Browsing by Author "Bajcetic, Milica (15727461400)"

Background: Angiotensin-converting enzyme inhibitors, such as enalapril, are foundational in treating pediatric heart failure. However, they are often administered off-label to young children using extemporaneous formulations. This study, conducted as part of the EU-funded Labeling of Enalapril from Neonates up to Adolescents (LENA) project, aimed to evaluate the acceptability and palatability of an age-appropriate enalapril orodispersible minitablet (ODMT). These factors are critical for ensuring adherence, efficacy, and safety in pediatric patients. Methods: An 8-week trial was conducted in children with heart failure caused by dilated cardiomyopathy or congenital heart disease. Enalapril ODMTs (0.25 mg or 1.0 mg) were dose-titrated and administered to 38 children aged 0–6 months and 22 children aged 6 months to 6 years. This study aimed to assess its acceptability and palatability, key factors contributing to adherence, and therefore, efficacy and safety. Results: Across all 169 assessments in 38 children aged 0–6 months and 22 aged 6 months to 6 years, complete or partial swallowability was observed, and the acceptability rate was 100%. There were no cases of choking, inhalation/coughing, or spitting out. A favorable or neutral rating was observed in 96% of palatability assessments based on observations of facial expressions. Acceptability and palatability were higher in subjects aged 6 months–6 years than 0–6 months, with no significant influence from repeated administration. Conclusions: Enalapril ODMTs are widely accepted and well-tolerated among young children, including neonates, with heart failure. These findings suggest that ODMTs are a suitable and effective method for administering pediatric medicinal products. © 2025 by the authors.

Objectives: The presence of cardiovascular risk factors in children may be important in the development of atherosclerosis in adulthood. Adequate control of blood pressure is a cornerstone in atherosclerosis prevention. The aim of the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD) was to identify risk factors for elevated blood pressure in school children. Methods: The YUSAD study is a multicentre follow-up study comprised of two cross-sectional surveys conducted five years apart. At baseline, 10-year-old children (3226 boys and 3074 girls [n=6300]) were randomly selected during periodical visits to primary health care centres. The risk factors measured were heart rate, weight, body mass index (BMI), waist-to-hip ratio, grade point average and current smoking status. Results: Significant age and sex differences were identified in systolic blood pressure, diastolic blood pressure and all investigated independent variables. In a multivariate analysis, diastolic blood pressure in 10-year-old boys was directly and significantly related to total cholesterol and height, whereas it was inversely related to weight. At follow-up, in the multivariate model, only BMI was a significant predictor of diastolic blood pressure in boys. In girls at baseline in the multivariate regression analysis, the only significant predictor of diastolic blood pressure was total cholesterol. In 15-year-old girls, diastolic blood pressure was significantly and directly related to BMI and heart rate, whereas it was inversely related to weight. For both 10- and 15-year-old male and female participants, none of the variables by multivariate analysis were a significant predictor of systolic blood pressure. Conclusions: Age, sex, heart rate, cholesterol and weight are the most important predictors of blood pressure in school children. © 2006 Pulsus Group Inc. All rights reserved.

Objectives: The presence of cardiovascular risk factors in children may be important in the development of atherosclerosis in adulthood. Adequate control of blood pressure is a cornerstone in atherosclerosis prevention. The aim of the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD) was to identify risk factors for elevated blood pressure in school children. Methods: The YUSAD study is a multicentre follow-up study comprised of two cross-sectional surveys conducted five years apart. At baseline, 10-year-old children (3226 boys and 3074 girls [n=6300]) were randomly selected during periodical visits to primary health care centres. The risk factors measured were heart rate, weight, body mass index (BMI), waist-to-hip ratio, grade point average and current smoking status. Results: Significant age and sex differences were identified in systolic blood pressure, diastolic blood pressure and all investigated independent variables. In a multivariate analysis, diastolic blood pressure in 10-year-old boys was directly and significantly related to total cholesterol and height, whereas it was inversely related to weight. At follow-up, in the multivariate model, only BMI was a significant predictor of diastolic blood pressure in boys. In girls at baseline in the multivariate regression analysis, the only significant predictor of diastolic blood pressure was total cholesterol. In 15-year-old girls, diastolic blood pressure was significantly and directly related to BMI and heart rate, whereas it was inversely related to weight. For both 10- and 15-year-old male and female participants, none of the variables by multivariate analysis were a significant predictor of systolic blood pressure. Conclusions: Age, sex, heart rate, cholesterol and weight are the most important predictors of blood pressure in school children. © 2006 Pulsus Group Inc. All rights reserved.

