Abstract Drug-drug interaction (DDI) is defined as a clinically significant change in the exposure and/or response to a drug caused by co-administration of another drug which may result in a precipitation of an adverse event or alteration of its therapeutic effects. The aim of this systematic review was to provide an overview of DDIs that were actually observed or evaluated in acute coronary syndrome (ACS) patients with particular focus on DDIs with clinical relevance. Electronic searches of the literature were conducted in the following databases: MEDLINE, EBSCO, Scopus, Google Scholar and SCIndeks. A total of 117 articles were included in the review. This review showed that ACS patients can be exposed to a variety of DDIs with diverse outcomes which include decreased efficacy of antiplatelet drugs, thrombolytics or anticoagulants, increased risk of bleeding, rhabdomyolysis, hepatotoxicity, adverse effects on cardiovascular system (e.g. QT interval prolongation, arrhythmias, excessive bradycardia, severe hypotension), serotonin syndrome and drug-induced fever. Majority of the DDIs involved antiplatelet drugs (e.g. aspirin, clopidogrel and ticagrelor). Evidence of some of the reported DDIs is inconclusive as some of the studies have shown conflicting results. There is a need for additional post-marketing and population-based studies to evaluate the true effects of disease states and other factors on the clinical outcomes of DDIs. Clinicians should be attentive to the potential for DDIs and their associated harm in order to minimize or, if possible, avoid medication-related adverse events in ACS patients.

Abstract Despite the great progress made in neonatal and perinatal medicine over the last couple of decades, sepsis remains one of the main causes of morbidity and mortality. Sepsis in pediatric population was defined at the Pediatric Sepsis Consensus Conference in 2005. There is still no consensus on the definition of neonatal sepsis. Neonatal sepsis is a sepsis that occurs in the neonatal period. According to the time of occurrence, neonatal sepsis can be of early onset, when it occurs within the first 72 hours of birth and results from vertical transmission, and of late onset, in which the source of infection is found most often in the environment and occurs after the third day of life. The most common causes of early-onset sepsis are Group B Streptococcus (GBS) and E. coli. Risk factors can be mother-related and newborn-related. Clinical symptoms and signs of sepsis are quite unspecific. The dysfunction of different organs may imitate sepsis. On the other hand, infectious and non-infectious factors may exist simultaneously. The start of the antimicrobial therapy in any newborn with suspected sepsis should not be delayed. Pentoxifylline may have potential benefits in preterm newborns with sepsis. The only proven intervention that has been shown to reduce the risk of early-onset neonatal sepsis is intrapartum intravenous antibiotic administration to prevent GBS infection. It is still a great challenge to discontinue antibiotic treatment in non-infected newborns as soon as possible, because any extended antibiotic use may later be associated with other pathological conditions.

Abstract This observational clinical study was composed of two substudies: a non-comparative one (n = 166), testing only lysozyme-based compounds (LBCs), and a comparative substudy (n = 275), testing both LBCs and bicarbonate-based local compounds (BBCs) on the healing of oral mucositis during radio- or chemotherapy. The density of ulcerations has decreased significantly after the treatment with lysozyme in both substudies. The density of ulcerations in the radiotherapy group was lower in patients treated with LBCs compared to patients treated with BBCs (p < 0.001). In the chemotherapy group, reduction of ulceration density was similar with both LBCs and BBCs. The LBCs reduced pain intensity during the intake of solid food and speech more than BBCs in both patient cohorts (p < 0.05). In the radiotherapy cohort, pain intensity when consuming liquid foods was reduced more with LBCs than with BBCs (p < 0.05). No adverse events were recorded. This study demonstrates the advantages of treating oral mucositis during radiotherapy or chemo-therapy with LBCs.

Abstract Vancomycin is a tricyclic glycopeptide antibiotic, mostly used in the treatment of severe staphylococcal and enterococcal infections, especially in orthopedic surgery. The purpose of this analysis was to develop a population pharmacokinetic (PPK) model of vancomycine in hospitalized patients with bone fractures and identify important factors which influence its clearance (CL). A total of ninety-nine measurements of vancomycin serum concentrations were used in our population modeling. A two-compartment model was applied to describe the pharmacokinetics of vancomycin using subroutines ADVAN3 and TRANS4. The study population included patients of both sexes, with the mean age of 62.12±14.69 years and body weight of 80.32±12.44kg. Vancomycin was administered as intravenous infusion with average daily dose of 1772.73±521.34mg. Out of twenty different factors evaluated in the study (including demographic, clinical and laboratory data), only daily dose of vancomycin (DD) and co-medication with piperacillin/tazobactam (PT) showed significant effect on clearance of vancomycin. The final model was described by the following equation: CL (l/h) = 0.03 + 0.000468 x DD + 0.675 x PT. Bootstrapping was used for validation of the final model. In conclusion, the main causes of variability in the clearance of vancomycin among adult patients with bone fractures are daily dose of vancomycin and co-medication with piperacillin/tazobactam.

