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Zlatkovic J.,Vinca Institute of Nuclear Sciences | Todorovic N.,Vinca Institute of Nuclear Sciences | Tomanovic N.,University of Belgrade | Boskovic M.,Vinca 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.

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.

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.

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.

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.

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