Investigation of spontaneous and induced secretion of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-inflammatory chemokine C-C Motif Chemokine Ligand 18 (CCL18) by monocytes isolated from blood of patients with long-term type 2 diabetes mellitus (T2DM), both with or without foot ulcers and the effect of the course use of the combined metabolic drug Kokarnit as part of complex therapy on the dynamics of the severity of symptoms of DSPN and the cytokine phenotype in patients with long-term non-healing ulcers of the lower extremities MATERIALS AND METHODS: 121 patients with T2DM, 79 without diabetic foot syndrome (DFS) and 42 patients with DFS were included. CD14+ monocytes were isolated from patients’ blood and stimulated by interferon-γ (IFN-γ) and interleukine-4 (IL-4) for induction of pro- and anti-inflammatory monocyte activation, respectively. The concentrations of TNF-α and CCL18 in the culture medium were measured using ELISA on day 1 and day 6 after cell stimulation in all patients before taking the combined metabolic drug Kokarnit. Then they were randomly allocated either to the control group (57 people), to whom Kokarnit was added to standard treatment, or to the comparison group. After a 9-day course of application of Kokarnit, the dynamics of indicators was evaluated on a TSS scale. Assessment of cytokine status was carried out in 18 people with long-term non-healing ulcerative defects of the lower extremities, on the first and ninth day of treatment. RESULTS: A correlation was found between HbA1c and levels of stimulated secretion of TNFα (r=0.726, p=0.027), CCL18 (r=-0.949, p=0.051) in patients with DSPN. In all patients with different duration of VDS, an increase in secretion of TNF-α and CCL18 was observed (p<0.05). However, stimulation of anti-inflammatory activation was not observed in patients with ulcerative defects lasting more than 6 months (p=0.033). The use of cocarnit in these patients had a decrease in stimulated secretion of TNFα and an increase in CCL18. Throughout the entire observation period with the therapy, the score for the symptoms of polyneuropathy on the TSS scale in patients of the control group was statistically significantly higher. CONCLUSION: Against the background of therapy in patients of the main group, a statistically significant dynamics of indicators on the TSS scale was established. The cytokine modulating ability of Kokarnit to switch the cytokine status into the category of anti-inflammatory

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

Integral assessment of congestion in patients with acute decompensated heart failure

Aim. To assess the prognostic value of the integral assessment using various modern methods for diagnosing congestion in patients hospitalized with acute decompensated heart failure (ADHF).Material and methods. This single-center prospective study included 165 patients with ADHF. All patients underwent a standard clinical and paraclinical examination, including assessing NT-proBNP levels, lung ultrasound B-lines, liver transient elastography, bioelectrical impedance vector analysis (BIVA) at admission and discharge. To assess clinical congestion, the Heart Failure Association consensus document scale was used. Long-term clinical outcomes were assessed by telephone survey 1, 3, 6, 12 months after discharge. As an end point, the allcause mortality and readmissions were estimated.Results. In patients hospitalized with ADHF, at discharge, differences were found in the incidence of residual congestion according to certain paraclinical methods — from 22 to 38%, subclinical — from 14,5 to 27%. When using the integral assessment of stagnation, the incidence of residual and subclinical congestion was 53,6% and 35%, respectively. Patients with residual congestion had more severe symptoms of congestion, compared with those with subclinical congestion. Patients in whom congestion was detected by 4 methods, in contrast to those by 1, 2, and 3 methods, had worse clinical and paraclinical parameters. There was a significant increase in the risk of all-cause mortality and readmission in the presence of congestion, identified by 3 (hazard ratio, 9,4 (2,2-40,6); p<0,001) and 4 methods (hazard ratio, 15,2 (3,3-68,1); p<0,001).Conclusion. For patients hospitalized with ADHF, integral assessment of residual and subclinical congestion at should be performed at discharge. The introduction of an integral assessment of congestion into routine practice will allow to identify a group of patients with more unfavorable prognostic characteristics in relation to the risk of death and readmissions, as well as to intensify drug therapy and followup at the outpatient stage

Substantiation of approaches to the correction of lipid metabolism disorders and non-alcoholic fatty liver disease in children with exogenous obesity

