Zlatkovic J.,Vinča Institute of Nuclear Sciences |
Todorovic N.,Vinča Institute of Nuclear Sciences |
Tomanovic N.,University of Belgrade |
Boskovic M.,Vinča Institute of Nuclear Sciences |
And 5 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014
Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15 mg/kg/day) or clozapine (20 mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21 days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine. © 2014 Elsevier B.V. All rights reserved.
Dordevic M.M.,University of Belgrade |
Jeremic D.A.,University of Belgrade |
Rodic M.V.,University of Novi Sad |
Simic V.S.,Medicines and Medical Devices Agency of Serbia |
And 2 more authors.
Polyhedron | Year: 2014
The reaction of an ethanolic solution of the newly synthesized 2-(diphenylphosphino)benzaldehyde 1-adamantoylhydrazone (HL) with aqueous solutions of K2[MCl4] (M = Pd(II), Pt(II)) resulted in neutral complexes of the general formulae [M(L)Cl]. These complexes have a square-planar structure that was achieved by tridentate PNO coordination of the monoprotonated Schiff base and a chloride ligand. The ligand and its metal complexes were analyzed for their antimicrobial activity and their in vitro cytotoxicity in human larynx carcinoma cells (Hep-2) and non-cancerous human lung fibroblast cells (MRC-5). The platinum(II) complex shows cytotoxicity towards Hep-2 cells comparable to oxaliplatin and exhibited improved selectivity for cancer cells. The ligand and its complexes were characterized by elemental analysis, NMR and IR spectroscopy, and single crystal X-ray diffraction analysis. © 2013 Elsevier Ltd. All rights reserved.
Petronijevic M.,Medicines and Medical Devices Agency of Serbia |
Ilic K.,University of Belgrade |
Suzuki A.,Duke University
Pharmacoepidemiology and Drug Safety | Year: 2011
Purpose: The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. Methods: Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. Results: Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). Conclusions: Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals. © 2011 John Wiley & Sons, Ltd.
Drljevic-Djuric K.M.,Medicines and Medical Devices Agency of Serbia |
Jovic V.D.,Serbian Institute for Multidisciplinary Research |
Lacnjevac U.C.,Serbian Institute for Multidisciplinary Research |
Avramov Ivic M.L.,University of Belgrade |
And 3 more authors.
Electrochimica Acta | Year: 2010
The oxidative behavior of antibiotic roxithromycin standard was studied at a gold electrode in 0.05 M NaHCO3 using cyclic linear sweep voltammetry and differential pulse voltammetry. It was found that the value of the oxidative peak of pure roxithromycin at 0.81 V vs. SCE in 0.05 M NaHCO 3 at a scan rate of 50 mV s-1 is a linear function of the concentration in a range 0.10006-0.654 mg cm-3. It was also found that peak current density at 0.75 V vs. SCE at a scan rate of 2 mV s -1, pulse amplitude of 25 mV and pulse time of 0.1 s exhibits linear dependence on the concentration of roxithromycin from 0.1006 to 0.476 mg cm -3. Roxithromycin as a content of solid dosage form and urine was quantitatively determined and the obtained results were checked by HPLC. © 2010 Elsevier Ltd.
Miljkovic M.M.,Medicines and Medical Devices Agency of Serbia |
Dobric S.,Military Medical Academy |
Dragojevic-Simic V.,Military Medical Academy
Pharmacoepidemiology and Drug Safety | Year: 2011
Purpose: Reliability and usefulness of scales for causality assessment in hepatotoxicity have not been fully explored. The goal of this study was to examine consistency between causality assessments obtained with two commonly used scales and their agreement with initial clinical assessments in hepatotoxicity reported in Serbia, and to review usefulness of these scales. Methods: We compared the two scales (CIOMS/RUCAM and NARANJO) in 80 cases reported during 1995-2009. The initial clinical assessments performed at the time of reporting served as a control for comparison with the subsequent causality assessments. The agreement between obtained causality assessments and the initial clinical assessments were analysed by Kappa weighted (Kw) statistical test. Results: In the 80 cases, the NARANJO scale showed better agreement with the initial clinical assessments (Kw: 0.62) than the CIOMS/RUCAM scale (Kw: 0.50) with moderate mutual agreement (Kw: 0.58). Results for 69 cases reported before the start of the study showed the same. In 11 cases reported in 2009 (after the start of the study) the CIOMS/RUCAM scale showed better agreement with the initial clinical assessments (Kw: 0.80) than the NARANJO scale (Kw: 0.70) with perfect mutual agreement (Kw: 1.0). Conclusion: The two scales showed good similarity and the same was true when their outcomes were compared with the clinical judgments provided by the reporting physicians. Both scales may be useful in pharmacovigilance and clinical practice, but the CIOMS/RUCAM scale provides more specific data. Our results also confirmed that the quality of data and documentation influence the reliability of the method. © 2011 John Wiley & Sons, Ltd.