Background: The angiotensin-converting enzyme inhibitor (ACEI) enalapril is often administered to infants and young children with heart failure (HF) in various dosing regimens and formulations not adapted for their age. Methods: This prospective, two-center, open-label 8-week study evaluated an age-appropriate formulation of orodispersible minitablets (ODMTs) of enalapril (0.25 mg and 1 mg) in children aged 0 to 6 years with HF due to congenital heart disease. An age/weight-based dosing schedule was followed. Measures of echocardiographic parameters, blood pressure, heart rate, modified Ross score, and biochemistry were obtained over the 8-week period. The following two groups were assessed: ACEI-naïve and ACEI-pretreated patients. Results: In total, 53 children (age range of 0.05 to 4.8 years) were enrolled and 29 were ACEI-naïve. The average enalapril dose was 0.098 mg/kg (0.06–0.17 mg/kg) in the naïve group and 0.15 mg/kg (0.07–0.3 mg/kg) in pretreated patients. After 8 weeks, the modified Ross score and left ventricular diastolic dimension (LVD) z-score showed a significant decrease in both groups (p < 0.005). During 8 weeks follow-up, there were no difference in the z-scores for the systolic blood pressure (p = 0.071) or heart rate (p = 0.146). Conclusions: Pediatric patients treated with ODMTs of enalapril for 8 weeks had favorable improvements in LVD and HF symptoms. © 2024 by the authors.

Objectives: This study was conducted to determine the effects of carvedilol adjunct to standard treatment on left ventricular function (LVF), estimated as ejection fraction (EF) and fractional shortening (FS) on echocardiography, in children with idiopathic dilated cardiomyopathy (DCM). A secondary end point was to characterize the antioxidant potential of carvedilol. Methods: Hospitalized children aged ≤16 years with clinically stable DCM and advanced congestive heart failure (HF) with modified New York Heart Association Classification for Children (NYHAC) functional classes II to IV and EF <40% were enrolled in this prospective, 12-month, 2-center, open-label study. Oral carvedilol was added to a standard regimen of an angiotensin-converting enzyme inhibitor, a diuretic, and digoxin in a dose-escalation design. Systolic and diastolic blood pressure (BP), heart rate (HR), and modified NYHAC were assessed before (baseline) and at 1, 3, 6, and 12 months of adjunct carvedilol treatment. EF and FS were analyzed before and at 6 and 12 months of carvedilol treatment. At each study visit, tolerability was assessed in terms of adverse events (AEs), treatment emergent signs and symptoms, physical examination including vital sign measurement (BP, HR, and body temperature), and laboratory analysis. Antioxidative enzyme activity was evaluated by measuring erythrocyte copper/zinc superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activity at baseline and 1, 3, 6, and 12 months of adjunct carvedilol treatment. For assessment of antioxidative enzyme activity, a control group comprised 29 age-matched healthy children. Results: Twenty-one children (12 boys, 9 girls; age range, 7 months to 16 years; 100% white) completed the study. Four patients discontinued carvedilol at the beginning of the study due to severe arrhythmia which required amiodarone therapy (2 patients), bradycardia and hypotension (1), and bronchospasm (1). Carvedilol (0.4 mg/kg/d in children ≤62.5 kg or 25 mg/d in children >62.5 kg) was associated with significant decreases from baseline in systolic BP (130 [4] vs 123 [3] mm Hg; P < 0.05), diastolic BP (85 [4] vs 77 [4] mm Hg; P < 0.05), and HR (81 [4] vs 65 [4] bpm; P < 0.001) after the first month of addition to standard therapy. At 6 months, there were significant improvements from baseline in EF (37.2% [2.4%] vs 50.2% [2.3%]; P < 0.001) and FS (18.37% [2.00%] vs 23.58% [0.90%]; P < 0.001). Modified NYHAC class was significantly improved in 80% of children (2.9 vs 2.3; P < 0.001) at 12 months. The highest dose of carvedilol (0.8 mg/kg/d in children ≤62.5 kg or 50 mg/d in children >62.5 kg) was well tolerated in all 21 children. No serious AEs that necessitated study drug discontinuation (tiredness, headache, vomiting) were observed. At baseline, mean (SE) erythrocyte SOD activity (2781 [116] vs 2406 [102] U/g Hb; P < 0.05) and GR activity (5.3 [0.3] vs 3.0 [0.2] μmol nicotinamide adenine dinucleotide phosphate [NADPH]/min/g Hb; P < 0.001) were significantly higher in children with DCM who received standard therapy compared with healthy controls.CAT activity (12.7[0.9] vs 18.5 [1.0]U/g Hb; P < 0.001) was significantly lower, while GSH-Px was unchanged. At 6 and 12 months of therapy, carvedilol plus standard treatment was associated with significant decreases from baseline in SOD (2516 [126] and 2550 [118], respectively, vs 2781 [116] U/g Hb; both, P<0.001) and GR (4.7 [0.3] and 4.1 [0.2], respectively, vs 5.3 [0.2] μmol NADPH/min/g Hb; P < 0.05 and P < 0.001) and increased CAT (16.9 [1.0] and 16.4 [0.7], respectively, vs 12.7 [0.9] U/g Hb; both, P < 0.001). Conclusions: These pediatric patients with DCM treated for 12 months with carvedilol (up to 0.8 mg/kg/d in children ≤62.5 kg or 50 mg/d in children >62.5 kg) were found to have significant improvements in LVF and symptoms of HF. Twelve months of carvedilol therapy was associated with antioxidant enzyme activities near those observed in healthy children. © 2008 Excerpta Medica Inc.

