Zoran Todorovic
@studiesinenglish.med.bg.ac.rs
Department of Pharmacology, Clinical Pharmacology and Toxicology
University of Belgrade Faculty of Medicine
Full Professor of Pharmacology, Clinical Pharmacology, and Toxicology (since 2008). Postdoc at the William Harvey Research Institute, London, UK (1999-2001). Visiting Scientist at the Dept. of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden (2016). Visiting Professor, Icahn School of Medicine at Mount Sinai, NYC (2017). Clinical Pharmacology Residency Program Chairman, UBFM (since 2021). Former Chairmen of Pharmacology, UBFM. Clinical pharmacologist at the 3rd level hospital (since 2011). Clinical trial experience: > 10 phase III/IV studies (role: clinical pharmacologist). More than 300 publications (> 70 CC/SCI in extenso publications) and more than 700 citations in CC/SCI journals. Council of Europe Expert in professional ethics and higher education reform, and member of the Serbian Royal Medical Board.
EDUCATION
MD Faculty of Medicine, University of Belgrade, 1989
MSc in Medicine (Pharmacology) Faculty of Medicine, University of Belgrade, 1993
PhD in Medicine (Pharmacology) Faculty of Medicine, University of Belgrade, 1996
Clinical Pharmacology (specialization) Faculty of Medicine, University of Belgrade, 1996
Clinical Pharmacology - Pharmacotherapy (sub-specialization) Faculty of Medicine, University of Belgrade, 2008
RESEARCH, TEACHING, or OTHER INTERESTS
Pharmacology (medical), Pharmacology
Scopus Publications
Scopus Publications
Vanja Kopilaš, Khrystyna Nasadiuk, Lucia Martinelli, Lenka Lhotska, Zoran Todorovic, Matjaz Vidmar, Helena Machado, Anna Lydia Svalastog, and Srećko Gajović
JMIR Publications Inc.
Background As the SARS-CoV-2 virus created a global pandemic and rapidly became an imminent threat to the health and lives of people worldwide, the need for a vaccine and its quick distribution among the population was evident. Due to the urgency, and on the back of international collaboration, vaccines were developed rapidly. However, vaccination rollouts showed different success rates in different countries and some also led to increased vaccine hesitancy. Objective The aim of this study was to identify the role of information sharing and context sensitivity in various vaccination programs throughout the initial COVID-19 vaccination rollout in different countries. Moreover, we aimed to identify factors in national vaccination programs related to COVID-19 vaccine hesitancy, safety, and effectiveness. Toward this end, multidisciplinary and multinational opinions from members of the Navigating Knowledge Landscape (NKL) network were analyzed. Methods From May to July 2021, 25 completed questionnaires from 27 NKL network members were collected. These contributors were from 17 different countries. The responses reflected the contributors’ subjective viewpoints on the status and details of the COVID-19 vaccination rollout in their countries. Contributors were asked to identify strengths, weaknesses, opportunities, and threats (ie, SWOT) of the respective vaccination programs. The responses were analyzed using reflexive thematic analysis, followed by frequency analysis of identified themes according to the represented countries. Results The perspectives of NKL network members showed a link between organizational elements of the vaccination rollout and the accompanying societal response, both of which were related to strengths and weaknesses of the process. External sociocultural variables, improved public communication around vaccination-related issues, ethical controversies, and the spread of disinformation were the dominant themes related to opportunities and challenges. In the SWOT 2×2 matrix, Availability and Barriers emerged as internal categories, whereas Transparent communication and promotion and Societal divide emerged as key external categories. Conclusions Inventory of themes and categories inspired by elements of the SWOT framework provides an informative multidisciplinary perspective for effective implementation of public health strategies in the battle against COVID-19 or any future pandemics of a similar nature.