BACKGROUND: According to the involvement of oxidative stress in the pathogenesis of obesity, the plasma level of coenzyme q10 in the correlation relationship with lipid metabolism disorders and functional liver state is of interest to study.AIM: Substantiation of approaches to the correction of lipid metabolism disorders and non-alcoholic fatty liver disease in children with exogenous obesity based on the content of coenzyme Q10 and its relationship with lipid profile and liver enzymes.MATERIALS AND METHODS: The single-center cross-sectional study enlisted the control (n=32, -1.0≤BMI SD score ≤+2.0) and obese (n=40, BMI SD score>+2.0) groups of children with the mean age of 12 yr. In all children BMI, lipidogram, liver enzymes (ALT and AST), plasma coenzyme Q10 and liver ultrasound examination were assessed.RESULTS: Patients of both groups were comparable (p> 0.05) in age and gender. The level of coenzyme Q10 in the compared groups was comparable (p> 0.05) and did not differ in patients with different degrees of obesity. According to the results of the study of the lipid profile in the obese children, the level of HDL was lower, and the level of LDL was higher than that in control group. The highest value of HDL was obtained in the patients with the 1st degree of obesity and the highest level of triglycerides — in the patients with the 4th degree of obesity. The control group demonstrated moderate correlations between endogenous coenzyme Q10 and total cholesterol (r=0.474, p=0.009) which persists in patients with the first degree of obesity (r = 0.548, p = 0.035). There was no difference in AST in the study groups, however, the main group demonstrated elevated ALT and ALT/AST ratio (p <0.001). The highest ALT and ALT / AST ratio were observed in patients with greatest degree of obesity. Eighteen obese children (45%) had ALT / AST ratio ≥1 (in the control group –one patient (3%) (p <0.001), while fourteen patients showed liver enlargement and structure change according to ultrasound (80%). The control group demonstrated moderate correlations between endogenous coenzyme Q10 and total cholesterol (r=0.474, p=0.009) and between coenzyme Q10 and ALT / AST ratio (r=0.412, p=0.023) . In the obese group there was correlation between AI and ALT / AST (r = 0.436, p = 0.006) and in patients with the 1st degree of obesity — between also coenzyme Q10 and ALT (r = 0.875, p <0.001).CONCLUSION: The disturbances in adequate control of cholesterol by coenzyme Q10 in obese children possibly confirming the involvement of oxidative stress in the pathogenesis of dyslipidemia and non-alcoholic fatty liver disease can serve as indication to use coenzyme Q10 in order to correct these complications

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

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

Особенности развития токсической нефропатии при проведении антибиотикотерапии

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.Антибактериальные препараты могут оказывать нефротоксическое действие, поскольку препараты этой группы преимущественно элиминируются почками. Цель работы — анализ данных литературы о механизмах, факторах риска и особенностях развития токсической нефропатии при проведении антибиотикотерапии. Рассмотрены механизмы развития острого интерстициального нефрита, острого некроза канальцев, отложения кристаллов внутри канальцев, проксимальной или дистальной тубулопатии с аномалиями расходования электролитов на фоне применения антибиотиков. Показано, что нефротоксичность наиболее часто ассоциирована с применением аминогликозидных, бета-лактамных антибактериальных средств, ванкомицина. Проанализирована зависимость нефротоксичности от липофильности антибактериальных препаратов и межлекарственного взаимодействия. Определено, что основными факторами риска развития нефропатии являются пожилой возраст, мужской пол, негроидная раса, гиповолемия, артериальная гипотензия, прием ингибиторов ангиотензинпревращающего фермента, блокаторов рецепторов ангиотензина II, нестероидных противовоспалительных препаратов или их комбинации, индивидуальные генетические особенности. Отмечена связь нефротоксичности и генетических особенностей систем метаболизма и выведения антибактериальных средств: изоферментов цитохрома P450, Р-гликопротеина, белков семейства множественной лекарственной резистентности MRP (multidrug resistance-associated protein) и MATE (multidrug and toxin extrusion protein), белка резистентности рака молочной железы BCRP (breast cancer resistance protein). Тяжелая генерализованная инфекция изменяет фармакокинетические параметры антибактериальных лекарственных средств, что следует учитывать при назначении гидрофильных антибиотиков, которые выводятся путем канальцевой секреции и реабсорбируются в почечных канальцах. Показано, что коррекция дозирования антибактериальных лекарственных препаратов на основе результатов терапевтического лекарственного мониторинга в совокупности с контролем функции почек является эффективным методом повышения безопасности антибиотикотерапии

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