Objectives: This study was conducted to determine the effects of carvedilol adjunct to standard treatment on left ventricular function (LVF), estimated as ejection fraction (EF) and fractional shortening (FS) on echocardiography, in children with idiopathic dilated cardiomyopathy (DCM). A secondary end point was to characterize the antioxidant potential of carvedilol. Methods: Hospitalized children aged ≤16 years with clinically stable DCM and advanced congestive heart failure (HF) with modified New York Heart Association Classification for Children (NYHAC) functional classes II to IV and EF <40% were enrolled in this prospective, 12-month, 2-center, open-label study. Oral carvedilol was added to a standard regimen of an angiotensin-converting enzyme inhibitor, a diuretic, and digoxin in a dose-escalation design. Systolic and diastolic blood pressure (BP), heart rate (HR), and modified NYHAC were assessed before (baseline) and at 1, 3, 6, and 12 months of adjunct carvedilol treatment. EF and FS were analyzed before and at 6 and 12 months of carvedilol treatment. At each study visit, tolerability was assessed in terms of adverse events (AEs), treatment emergent signs and symptoms, physical examination including vital sign measurement (BP, HR, and body temperature), and laboratory analysis. Antioxidative enzyme activity was evaluated by measuring erythrocyte copper/zinc superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activity at baseline and 1, 3, 6, and 12 months of adjunct carvedilol treatment. For assessment of antioxidative enzyme activity, a control group comprised 29 age-matched healthy children. Results: Twenty-one children (12 boys, 9 girls; age range, 7 months to 16 years; 100% white) completed the study. Four patients discontinued carvedilol at the beginning of the study due to severe arrhythmia which required amiodarone therapy (2 patients), bradycardia and hypotension (1), and bronchospasm (1). Carvedilol (0.4 mg/kg/d in children ≤62.5 kg or 25 mg/d in children >62.5 kg) was associated with significant decreases from baseline in systolic BP (130 [4] vs 123 [3] mm Hg; P < 0.05), diastolic BP (85 [4] vs 77 [4] mm Hg; P < 0.05), and HR (81 [4] vs 65 [4] bpm; P < 0.001) after the first month of addition to standard therapy. At 6 months, there were significant improvements from baseline in EF (37.2% [2.4%] vs 50.2% [2.3%]; P < 0.001) and FS (18.37% [2.00%] vs 23.58% [0.90%]; P < 0.001). Modified NYHAC class was significantly improved in 80% of children (2.9 vs 2.3; P < 0.001) at 12 months. The highest dose of carvedilol (0.8 mg/kg/d in children ≤62.5 kg or 50 mg/d in children >62.5 kg) was well tolerated in all 21 children. No serious AEs that necessitated study drug discontinuation (tiredness, headache, vomiting) were observed. At baseline, mean (SE) erythrocyte SOD activity (2781 [116] vs 2406 [102] U/g Hb; P < 0.05) and GR activity (5.3 [0.3] vs 3.0 [0.2] μmol nicotinamide adenine dinucleotide phosphate [NADPH]/min/g Hb; P < 0.001) were significantly higher in children with DCM who received standard therapy compared with healthy controls.CAT activity (12.7[0.9] vs 18.5 [1.0]U/g Hb; P < 0.001) was significantly lower, while GSH-Px was unchanged. At 6 and 12 months of therapy, carvedilol plus standard treatment was associated with significant decreases from baseline in SOD (2516 [126] and 2550 [118], respectively, vs 2781 [116] U/g Hb; both, P<0.001) and GR (4.7 [0.3] and 4.1 [0.2], respectively, vs 5.3 [0.2] μmol NADPH/min/g Hb; P < 0.05 and P < 0.001) and increased CAT (16.9 [1.0] and 16.4 [0.7], respectively, vs 12.7 [0.9] U/g Hb; both, P < 0.001). Conclusions: These pediatric patients with DCM treated for 12 months with carvedilol (up to 0.8 mg/kg/d in children ≤62.5 kg or 50 mg/d in children >62.5 kg) were found to have significant improvements in LVF and symptoms of HF. Twelve months of carvedilol therapy was associated with antioxidant enzyme activities near those observed in healthy children. © 2008 Excerpta Medica Inc.

