The Impact of Copper Ions on the Activity of Antibiotic Drugs.

Copper (Cu) is an essential trace metal and its concentration in body plasma is tightly regulated. An increase in Cu concentration in body fluids is observed in numerous pathological conditions, including infections caused by microorganisms. Evidence shows that Cu ions can impact the activity of antibiotics by increasing efficiency or diminishing/neutralizing antibiotic activity, forming complexes which may lead to antibiotic structure degradation. Herein, we represent the evidence available on Cu-antibiotic interactions and their possible impact on antimicrobial therapy efficiency. So far, in vitro studies described interactions between Cu ions and the majority of antibiotics in clinical use: penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, tetracyclines, fluoroquinolones, isoniazid, metronidazole. In vitro-described degradation or lower antimicrobial activity of amoxicillin, ampicillin, cefaclor, ceftriaxone, and meropenem in the presence of Cu ions suggest caution when using prescribed antibiotics in patients with altered Cu levels. On the other hand, several Cu-dependent compounds with antibacterial activity including the drug-resistant bacteria were discovered, such as thiosemicarbazones, disulfiram, dithiocarbamates, 8-hydroxiquinoline, phenanthrolines, pyrithione. Having in mind that the development of new antibiotics is already marked as inadequate and does not meet global needs, the potential of Cu-antibiotic interactions to change the efficiency of antimicrobial therapy requires further investigation.

Pharmacotherapy in paediatric heart failure: a Delphi process.

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.

Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury.

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.

Impact of Antibiotic Consumption on Antimicrobial Resistance to Invasive Hospital Pathogens.

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 (ß = 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% (ß = 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.

Mechanisms of redox balance and inflammatory response after the use of methylprednisolone in children with multisystem inflammatory syndrome associated with COVID-19.

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.

Influence of Age, Heart Failure and ACE Inhibitor Treatment on Plasma Renin Activity in Children: Insights from a Systematic Review and the European LENA Project.

BACKGROUND: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children. METHODS: We conducted a systematic literature search to identify studies on PRA levels in healthy children and in children with heart failure. In addition, we analysed PRA data measured before (n = 35, aged 25 days-2.1 years), 4 hours after (n = 34) and within the first 8 days of enalapril treatment (n = 29) in children with heart failure from the European project Labeling of Enalapril from Neonates up to Adolescents (LENA). RESULTS: Age has a profound effect on PRA levels in healthy children, as PRA levels in the literature are up to about 7 times higher in neonates than in older children. Children with heart failure younger than 6 months showed 3-4 times higher PRA levels than healthy peers in both the literature and the LENA studies. In the LENA studies, the ACEi enalapril significantly increased median predose PRA by a factor of 4.5 in children with heart failure after 4.7 ± 1.6 days of treatment (n = 29, p < 0.01). Prior to treatment with enalapril, LENA subjects with symptomatic heart failure (Ross score ≥3) had a significantly higher PRA than LENA subjects with asymptomatic heart failure of comparable age (Ross score ≤2, p < 0.05). CONCLUSIONS: Age, heart failure and ACEi treatment have a notable influence on PRA and must be considered when assessing PRA as a clinically meaningful parameter. CLINICAL TRIAL REGISTRATION: The trials are registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu). TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18.

Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).

Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.

Microbiology of Healthcare-Associated Infections: Results of a Fourth National Point Prevalence Survey in Serbia.

Millions of patients acquire healthcare-associated infections (HAIs) every year, putting them at risk for serious complications and prolonged hospitalization. Point prevalence surveys (PPS), guided by the European Centre for Disease Prevention and Control framework, are one of the primary methods by which countries in the European Union conduct surveillance of HAIs. Serbia, though not in the EU, implemented this approach in its national PPS. The microbiological and antimicrobial resistance (AMR) analyses comprised patients in 61 out of 65 hospitals included in the fourth PPS conducted in November 2017. A total of 515/12,380 (4.2%) of the adult patients included in the PPS had at least one HAI, with intensive care units carrying the highest prevalence of 15.9%. Urinary tract and surgical site infections were the most frequently identified types of HAIs (23.9% and 23.0%, respectively). Enterobacterales comprised almost half (47.0%) of all causative agents, most notably Klebsiella spp. (16.7%). AMR was very high for most pathogens-80.5% of nonfermentative Gram-negative bacilli were resistant to carbapenems whereas 62.9% of Enterobacterales were resistant to third generation cephalosporins. The calculated AMR index of 61% is one of the highest in Europe. Further efforts are needed to reduce the burden of HAIs in Serbia that carry very high resistance rates to antibiotics currently used in clinical practice.