Versporten A.,University of Antwerp |
Abilova V.,Analytical Expertise Center for Medicines |
Pyshnik G.,Ministry of Health |
Spasojevic T.,Agency for Medicines and Medical Devices of Bosnia and Herzegovina |
And 10 more authors.
The Lancet Infectious Diseases | Year: 2014
Background: There are no reliable data on antibiotic use in non-European Union (EU) southern and eastern European countries and newly independent states. We aimed to collect valid, representative, comparable data on systemic antimicrobial use in these non-EU countries of the WHO European region. Methods: Validated 2011 total national wholesale antibiotic-use data of six southern and eastern European countries and regions and seven newly independent states were analysed in accordance with the WHO anatomical therapeutic chemical (ATC)/defined daily doses (DDD) method and expressed in DDD/1000 inhabitants per day (DID). Findings: Total (outpatients and hospital care) antibiotic use ranged from 15·3 DID for Armenia to 42·3 DID for Turkey. Co-amoxiclav was mainly used in Georgia (42·9% of total antibiotic use) and Turkey (30·7%). Newly independent states used substantial quantities of ampicillin and amoxicillin (up to 55·9% of total antibiotic use in Azerbaijan). Montenegro and Serbia were the highest consumers of macrolides (15·8% and 19·5% of total antibiotic use, respectively), mainly azithromycin. Parenteral antibiotic treatment is common practice: 46·4% of total antibiotic use in Azerbaijan (mainly ampicillin; 5·3 DID) and 31·1% of total antibiotic use in Tajikistan (mainly ceftriaxone 4·7 DID). Interpretation: This study provides publicly available total antibiotic-use data for 13 non-EU countries and areas of the WHO European region. These data will raise awareness of inappropriate antibiotic use and stimulate policy makers to develop action plans. The established surveillance system provides a method to develop quality indicators of antibiotic use and to assess the effect of policy and regulatory actions. Funding: Netherlands Ministry of Health, Welfare, and Sport, and EU. © 2014 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved.
Mijac V.,University of Belgrade |
Opavski N.,University of Belgrade |
Markovic M.,University of Belgrade |
Gajic I.,University of Belgrade |
And 3 more authors.
Epidemiology and Infection | Year: 2015
We report the first study of macrolide resistance in respiratory tract pathogens in a Serbian paediatric population. It included 5293 Streptococcus pneumoniae, 4297 Streptococcus pyogenes, 2568 Moraxella catarrhalis and 1998 Haemophilus influenzae isolates derived from the respiratory tract and 110 invasive isolates from children aged up to 18 years during 2004-2009. Over the 6-year period, a significant increase (P <0 ·01) in macrolide resistance was found in both S. pneumoniae and S. pyogenes that reached 45% and 19%, respectively, in 2009. In the same period, consumption of macrolides increased continually from 2·46 to 5·8 defined daily dose/1000 inhabitants per day. The increase in macrolide resistance in S. pyogenes correlated with consumption of total macrolide and long-acting macrolides (r = 0·879, P = 0·05 and r = 0·922, P = 0·026, respectively). A similar trend was observed in pneumoccoci, although it did not reach statistical significance. The growing problem of macrolide resistance in pneumococci and S. pyogenes in Serbia requires further vigilant surveillance. © 2014 Cambridge University Press.