Background/Aims: Reactive oxygen species play an important role in the pathogenesis of kidney ischemia/reperfusion injury (IRI) which may be influenced by immunosuppressive therapy. Pertinent to this, we investigated the effects of the mTOR inhibitor everolimus on redox settings and the activity of the anti-oxidative system in kidneys exposed to IRI. Methods: C57BL/6 mice were subjected to IRI by clamping both renal pedicles for 45 min. Everolimus was applied in daily, subcutaneous doses (0.25 mg/kg body weight), starting 1 day before IRI induction. Both everolimus-treated and non-treated mice were sacrificed at several time points, starting 30 min and finishing 7 days after IRI induction. Markers of oxidation such as glutathione and NADPH levels and anti-oxidative enzyme activities were determined in the kidneys. Results: In comparison to both sham and non-treated animals, the treatment with everolimus resulted in an increased level of markers of oxidation, including a lower level of glutathione, increased level of oxidized glutathione and reduced level of NADPH. The activity of superoxide dismutase was reduced in both experimental groups, but the effects were less pronounced in everolimus-treated animals. In the early phase of reperfusion, everolimus-treated animals showed higher activity of glutathione reductase in comparison to non-treated animals, whereas the activities of glutathione peroxidase and catalase were generally similar. The treatment with everolimus significantly reduced heme oxygenase-1 expression and increased iNOS mRNA expression when compared to non-treated animals. Conclusion: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress. Copyright © 2013 S. Karger AG, Basel.