Maja Stojković, Zoran Todorović, Dragana Protic, Strahinja Stevanovic, Dragana Medić, Claude L. Charvet, Djordje S. Marjanović, Jelena Nedeljković Trailović, and Saša M. Trailović
Frontiers Media SA
The control of parasitic nematode infections relies mostly on anthelmintics. The potential pharmacotherapeutic application of phytochemicals, in order to overcome parasite resistance and enhance the effect of existing drugs, is becoming increasingly important. The antinematodal effects of carveol was tested on the free-living nematode Caenorhabditis elegans and the neuromuscular preparation of the parasitic nematode Ascaris suum. Carveol caused spastic paralysis in C. elegans. In A. suum carveol potentiated contractions induced by acetylcholine (ACh) and this effect was confirmed with two-electrode voltage-clamp electrophysiology on the A. suum nicotinic ACh receptor expressed in Xenopus oocytes. However, potentiating effect of carveol on ACh-induced contractions was partially sensitive to atropine, indicates a dominant nicotine effect but also the involvement of some muscarinic structures. The effects of carveol on the neuromuscular system of mammals are also specific. In micromolar concentrations, carveol acts as a non-competitive ACh antagonist on ileum contractions. Unlike atropine, it does not change the EC50 of ACh, but reduces the amplitude of contractions. Carveol caused an increase in Electrical Field Stimulation-evoked contractions of the isolated rat diaphragm, but at higher concentrations it caused an inhibition. Also, carveol neutralized the mecamylamine-induced tetanic fade, indicating a possibly different pre- and post-synaptic action at the neuromuscular junction.
Milica Brajkovic, Miodrag Vukcevic, Sofija Nikolic, Marija Dukic, Marija Brankovic, Ana Sekulic, Viseslav Popadic, Mihailo Stjepanovic, Aleksandra Radojevic, Ljiljana Markovic-Denic,et al.
MDPI AG
Introduction: Risk stratification in patients with COVID-19 is a challenging task. Early warning scores (EWSs) are commonly used tools in the initial assessment of critical patients. However, their utility in patients with COVID-19 is still undetermined. Aim: This study aimed to discover the most valuable predictive model among existing EWSs for ICU admissions and mortality in COVID-19 patients. Materials and methods: This was a single-center cohort study that included 3608 COVID-19 patients admitted to the University Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia, between 23 June 2020, and 14 April 2021. Various demographic, laboratory, and clinical data were collected to calculate several EWSs and determine their efficacy. For all 3608 patients, five EWSs were calculated (MEWS, NEWS, NEWS2, REMS, and qSOFA). Model discrimination performance was tested using sensitivity, specificity, and positive and negative predictive values. C statistic, representing the area under the receiver operating characteristic (ROC) curve, was used for the overall assessment of the predictive model. Results: Among the evaluated prediction scores for 3068 patients with COVID-19, REMS demonstrated the highest diagnostic performance with the sensitivity, PPV, specificity, and NPV of 72.1%, 20.6%, 74.9%, and 96.8%, respectively. In the multivariate logistic regression analysis, aside from REMS, age (p < 0.001), higher CT score (p < 0.001), higher values of urea (p < 0.001), and the presence of bacterial superinfection (p < 0.001) were significant predictors of mortality. Conclusions: Among all evaluated EWSs to predict mortality and ICU admission in COVID-19 patients, the REMS score demonstrated the highest efficacy.
I. Gajic, M. Jovicevic, V. Popadic, A. Trudic, J. Kabic, D. Kekic, A. Ilic, S. Klasnja, M. Hadnadjev, D.J. Popadic,et al.
Elsevier BV
Marija Dukić, Tijana Radonjić, Igor Jovanović, Marija Zdravković, Zoran Todorović, Nemanja Kraišnik, Bojana Aranđelović, Olga Mandić, Višeslav Popadić, Novica Nikolić,et al.
MDPI AG
Alcoholic liver disease (ALD) is a consequence of excessive alcohol use. According to many studies, alcohol represents a significant socioeconomic and health risk factor in today’s population. According to data from the World Health Organization, there are about 75 million people who have alcohol disorders, and it is well known that its use leads to serious health problems. ALD is a multimodality spectrum that includes alcoholic fatty liver disease (AFL) and alcoholic steatohepatitis (ASH), consequently leading to liver fibrosis and cirrhosis. In addition, the rapid progression of alcoholic liver disease can lead to alcoholic hepatitis (AH). Alcohol metabolism produces toxic metabolites that lead to tissue and organ damage through an inflammatory cascade that includes numerous cytokines, chemokines, and reactive oxygen species (ROS). In the process of inflammation, mediators are cells of the immune system, but also resident cells of the liver, such as hepatocytes, hepatic stellate cells, and Kupffer cells. These cells are activated by exogenous and endogenous antigens, which are called pathogen and damage-associated molecular patterns (PAMPs, DAMPs). Both are recognized by Toll-like receptors (TLRs), which activation triggers the inflammatory pathways. It has been proven that intestinal dysbiosis and disturbed integrity of the intestinal barrier perform a role in the promotion of inflammatory liver damage. These phenomena are also found in chronic excessive use of alcohol. The intestinal microbiota has an important role in maintaining the homeostasis of the organism, and its role in the treatment of ALD has been widely investigated. Prebiotics, probiotics, postbiotics, and symbiotics represent therapeutic interventions that can have a significant effect on the prevention and treatment of ALD.