Milovanovic S.,Medicines and Medical Devices Agency of Serbia |
Otasevic B.,University of Belgrade |
Zecevic M.,University of Belgrade |
Zivanovic L.,University of Belgrade |
Protic A.,University of Belgrade
Journal of Pharmaceutical and Biomedical Analysis | Year: 2012
A simple, rapid, isocratic reversed-phase high-performance liquid chromatographic method was developed and validated for the analysis of moxonidine and its impurities in tablet formulations. The chromatographic separation was achieved on a Symmetry shield C18 column (250mm×4.6mm, 5μm) by employing a mobile phase consisting of methanol-potassium phosphate buffer (0.05M) mixture (15:85, v/v) (pH 3.5) at a flow rate of 1mlmin -1; detection at 255nm. Central composite design technique and response surface method were used to evaluate the effects of variations of selected factors (buffer pH value, column temperature, methanol content) in order to achieve the best isocratic separation within short analysis time (less than 10min), as well as for robustness test considerations. The method fulfilled the validation criteria: specificity, linearity, accuracy, precision, limit of detection and limit of quantitation. The method was successfully applied for the analysis of commercial moxonidine tablets. © 2011 Elsevier B.V.
Malenovic A.,University of Belgrade |
Dotsikas Y.,National and Kapodistrian University of Athens |
Maskovic M.,Medicines and Medical Devices Agency of Serbia |
Jancic-Stojanovic B.,University of Belgrade |
And 2 more authors.
Microchemical Journal | Year: 2011
In the current paper the application of multiobjective optimization (MOOP) technique, via Derringer's desirability function, to a microemulsion liquid chromatographic (MELC) method is described. Chromatographic separation of perindopril tert-butylamine and its four impurities was selected as the case study. Central composite design (CCD) with fractional factorial design, ±. 0.5 α star design and four replications in central point was applied for a response surface study, in order to examine in depth the effects of the most important factors. As factors that influence the system mostly (i) content of ethyl acetate and (ii) butyl acetate in composite internal phase, (iii) content of sodium dodecyl sulfate (surfactant) and (iv) n-butanol (co-surfactant), as well as (v) pH of the mobile phase were selected. Retention factor of (a) perindoprilat and (b) impurity Y 31 and (c) resolution factor for impurities Y 32 and 33 were chosen for simultaneous optimization. By adjustment of the importance coefficients and weights, according to defined objectives, the optimal mobile phase composition was predicted to be: 0.24% w/v butyl acetate, 0.3% w/v ethyl acetate, 2% w/v SDS, 7.75% w/v n-butanol and pH of the mobile phase 3.7. The sensitivity analysis of desirability function for these optimal conditions was conducted for the first time in LC separations, by applying a sensitivity procedure. The performed sensitivity analysis confirmed that the higher overall desirability does not necessarily mean a better solution. The accuracy of prediction might be affected if the optimal levels of input variables, achieved from several design points, end up with equal settings and different corresponding overall desirability. In our study this was not the issue, which confirmed the adequacy of predicted optimum. © 2011 Elsevier B.V.
Petronijevic M.,Medicines and Medical Devices Agency of Serbia |
Ilic K.,University of Belgrade
Journal of Clinical Pharmacology | Year: 2013
Patient gender and age are considered to be the risk factors for developing drug-induced liver injury (DILI). The aim of this study was to analyze gender and age differences in reporting of drug-induced hepatic failure (HF) to the VigiBase. VigiBasewas screened for the HF reports submitted from 2000 to 2009. The information retrieved referred to the suspected drug, age, gender, and a reporting country. Variables were examined by using descriptive statistics and the binomial test. During the 10-year period there were in total 6 370 HF reports from 38 countries. After the exclusion of cases with missing gender data (379 cases), females counted for 54.03%. The largest portion of HF cases referred to age <55 (42.57%) with female predominance (56.81%), whereas age 55 (32.57%) showed almost even gender distribution. Overall, there were 941 different drugs or their combinations reported. Females significantly predominated in HF cases associated with analgesics, antiepileptics, antiinflamatory and antirheumatic drugs, psychoanaleptics, antibacterials for systemic use, and antidiabetic drugs. Males were significantly overrepresented in HF cases associated with antivirals for systemic use. Differences between genders and/or age groups in the reporting of drug-induced HF depend on drug and/or drug class but may be influenced by multiple factors. © The Author(s) 2013.