Background: Antimicrobial resistance (AMR) poses an important global health challenge in the 21st century. A previous study has quantified the global and regional burden of AMR for 2019, followed with additional publications that provided more detailed estimates for several WHO regions by country. To date, there have been no studies that produce comprehensive estimates of AMR burden across locations that encompass historical trends and future forecasts. Methods: We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen–drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; the proportion of infectious deaths attributable to a given infectious syndrome; the proportion of infectious syndrome deaths attributable to a given pathogen; the percentage of a given pathogen resistant to an antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level. Findings: In 2021, we estimated 4·71 million (95% UI 4·23–5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00–1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000–372 000] and 57 200 attributable deaths [34 100–80 300] in 1990, to 550 000 associated deaths [500 000–600 000] and 130 000 attributable deaths [113 000–146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000–834 000) in 1990, to 1·03 million associated deaths (909 000–1·16 million) in 2021, and from 127 000 attributable deaths (82 100–171 000) in 1990, to 216 000 (168 000–264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56–2·26) deaths attributable to AMR and 8·22 million (6·85–9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2–69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5–89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (–6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8–102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08–13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths. Interpretation: This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050. Funding: UK Department of Health and Social Care's Fleming Fund using UK aid, and the Wellcome Trust. © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Background: Upper respiratory infections (URIs) are the leading cause of acute disease incidence worldwide and contribute to a substantial health-care burden. Although acute otitis media is a common complication of URIs, the combined global burden of URIs and otitis media has not been studied comprehensively. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 to explore the fatal and non-fatal burden of the two diseases across all age groups, including a granular analysis of children younger than 5 years, in 204 countries and territories from 1990 to 2021. Methods: Mortality due to URIs and otitis media was estimated with use of vital registration and sample-based vital registration data, which are used as inputs to the Cause of Death Ensemble model to separately model URIs and otitis media mortality by age and sex. Morbidity was modelled with a Bayesian meta-regression tool using data from published studies identified via systematic reviews, population-based survey data, and cause-specific URI and otitis media mortality estimates. Additionally, we assessed and compared the burden of otitis media as it relates to URIs and examined the collective burden and contributing risk factors of both diseases. Findings: The global number of new episodes of URIs was 12·8 billion (95% uncertainty interval 11·4 to 14·5) for all ages across males and females in 2021. The global all-age incidence rate of URIs decreased by 10·1% (–12·0 to –8·1) from 1990 to 2019. From 2019 to 2021, the global all-age incidence rate fell by 0·5% (–0·8 to –0·1). Globally, the incidence rate of URIs was 162 484·8 per 100 000 population (144 834·0 to 183 289·4) in 2021, a decrease of 10·5% (–12·4 to –8·4) from 1990, when the incidence rate was 181 552·5 per 100 000 population (160 827·4 to 206 214·7). The highest incidence rates of URIs were seen in children younger than 2 years in 2021, and the largest number of episodes was in children aged 5–9 years. The number of new episodes of otitis media globally for all ages was 391 million (292 to 525) in 2021. The global incidence rate of otitis media was 4958·9 per 100 000 (3705·4 to 6658·6) in 2021, a decrease of 16·3% (–18·1 to –14·0) from 1990, when the incidence rate was 5925·5 per 100 000 (4371·8 to 8097·9). The incidence rate of otitis media in 2021 was highest in children younger than 2 years, and the largest number of episodes was in children aged 2–4 years. The mortality rate of URIs in 2021 was 0·2 per 100 000 (0·1 to 0·5), a decrease of 64·2% (–84·6 to –43·4) from 1990, when the mortality rate was 0·7 per 100 000 (0·2 to 1·1). In both 1990 and 2021, the mortality rate of otitis media was less than 0·1 per 100 000. Together, the combined burden accounted for by URIs and otitis media in 2021 was 6·86 million (4·24 to 10·4) years lived with disability and 8·16 million (4·99 to 12·0) disability-adjusted life-years (DALYs) for all ages across males and females. Globally, the all-age DALY rate of URIs and otitis media combined in 2021 was 103 per 100 000 (63 to 152). Infants aged 1–5 months had the highest combined DALY rate in 2021 (647 per 100 000 [189 to 1412]), followed by early neonates (aged 0–6 days; 582 per 100 000 [176 to 1297]) and late neonates (aged 7–24 days; 482 per 100 000 [161 to 1052]). Interpretation: The findings of this study highlight the widespread burden posed by URIs and otitis media across all age groups and both sexes. There is a continued need for surveillance, prevention, and management to better understand and reduce the burden associated with URIs and otitis media, and research is needed to assess their impacts on individuals, communities, economies, and health-care systems worldwide. Funding: Bill & Melinda Gates Foundation. © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

The aim of our investigation is to correlate the wholesale data on antibiotic consumption expressed in daily doses per 1000 inhabitants per day (DID) with the resistance rate of invasive pathogen bacteria from 2017 to 2021. The data on antimicrobial resistance were collected from an analysis of the primary isolates of hospitalized patients. According to the CAESAR manual, the selected pathogens isolated from blood culture and cerebrospinal fluids were tested. The consumption of antibiotics for systematic use showed a statistically significant increasing trend (β = 0.982, p = 0.003) from 21.3 DID in 2017 to 34.5 DID in 2021. The ratio of the utilization of broad-spectrum to narrow-spectrum antibiotics increased by 16% (β = 0.530, p = 0.358). The most consumed antibiotic in 2021 was azithromycin (15% of total consumption), followed by levofloxacin (13%) and cefixime (12%). A statistically positive significant correlation was discovered between the percentage of resistant isolates of K. pneumoniae and consumption of meropenem (r = 0.950; p = 0.013), ertapenem (r = 0.929; p = 0.022), ceftriaxone (r = 0.924; p = 0.025) and levofloxacin (r = 0.983; p = 0.003). Additionally, the percentage of resistant isolates of E. coli and consumption of ertapenem showed significant correlation (r = 0.955; p = 0.011). Significant correlation with consumption of the antibiotics widely used at the community level, such as levofloxacin, and resistance isolated in hospitals indicates that hospital stewardship is unlikely to be effective without a reduction in antibiotic misuse at the community level. © 2023 by the authors.