Tomislav Pejčić, Zoran Todorović, Siniša Đurašević, and Lazar Popović
MDPI AG
Prostate cancer (PCa) is today the second most common cancer in the world, with almost 400,000 deaths annually. Multiple factors are involved in the etiology of PCa, such as older age, genetic mutations, ethnicity, diet, or inflammation. Modern treatment of PCa involves radical surgical treatment or radiation therapy in the stages when the tumor is limited to the prostate. When metastases develop, the standard procedure is androgen deprivation therapy, which aims to reduce the level of circulating testosterone, which is achieved by surgical or medical castration. However, when the level of testosterone decreases to the castration level, the tumor cells adapt to the new conditions through different mechanisms, which enable their unhindered growth and survival, despite the therapy. New knowledge about the biology of the so-called of castration-resistant PCa and the way it adapts to therapy will enable the development of new drugs, whose goal is to prolong the survival of patients with this stage of the disease, which will be discussed in this review.
Tijana Radonjić, Marija Dukić, Igor Jovanović, Marija Zdravković, Olga Mandić, Višeslav Popadić, Maja Popović, Novica Nikolić, Slobodan Klašnja, Anica Divac,et al.
MDPI AG
The proportion of elderly people in the world population is constantly increasing. With age, the risk of numerous chronic diseases and their complications also rises. Research on the subject of cellular senescence date back to the middle of the last century, and today we know that senescent cells have different morphology, metabolism, phenotypes and many other characteristics. Their main feature is the development of senescence-associated secretory phenotype (SASP), whose pro-inflammatory components affect tissues and organs, and increases the possibility of age-related diseases. The liver is the main metabolic organ of our body, and the results of previous research indicate that its regenerative capacity is greater and that it ages more slowly compared to other organs. With age, liver cells change under the influence of various stressors and the risk of developing chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) and hepatocellular carcinoma (HCC) increases. It has been proven that these diseases progress faster in the elderly population and in some cases lead to end-stage liver disease that requires transplantation. The treatment of elderly people with chronic liver diseases is a challenge and requires an individual approach as well as new research that will reveal other safe and effective therapeutic modalities.
Slobodan Klasnja, Andrea Manojlovic, Viseslav Popadic, Tatjana Ivankovic, Nebojsa Ninkovic, Nina Rajovic, Maja Popovic, Novica Nikolic, Milica Brajkovic, Aleksandra Radojevic,et al.
MDPI AG
Introduction: Thrombotic complications, such as pulmonary embolism, are common in COVID-19 patients. Point-of-care ultrasound is a highly recommended tool for orientation in critically ill patients with suspected or confirmed complications. Methods: An observational study was conducted on 32 consecutive patients with confirmed pulmonary embolism and COVID-19 infection treated in the Intensive Care Unit of the University Hospital Medical Center “Bežanijska kosa”, Belgrade, Serbia, between April 2021 and March 2022. Predictors of the need for oxygen support were determined, while point-of-care echocardiographic parameters and various anamnestic, laboratory, and clinically significant parameters were correlated with the Pulmonary Embolism Severity Index (PESI) score. Results: More than two-thirds of patients in our study had PE symptoms present at hospital admission (68.8%). The majority of patients had segmental pulmonary embolism (48.4%), with high to very high PESI score values in 31.3% of patients. Pneumonia was present in 68.8% of the study population. The PESI score was negatively correlated with diastolic blood pressure and SaO2 at the time of PE diagnosis, LV ejection fraction, and PVAT. A positive correlation was found between the PESI score, maximum CRP, and D-dimer at the time of PTE diagnosis. A larger right ventricular diameter was associated with a greater need for oxygen support. Conclusion: Point-of-care echocardiography is a valuable tool for the risk assessment of COVID-19 patients with pulmonary embolism. