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Hydralazine (HL), a frequently prescribed oral antihypertensive drug, shows redox interactions with transition metals such as copper that are not fully understood. Copper may be present at high concentrations in the digestive tract and can affect oral drugs. An important parameter for such interactions is pH, which changes from acidic in the gastric juice to neutral pH in intestines. In this study, we examined interactions of HL with Cu2+ ions in conditions that mimic pH shift in the digestive tract using UV–Vis, Raman and EPR spectroscopy, cyclic voltammetry and oximetry. In the acidic solution, Cu2+ formed a stable mononuclear complex with two bidentate coordinated HL molecules. On the other hand, at neutral pH, Cu2+ initiated oxidation and degradation of HL. The degradation was more rapid in the HL-Cu2+ system that was initially prepared at acidic pH and then shifted to neutral pH. The formation of the complex at acidic pH increases the availability of Cu2+ for redox reactions after the shift to neutral pH at which Cu2+ is poorly soluble. These results imply that the change of pH along the digestive tract may promote HL degradation by allowing the formation of the complex at gastric pH which makes Cu2+ available for subsequent oxidation of HL at neutral pH. This is the peer-reviewed version of the following article: Korać Jačić, J., Bajuk-Bogdanović, D., Savić, S., Božić Cvijan, B., Spasojević, M.,& MIlenković, M. R.. (2023). Coordination of hydralazine with Cu2+ at acidic pH promotes its oxidative degradation at neutral pH. in Journal of Inorganic Biochemistry Elsevier., 243, 112181. [https://doi.org/10.1016/j.jinorgbio.2023.112181] more...

The specific characteristics of the pediatric population, the lack of evidence, as well as the small number of studies made treatment of septic shock in children one of the biggest challenges in intensive care units. The Surviving Sepsis Campaign issued in 2020 new guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. The first guide on this topic was published in 2004, and has been reviewed every four years since. Sepsis is a leading cause of healthcare utilization for children worldwide, and early recognition and appropriate management of children with sepsis and sepsis-associated organic dysfunction are crucial for the outcome. Although the new guidelines covered publications up to May 2017, this review also included some recently published studies. Following the innovations in this area, practical application and implementation of guidelines are important for the management of septic shock and sepsis-associated organ dysfunction in children. more...

Item does not contain fulltext Aim: Clinical research in pediatrics is progressively initiated by academia. As the reliability of pharmacodynamic measures is closely linked to the quality of bioanalytical data, bioanalytical quality assurance is crucial. However, clear guidance on comprehensive bioanalytical quality monitoring in the academic environment is lacking. Methods & results: By applying regulatory guidelines, international recommendations and scientific discussions, a five-step quality control system for monitoring the bioanalysis of aldosterone by immunoassay was developed. It comprised performance qualification, calibration curve evaluation, analysis of the intra- and inter-run performance via quality control samples, incurred sample reanalysis and external quality assessment by interlaboratory testing. A total of 55 out of 70 runs were qualified for the quantification of aldosterone in the study sample enabling the evaluation of 954 pediatric samples and demonstrating reliability over the 29-month bioanalysis period. Conclusion: The bioanalytical quality control system successfully monitored the aldosterone assay performance and proved its applicability in the academic environment. more...

Contains fulltext : 220641.pdf (Publisher’s version ) (Closed access) While the role of plasma renin activity (PRA) in heart failure has been widely studied in adults, comprehensive data on pediatric heart failure remain lacking. This drawback is increasingly being addressed by academic research. Nevertheless, such pediatric investigations are commonly conducted only once due to ethical constraints. Therefore, the quality of bioanalytical data must be ensured to acquire meaningful insights into maturing humoral parameters. However, appropriate post-validation assessment of bioanalytical runs is currently underrepresented by regulatory guidance. Thus, for applications in an academic environment, an easy-to-handle six-step bioanalytical quality control system was designed based on regulatory guidelines (e.g. U.S. Food and Drug Administration) combined with international recommendations (e.g. Clinical and Laboratory Standards Institute) and current scientific discussion. Its applicability to an enzyme-linked immunosorbent assay for determination of PRA was investigated within three pediatric trials of the EU-funded "Labeling of Enalapril in Neonates up to Adolescents" project. This quality control system identified 15 % bioanalytical runs as non-compliant to the predefined specifications and ensured the reliable quantification of 940 pharmacodynamic samples. The inter-run assessment of quality controls was able to demonstrate the comparability of the study results. Furthermore, 86 % of incurred sample reanalysis pairs complied with regulatory requirements (>67 %), thus underlining the long-term reproducibility of the utilized ligand-binding assay. Successful participation in interlaboratory testing confirmed the accuracy of the applied method throughout the entire study period. Further investigations showed no notable differences between the five applied lots of the PRA assay. The applicability of this quality control system was proven in an academic environment and ensured reliable results for PRA over the entire 24-month study period. more...