The aim of our investigation is to correlate the wholesale data on antibiotic consumption expressed in daily doses per 1000 inhabitants per day (DID) with the resistance rate of invasive pathogen bacteria from 2017 to 2021. The data on antimicrobial resistance were collected from an analysis of the primary isolates of hospitalized patients. According to the CAESAR manual, the selected pathogens isolated from blood culture and cerebrospinal fluids were tested. The consumption of antibiotics for systematic use showed a statistically significant increasing trend (β = 0.982, p = 0.003) from 21.3 DID in 2017 to 34.5 DID in 2021. The ratio of the utilization of broad-spectrum to narrow-spectrum antibiotics increased by 16% (β = 0.530, p = 0.358). The most consumed antibiotic in 2021 was azithromycin (15% of total consumption), followed by levofloxacin (13%) and cefixime (12%). A statistically positive significant correlation was discovered between the percentage of resistant isolates of K. pneumoniae and consumption of meropenem (r = 0.950; p = 0.013), ertapenem (r = 0.929; p = 0.022), ceftriaxone (r = 0.924; p = 0.025) and levofloxacin (r = 0.983; p = 0.003). Additionally, the percentage of resistant isolates of E. coli and consumption of ertapenem showed significant correlation (r = 0.955; p = 0.011). Significant correlation with consumption of the antibiotics widely used at the community level, such as levofloxacin, and resistance isolated in hospitals indicates that hospital stewardship is unlikely to be effective without a reduction in antibiotic misuse at the community level. © 2023 by the authors.

Background: Multisystem inflammatory syndrome in children (MIS-C) associated with being infected with coronavirus-19 (COVID-19) is a life-threatening condition resulting from cytokine storm, increased synthesis of reactive oxygen species (ROSs), and hyperinflammation occurring in genetically predisposed children following an infection with SARS-CoV-2. Aim: The primary aims of our study were to identify changes in the activity of antioxidant enzymes in erythrocytes and total oxidative status in plasma after being treated with methylprednisolone (MP). Methods: A prospective cohort study of 67 children (56.7% male) under 18 with MIS-C being treated with MP was conducted at the Mother and Child Health Institute from January 2021 to April 2022. The impact of the therapy was assessed on the basis of the clinical condition, haematological and biochemical blood parameters, and echocardiographic findings. Results: 59.7% of patients presented cardiovascular (CV) manifestations, while myocardial dysfunction was observed in half of all patients (50.7%). A severe clinical course was observed in 22/67 patients. Children with CV involvement had a significantly higher relative concentration of B lymphocytes and lower relative concentration of NK cells than patients without CV issues (p < 0.001 and p = 0.004, respectively). Patients with severe MIS-C had a lower relative count of NK cells than those with moderate MIS-C (p = 0.015). Patients with myocardial dysfunction had a higher total oxidative plasma status (TOPS) than children without (p = 0.05), which implicates pronounced oxidative stress in the former cohort. In patients with shock, lower erythrocytes superoxide dismutase (SOD) activity was observed on admission compared to patients without shock (p = 0.04). After MP was administered, TOPS was significantly reduced, while catalase (CAT) and SOD activity increased significantly. Treatment failure (TF) was observed in 6 patients, only females (p=0.005). These patients were younger (p=0.05) and had lower CAT activity on admission (p=0.04) than patients with favorable treatment responses. In the group of patients with TF, TOPS increased after treatment (before 176.2 ± 10.3 mV, after 199.0 ± 36.7 mV). Conclusion: MP leads to rapid modulation of TOPS and increases the activity of antioxidant enzymes in erythrocytes resulting in clinical and echocardiographic improvement. Based on the observed changes in the activity of the antioxidant enzymes, we can conclude that s hydrogen peroxide is the dominant ROS in patients with MIS-C. Patients with TF showed reduced CAT activity, whereas the treatment with MP led to pronounced oxidation. This implies that low CAT activity may be a contraindication for using MP. Copyright © 2023 Krasic, Vukomanovic, Ninic, Pasic, Samardzija, Mitrovic, Cehic, Nesic and Bajcetic.