A nationwide assessment of the burden of healthcare-associated infections and antimicrobial use among surgical patients: results from Serbian point prevalence survey, 2017.

BACKGROUND: As the only non-European Union (EU) country, Serbia participated in a second point prevalence survey of healthcare-associated infections (HAIs) and antimicrobial use (AMU) organized by the European Centre for Disease Prevention and Control (ECDC) in the EU countries. Here, we aimed to estimate the prevalence of HAI and AMU in patients who had recently undergone a surgery and to compare risk profile, HAI rates, and AMU among surgical patients and non-surgical patients. METHODS: A national PPS was performed in 65 Serbian acute-care hospitals, in November 2017. In this paper, the data of 61 hospitals for adult acute-care were analyzed. To ensure the comparability of study design we used the Serbian translation of ECDC case definitions and ECDC PPS protocol. The trained infection control staff, led by a hospital coordinator, reviewed medical records to identify HAI active at the time of the survey and AMU. Only inpatients admitted to the ward before 8 a.m. on the day if the survey were included. RESULTS: A total of 12,478 patients from 61 hospitals for adult acute-care were eligible for inclusion in this study. Significantly higher proportions of surgical patients were female, belonged to the 60-to-79 age group, and were less severely ill. Also, extrinsic factors (invasive devices, hospitalization at the ICU, and prior antibiotics therapy) were more frequent in surgical patients. Prevalence of HAIs was higher among surgical patients (261/3626; 7.2%) than among non-surgical patients (258/8852; 2.9%) (p < 0.0001). The highest prevalence of all HAIs was noted in patients who had kidney transplantation (4/11; 36.4%), while SSIs were the most prevalent among patients who had peripheral vascular bypass surgery (3/15; 20.0%). Non-surgical patients received treatment for community-acquired infections in significantly higher proportion (2664/8852; 64.3) (p < 0.001). Surgical prophylaxis for more than 1 day was applied in 71.4% of surgical patients. CONCLUSION: We have provided an insight into the burden of HAIs and AMU among Serbia acute-care hospitals, and highlighted several priority areas and targets for quality improvement.

Oxidative status of maternal blood in pregnancies burdened by inherited thrombophilias.

Oxidative status of maternal blood represents an important parameter of pregnancy that is involved in both, regulation of physiological processes and (if significantly altered) development of different pregnancy complications. Inherited thrombophilias represent genetic disorders that increase the risk of thromboembolism in pregnancy. Little is known about the impact of thrombophilia on the oxidative status of maternal blood. In this study, we analyzed oxidative status of blood of 56 women with pregnancies burdened by inherited thrombophilias. The status was established at three different trimesters using biochemical assays and electrochemical measurements, and it was compared to 10 age- and trimester-matching controls. Activities of superoxide dismutase, catalase, and glutathione reductase in the 1st and the 2nd trimester of thrombophilic pregnancy were lower than controls. Also, there was less oxidation in the plasma, according to higher concentration of reduced thiols and lower oxidation-reduction potential. Therefore, it appears that thrombophilic mothers do not experience oxidative stress in the circulation in the first two trimesters. However, the rise in GPx, GR and SOD activities in the 3rd trimester of thrombophilic pregnancy implies that the risk of oxidative stress is increased during the late pregnancy. These results are important for developing antioxidative treatment that could tackle thrombophilia-related pregnancy complications.