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies.

Introduction: Inappropriate design of experimental studies in medicine inevitably leads to inaccurate or false results, which serve as basis for erroneous and biased conclusions. Aim The aim of our study was to investigate prevalence of implementing basic principles of experimental design (local control, replication and randomization) in preclinical experimental studies, performed either on animals in vivo, or animal/human material in vitro. Material and Methods Preclinical experimental studies were retrieved from the PubMed database, and the sample for analysis was randomly chosen from the retrieved publications. Implementation rate of basic experimental research principles (local control, randomization and replication) was established by careful reading of the sampled publications and their checking against predefined criteria. Results Our study showed that only a minority of experimental preclinical studies had basic principles of design completely implemented (7%), while implementation rate of single aspects of appropriate experimental design varied from as low as 9% to maximum 86%. Average impact factor of the surveyed studies was high, and publication date relatively recent, suggesting generalizability of our results to highly ranked contemporary journals. Conclusion Prevalence of experimental preclinical studies that did not implement completely basic principles of research design is high, raising suspicion to validity of their results. If incorrect and biased, results of published studies may mislead authors of future studies and cause conduction of fruitless research that will waste precious resources.

OBJECTIVES Urinary tract infections (UTIs) are common problems in women, and important reason for visiting primary care physicians, resulting in substantial financial burden to community. The aim of this study was to determine the resistance rates of E. coli to commonly prescribed antimicrobial drugs for community-acquired UTIs in women and to establish the association between age and resistance to antibiotics among isolates of E. coli from urine. METHODS The study was designed as a retrospective cross-sectional study during the 5-years period. It was conducted on a sample of urinary tract isolates of E. coli taken from women with community-acquired UTIs. After prevalence of E. coli resistance to antibiotics was established, the analysis of risk factors for emergence of resistance was conducted. RESULTS There were 10,734 isolates of E. coli, comprising 70.62% of all samples analyzed. E. coli was the most frequently resistant to ampicillin (54.68%), followed by trimethoprim-sulphamethoxazole (37.46%), first and second generation cephalosporins (cephalexin and cefaclor) (29.53% both), and ciprofloxacin (23.80%). Less than 50% of E. coli isolates was sensitive to all three tested antibiotics, and nearly 13% acquired triple-resistance. Prevalence of isolates resistant to two or three agents was higher in the subgroup of women older than 65 years. CONCLUSIONS Empirical choice of antimicrobial agent for community-acquired non-complicated UTIs in women should be individualized on the basis of the patient's age, prevalence of resistance in the local community, and compliance history of the patient.

Abstract Background: Drug-drug interactions are defined as modifications of the drug action that result from the simultaneous administration of another individual drug or several drugs. Nowadays, potential drug-drug interactions (DDIs) are most frequently detected and analyzed using personal digital assistant software programs (online interaction checker tools). Objective: To determine the risk factors for the emergence of all drug-drug interactions in surgical patients with particular emphasis on clinically significant interactions. Patients and methods: This was a retrospective cohort analysis of patients treated at the Surgical Clinic of the Clinical Center Kragujevac. Three interaction checkers were used to reveal drug-drug interactions: Medscape, Epocrates and Micromedex. Results: The study included total of 200 patients, aged 58.54±17.08 years. Average number of drug-drug interactions per patient was between 10.50±9.10 (Micromedex) and 18.75±17.14 (Epocrates). Number of prescribed drugs, antidepressive therapy, antiarrhythmic therapy, number of pharmacological/therapeutic subgroups (2nd level of ATC classification) prescribed, delirium or dementia, diabetes, heart failure, and number of physicians who prescribed drugs to single patient were identified as risk factors for drug-drug interactions while length of hospitalization in days and age of patient in years emerged as protective factors. Conclusion: Drug-drug interactions are relatively common in surgical patients and predisposed by factors such as number of prescribed drugs or drug group per patient, number of physicians who prescribed drugs, antidepressive therapy, antiarrhythmic therapy, presence of delirium or dementia, diabetes and heart failure. On the other hand, prolonged hospitalization and higher age are factors that reduce the risk of interactions in surgical patients.