Background: Multisystem inflammatory syndrome in children (MIS-C) associated with being infected with coronavirus-19 (COVID-19) is a life-threatening condition resulting from cytokine storm, increased synthesis of reactive oxygen species (ROSs), and hyperinflammation occurring in genetically predisposed children following an infection with SARS-CoV-2. Aim: The primary aims of our study were to identify changes in the activity of antioxidant enzymes in erythrocytes and total oxidative status in plasma after being treated with methylprednisolone (MP). Methods: A prospective cohort study of 67 children (56.7% male) under 18 with MIS-C being treated with MP was conducted at the Mother and Child Health Institute from January 2021 to April 2022. The impact of the therapy was assessed on the basis of the clinical condition, haematological and biochemical blood parameters, and echocardiographic findings. Results: 59.7% of patients presented cardiovascular (CV) manifestations, while myocardial dysfunction was observed in half of all patients (50.7%). A severe clinical course was observed in 22/67 patients. Children with CV involvement had a significantly higher relative concentration of B lymphocytes and lower relative concentration of NK cells than patients without CV issues (p < 0.001 and p = 0.004, respectively). Patients with severe MIS-C had a lower relative count of NK cells than those with moderate MIS-C (p = 0.015). Patients with myocardial dysfunction had a higher total oxidative plasma status (TOPS) than children without (p = 0.05), which implicates pronounced oxidative stress in the former cohort. In patients with shock, lower erythrocytes superoxide dismutase (SOD) activity was observed on admission compared to patients without shock (p = 0.04). After MP was administered, TOPS was significantly reduced, while catalase (CAT) and SOD activity increased significantly. Treatment failure (TF) was observed in 6 patients, only females (p=0.005). These patients were younger (p=0.05) and had lower CAT activity on admission (p=0.04) than patients with favorable treatment responses. In the group of patients with TF, TOPS increased after treatment (before 176.2 ± 10.3 mV, after 199.0 ± 36.7 mV). Conclusion: MP leads to rapid modulation of TOPS and increases the activity of antioxidant enzymes in erythrocytes resulting in clinical and echocardiographic improvement. Based on the observed changes in the activity of the antioxidant enzymes, we can conclude that s hydrogen peroxide is the dominant ROS in patients with MIS-C. Patients with TF showed reduced CAT activity, whereas the treatment with MP led to pronounced oxidation. This implies that low CAT activity may be a contraindication for using MP. Copyright © 2023 Krasic, Vukomanovic, Ninic, Pasic, Samardzija, Mitrovic, Cehic, Nesic and Bajcetic.

Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N-acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO-induced renal cell death and nephrotoxicity in both LLCPK-1 cells and a rat model. To facilitate the use of NAC in preventing IFO-induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM•h (range, 9.92-30.02 mM•h), compared to the mean systemic exposure found in treated children (14.48 mM•h; range, 6.22-32.96 mM•h). They also report 2 pediatric cases in which NAC-attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO-induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children. © 2012 American College of Clinical Pharmacology, Inc.

Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N-acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO-induced renal cell death and nephrotoxicity in both LLCPK-1 cells and a rat model. To facilitate the use of NAC in preventing IFO-induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM•h (range, 9.92-30.02 mM•h), compared to the mean systemic exposure found in treated children (14.48 mM•h; range, 6.22-32.96 mM•h). They also report 2 pediatric cases in which NAC-attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO-induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children. © 2012 American College of Clinical Pharmacology, Inc.

This randomized, single-blind, parallel-group study was performed to assess pharmacokinetic interactions potentially occurring during concomitant use of telmisartan and nisoldipine. Patients with essential hypertension (n = 37) were treated with once-daily doses of telmisartan, nisoldipine, or their combination for 6 weeks. The regimen was started at low dose with an increase of dosage after 3 weeks of treatment. AUCss (132%; P <.01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/fss (-54%; P <.05) and Vz/fss (-72%; P <.05) were significantly lower. Regarding pharmacokinetic parameters of nisoldipine, significant differences between treatment groups were not detected. In conclusion, the results of this study strongly suggest that concomitant treatment with nisoldipine enhances telmisartan bioavail-ability in hypertensive individuals. Larger crossover trials will have to establish these observations and investigate whether interaction of both drugs affects telmisartan efficacy and tolerability in clinical use. ©2007 the American College of Clinical Pharmacology.