An increase in the copper pool in body fluids has been related to a number of pathological conditions, including infections. Copper ions may affect antibiotics via the formation of coordination bonds and/or redox reactions. Herein, we analyzed the interactions of Cu more...

An increase in the copper pool in body fluids has been related to a number of pathological conditions, including infections. Copper ions may affect antibiotics via the formation of coordination bonds and/or redox reactions. Herein, we analyzed the interactions of Cu2+ with eight β-lactam antibiotics using UV–Vis spectrophotometry, EPR spectroscopy, and electrochemical methods. Penicillin G did not show any detectable interactions with Cu2+. Ampicillin, amoxicillin and cephalexin formed stable colored complexes with octahedral coordination environment of Cu2+ with tetragonal distortion, and primary amine group as the site of coordinate bond formation. These β-lactams increased the solubility of Cu2+ in the phosphate buffer. Ceftazidime and Cu2+ formed a complex with a similar geometry and gave rise to an organic radical. Ceftriaxone-Cu2+ complex appears to exhibit different geometry. All complexes showed 1:1 stoichiometry. Cefaclor reduced Cu2+ to Cu1+ that further reacted with molecular oxygen to produce hydrogen peroxide. Finally, meropenem underwent degradation in the presence of copper. The analysis of activity against Escherichia coli and Staphylococcus aureus showed that the effects of meropenem, amoxicillin, ampicillin, and ceftriaxone were significantly hindered in the presence of copper ions. The interactions with copper ions should be taken into account regarding the problem of antibiotic resistance and in the selection of the most efficient antimicrobial therapy for patients with altered copper homeostasis. This is the peer-reviewed version of the following article: Božić, B.; Korać, J.; Stanković, D. M.; Stanić, M.; Romanović, M.; Pristov, J. B.; Spasić, S.; Popović-Bijelić, A.; Spasojević, I.; Bajčetić, M. Coordination and Redox Interactions of β-Lactam Antibiotics with Cu2+ in Physiological Settings and the Impact on Antibacterial Activity. Free Radical Biology and Medicine 2018, 129, 279–285. [https://doi.org/10.1016/j.freeradbiomed.2018.09.038] The published version: [https://cer.ihtm.bg.ac.rs/handle/123456789/3936] Supporting information: [https://cer.ihtm.bg.ac.rs/handle/123456789/4489] more...

OBJECTIVES: The aim of this study is to analyze the availability and coverage by health insurance reimbursement of pediatric formulations labeled for children up to the age of 12 in Serbia. To provide good insight in general availability of pediatric medicines, results were compared with the World Health Organization's (WHO) “Model List of Essential Medicines for Children” and with published evidence. MATERIALS AND METHODS: Sources of information about medicines are the Summary of Product Characteristics, National Health Insurance Fund (NHIF) Drug Lists, WHO Model Lists of Essential Medicines for Children, and Serbia's official drug registry (2013). RESULTS: Out of total number of medicines in Serbia, only 49% (496) were available for children. Of all available drugs for children, 66% were with license and majority were parenteral formulation (57%), followed by drugs for local use (28%) and formulations for oral use (23%). The lowest availability of medicines was for children 0–27 days. From the total number of licensed medicines for children up to 12 years old, NHIF covers 64% of drugs. The availability of the WHO essential medicines for children in Serbia was 51%, from which 92% were licensed for pediatric use. CONCLUSIONS: Our results demonstrated the alarming lack of pediatric suitable formulations in Serbia. Significant differences in the availability of drugs suitable for children exist worldwide. From global health point of view, the differences in the access to children formulations should, therefore, be of the highest priority. more...