Abstract Neonatal respiratory distress syndrome (NRDS) is a consequence of immaturity at birth and it is still associated with relatively high mortality rate. The aim of this study was to identify the factors associated with the occurrence of fatal outcome in newborns with neonatal respiratory distress syndrome.The research was designed as a case-control study nested in a retrospective cohort, and it enrolled newborns treated during 2015 at Pediatric Clinic of Clinical Center in Kragujevac. Diagnosis of NRDS and decision about the treatment were left at the discretion of attending pediatricians. The cases were patients with fatal outcome, while controls were randomly selected from the pool of survivors and matched with each case by gender in a ratio of 4:1. The study included 371 newborns, of whom 201 (54.2%) were male and 170 (45.8%) female. Lethal outcome occurred in 36 newborns (9,7%). Significant association was found between death and APGAR score (ORadjusted: 0.516, 95% CI: 0.322-0.827), weight on delivery (ORadjusted: 0.996, 95% CI: 0.993-0.999), duration of hospitalization (ORadjusted: 0.901, 95% CI: 0.835-0.972) and mechanical ventilation (ORadjusted: 165.256, 95% CI: 7.616-3585.714). Higher gestational age, higher birth weight, higher APGAR score and longer duration of hospitalization were singled out as protective factors, while use of mechanical ventilation increased the risk of death. Major limitations of the study were retrospective nature and relatively small number of identified cases. Postponing delivery and delivery in institution with neonatal intensive care unit are crucial for survival of newborns with NRDS.

Introduction: Beneficial effect of local administration of lysozyme in patients with recurrent aphthous stomatitis was demonstrated, but there are no published studies focused on treatment of chemotherapy or radiotherapy induced oral mucositis with lysozyme. Aim: The aim of this study was to compare efficacy and safety of Lysobact Complete spray (lysozyme, cetylpyridinium, and lidocaine) and compounded medication for local use in the treatment of radio- and chemo-therapy induced oral mucositis. Patients and Methods: This observational, phase IV study was designed as prospective cohort investigation, and conducted at two sites, Clinical Hospital Zenica and University Clinical Center Tuzla, Bosnia & Herzegovina, from August to November, 2018. The patients with oral mucositis after radio- or chemo-therapy were treated by either registered lysozyme-based or compounded medication (standardized and bicarbonate-based) for 21 days. Results: Both lysozyme-based (Lysobact Complete Spray) spray (lysozyme, cetylpyridinium and lidocaine) and compounded medication for local use were effective in local treatment of chemotherapy and radiotherapy-induced oral mucositis. However, lysozyme-based preparation was more effective, since signs of inflammation, number of oral ulcers and intensity of pain during eating and speaking withdrew to a greater extent than with highly variable compounded medication for local use. No adverse events were recorded in both treatment arms. Conclusions: Locally administered spray with fixed combination of lysozyme, cetylpyridinium and lidocaine (Lysobact Complete Spray) is very efficient and completely safe treatment of both radiotherapy and chemotherapy-induced oral mucositis.

Aim To develop and validate a screening questionnaire for migraine without aura with sufficient diagnostic accuracy to be used in primary care settings. Methods The study was designed as cross-sectional, multicentric, diagnostic accuracy trial of new questionnaire for screening patients who visit general practitioners, with an aim to reveal migraine without aura. The instrument was constructed for the purpose of this study, and validated on the sample of 429 primary care outpatients. The gold standard of diagnosing migraine without aura was clinical estimate by a neurologist based on the International Classification of Headache Disorders 3rd edition (ICHD-III) criteria. Diagnostic accuracy of the instrument was tested through construction of the Receiver Operator Curve. Results The Balkan Migraine Screening Questionnaire (BMSQ) instrument showed good diagnostic accuracy (sensitivity 83.4% and specificity 79.9%) for migraine without aura, with significant screening yield among previously undiagnosed patients of 75.9%. The study also confirmed a high percentage of patients with hidden migraine without aura (MWA) (52.9%) revealed by the BMSQ and the ICHD-III criteria that would otherwise remain undiagnosed. Conclusion The BMSQ is a valid and reliable clinical instrument for revealing migraine without aura, which could be easily selfadministered by patients. It has high screening yield, discovering majority of patients with previously undiagnosed migraine without aura, whose definite diagnosis should later on be confirmed by the attending physicians using the ICHD-III criteria.