The influence of various morphologic and hemodynamic carotid plaque characteristics on neurological events onset and deaths.

A group of 72 patients with 111 asymptomatic carotid stenoses (ACS), mean age 65.42 +/- 9.21, and a group of 36 patients with 58 symptomatic carotid stenoses (SCS), mean age 67.63 +/- 8.79, were analyzed prospectively during a 3-year follow-up period. All patients underwent color duplex scan sonography (CDS), carotid arteriography, computed tomography (CT) scan, and neurological examination. The aim of the study was to analyze the correlation between echo plaque morphology (degree and plaque quality), local hemodynamic plaque characteristics, ischemic CT findings, and onset of new neurological events and deaths. The results analysis showed significantly more ACS in the group of 30-49% stenosis (p < 0.001), but significantly more SCS in the group of 70-89% (p < 0.0001) and > or = 90% stenosis (p < 0.05). Fibrous plaque was more frequent in the ACS group (p < 0.001), while ulcerated and mixed plaques were more frequent in the SCS group (both p < 0.0001). In the SCS group, a significantly higher frequency of increased peak systolic and end diastolic velocities was noted at the beginning and end of the study (both p < 0.01), as well as for contralateral common (CCA) or internal carotid artery (ICA) occlusion (p < 0.05 and p < 0.01, respectively), but reduced carotid blood flow volume (p < 0.05) only at the end of the study. In the ACS group, the best correlation with new neurological events and deaths was shown with positive CT findings, peak systolic flow velocity over 210 cm/sec, end diastolic flow velocity over 110 cm/sec, plaque stenosis > or = 70%, plaque ulceration, mixed plaque (all p < 0.0001); stenosis > or = 50% (p < 0.001); and reduced carotid blood flow volume (p < 0.05).

Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey.

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.

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study.

INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

Effects of carvedilol on left ventricular function and oxidative stress in infants and children with idiopathic dilated cardiomyopathy: a 12-month, two-center, open-label study.

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 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) 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] micromol 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] micromol 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) 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.

The Role of Quinidine in the Pharmacological Therapy of Ventricular Arrhythmias 'Quinidine'.

Historically, quinidine was the first medicine used in the therapy of heart arrhythmias. Studies in the early 20th century identified quinidine, a diastereomer of the antimalarial quinine, as the most potent of the antiarrhythmic substances extracted from the cinchona plant. Quinidine is used by the 1920s, as an antiarrhythmic agent to maintain sinus rhythm after the conversion from atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or ventricular fibrillation. Its value in chronic prophylaxis of relapse of ventricular arrhythmia was brought under suspicion after publishing of meta analysis that showed that the application of quinidine increases mortality. Due to numerous proofs of increased risk for the appearance of ventricular arrhythmia and sudden death, as well as a number of other adverse effects and drug interactions, quinidine was withdrawn from use and in the recent years has become unavailable in many countries. On the other hand, recent studies have demonstrated that quinidine is the only oral medication that has consistently shown efficacy in preventing arrhythmias and terminating storms due to recurrent ventricular fibrillation, in patients with Brugada syndrome, idiopathic ventricular fibrillation and early repolarization syndrome. Quinidine is also the only antiarrhythmic drug that normalized the QT interval in patients with the congenital short QT syndrome. The aim of this review is to provide good insight into pro and contra arguments for quinidine use in ventricular arrhythmias evidence based on recently published literature.

Coordination and redox interactions of ß-lactam antibiotics with Cu2+ in physiological settings and the impact on antibacterial activity.

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 ß-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 ß-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.

Pharmacokinetics of oral doses of telmisartan and nisoldipine, given alone and in combination, in patients with essential hypertension.

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. AUC(ss) (132%; P < .01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/f(ss) (-54%; P < .05) and Vz/f(ss) (-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 bioavailability 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.

Availability of pediatric-evaluated formulations in Serbia.

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.

Mechanisms of redox interactions of bilirubin with copper and the effects of penicillamine.

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 O2 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.

Cardiovascular risk factors and blood pressure in a primary care unit: Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD).

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.