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arrhythmia and sudden death, as well as a number of other adverse effects and drug interactions, quinidine was withdrawn from use and in the recent years has become unavailable in many countries.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.

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.

Use of antibiotics in paediatric primary care settings in Serbia.

OBJECTIVE: The aim of the study was to compare the quality of antibiotic use among children in primary settings with the internationally developed disease-specific 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.