This randomized, single-blind, parallel-group study was performed to assess pharmacokinetic interactions potentially occurring during concomitant use of telmisartan and nisoldipine. Patients with essential hypertension (n = 37) were treated with once-daily doses of telmisartan, nisoldipine, or their combination for 6 weeks. The regimen was started at low dose with an increase of dosage after 3 weeks of treatment. AUCss (132%; P <.01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/fss (-54%; P <.05) and Vz/fss (-72%; P <.05) were significantly lower. Regarding pharmacokinetic parameters of nisoldipine, significant differences between treatment groups were not detected. In conclusion, the results of this study strongly suggest that concomitant treatment with nisoldipine enhances telmisartan bioavail-ability in hypertensive individuals. Larger crossover trials will have to establish these observations and investigate whether interaction of both drugs affects telmisartan efficacy and tolerability in clinical use. ©2007 the American College of Clinical Pharmacology.

Objective To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting. Methods A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology. Results Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination. Conclusions Despite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children. © 2019 BMJ Publishing Group Limited.

Background: Little evidence exists to support pharmacotherapeutic strategies for heart failure management in paediatrics. A recent Europe-wide survey suggests that this translates into substantial variability in clinical practice.Objective: To conduct a formal discussion among an expert group of paediatric cardiology physicians on controversial aspects regarding the pharmacotherapy of children heart failure, facilitate consensus, and highlight areas of agreement and disagreement.Methods: A two-round modified Delphi process was conducted between July and August 2015. Topics addressed were predominantly selected from the results of a previous Europe-wide survey. Fourteen statements were presented for discussion grouped under three categories; Angiotensin-converting-enzyme-inhibitors: Considerations for optimal dosage; Angiotensin-converting-enzyme-inhibitors for the management of CHDs; Neurohumoral antagonists for the management of dilated cardiomyopathy-related heart failure.Results: A total of 13 paediatricians dedicated to cardiology from across Europe and the United States of America completed the study; of them, 92% had a working experience in the field of more than 10 years and were working in a specific paediatric cardiology unit. Agreement on the acceptance/rejection of 11 statements was achieved. Results show agreement on the importance of a set of topics relevant to the standardisation of the therapy as well as consensus upon specific therapeutic attitudes.Conclusions: We have found areas of common thinking and motivation, which can provide a means of triggering scientific collaboration. Our results might also contribute to disseminate available paediatric evidence and promote reducing unjustified variability in everyday practice. Until solid evidence is available, other research methods can contribute to advancing the goal of safe and effective paediatric heart failure pharmacotherapy. © Cambridge University Press 2019.

Objective The aim of the study was to compare the quality of antibiotic use among children in primary settings with the internationally developed diseasespecific quality indicators and with National Guidelines. Design Prescriptions of systemic antibiotics to the paediatric population (<18 years) at the primary level of healthcare for the period between 2011 and 2013 were analysed by using the National Health Insurance Fund's outpatient reimbursement database. Results The mean annual number of antibiotic prescriptions was 1.887.615, while the mean annual number of children receiving antibiotics was 728.285. The prescription rate slightly decreased by 10% from 1.516 antibiotic prescriptions per 1000 persons per year in 2011 to 1.365 in 2013. The highest percentage of prescribed antibiotics was observed in the group of children aged 2-23 months. The mean annual prevalence of antibiotic prescriptions was 54%. The percentage of patients prescribed an antibiotic for acute upper respiratory tract infections, acute tonsillitis and acute otitis media (AOM) was above the proposed range (?20), 87%-96%. These three diagnoses represent more than 69% of all indications for prescribing antibiotics. The percentage of patients prescribed a recommended antibiotic was below the proposed range (?80%), 1%-17%, while the adherence rate to National Guidelines was low, 19%-28%. The percentage of patients prescribed quinolones was above the proposed range for AOM (?5%), 7%. There were no significant differences in indicators value at the regional level in Serbia. Conclusions Antibiotic use among children in Serbia is extremely high compared with that in most other European countries. Major problems are frequent use of antibiotics for indications that usually receive no benefit from this treatment and the use of broad-spectrum antibiotics.