Toxic effects of unconjugated bilirubin (BR) in neonatal hyperbilirubinemia have been related to redox and/or coordinate interactions with Cu2+. However, the development and mechanisms of such interactions at physiological pH have not been resolved. This study shows that BR reduces Cu2+ to Cu1+ in 1:1 stoichiometry. Apparently, BR undergoes degradation, i.e. BR and Cu2+ do not form stable complexes. The binding of Cu2+ to inorganic phosphates, liposomal phosphate groups, or to chelating drug penicillamine, impedes redox interactions with BR. Cu1+ undergoes spontaneous oxidation by O-2 resulting in hydrogen peroxide accumulation and hydroxyl radical production. In relation to this, copper and BR induced synergistic oxidative/damaging effects on erythrocytes membrane, which were alleviated by penicillamine. The production of reactive oxygen species by BR and copper represents a plausible cause of BR toxic effects and cell damage in hyperbilirubinemia. Further examination of therapeutic potentials of copper chelators in the treatment of severe neonatal hyperbilirubinemia is needed. This is the peer-reviewed version of the following article: Božić, B.; Korać, J.; Stanković, D. M.; Stanić, M.; Popović-Bijelić, A.; Bogdanović Pristov, J.; Spasojević, I.; Bajčetić, M. Mechanisms of Redox Interactions of Bilirubin with Copper and the Effects of Penicillamine. Chemico-Biological Interactions 2017, 278, 129–134. [https://doi.org/10.1016/j.cbi.2017.10.022] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3106] more...

Background/ObjectiveA lack of appropriately evaluated medicines for paediatric population is a major problem as it often leads to inadequate treatment of children. The aim of this study was to investigate the availability of paediatric formulations labelled for children up to the age of 12 years old in Serbia in 2013, as well as the availability of paediatric medicines reimbursed by the Republic Health Insurance Fund (RFZO). The availability of paediatric formulations in Serbia is also compared with the ‘Model List of Essential Medicines for Children’ by World Health Organization's (WHO).MethodsSources of information about medicines were: the Summary of Product Characteristics (SmPc), RFZO Drug Lists, WHO Model Lists of Essential Medicines for Children, and Serbia's official drug registry, editions 2013.ResultsIn Serbia only 49% (496) of INN drugs were suitable for children of which only 66% were licensed for paediatric use. Majority of licensed drugs were parenteral formulations, 57%, followed by drugs for local use, 28%, and formulations for oral use, 23%. The lowest availability of medicines was for children 0–27 days old. From the total number of licensed medicines for children up to 12 years old, the Republic Fund for Health Insurance covers 64% of drugs and from each therapeutic group at least one medicine is reimbursed by fund. The availability of WHO essential medicines for children in Serbia was 51%, from which 92% were licensed for paediatric use.ConclusionOur study showed that from already unsatisfactory number of available drugs for children only 66% is licensed. Limited availability of paediatric medicines for all ages of this population and for a broad range of therapeutic areas still represents a cause for concern in our country. more...

Background/ObjectiveAntibiotics are the most irrational prescribed drugs among the paediatric population. The aim of this study was to evaluate the seasonal variations in antibiotic prescribing profile among children in primary care settings in Serbia.MethodsPrescriptions of systemic antibiotics to the paediatric population (ResultsThe average number of antibiotic prescriptions was 1.887.615, while the average number of children receiving antibiotics was 728.285. The average annual rate was 1.394 antibiotic prescriptions per 1000 children. Significant differences in prescription rates in winter months compared to summer months were observed (t=5.51 pConclusionsSignificant seasonal variations in prescription practice and frequently used broad-spectrum antibiotics indicate that antibiotic prescribing is inappropriate. more...

ObjectiveThe aim of the study was to compare the quality of antibiotic use among children in primary care settings for acute upper respiratory tract infections, acute tonsillitis and acute otitis media (AOM) with the internationally developed disease-specific antibiotic prescribing quality indicators (APQI) and with National Guidelines.MethodsPrescriptions of systemic antibiotics to the paediatric population (ResultsDuring the followed up period acute upper respiratory infections, 42%, acute tonsillitis, 25%, and AOM/myringitis, 2%, represented more than 69% of the all indications for prescribing antibiotics. 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%. 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.ConclusionBased on results for disease-specific quality indicators for the most common children diseases and low adherence rates with our National guidelines we can conclude that antibiotic use is inappropriate in Serbia. more...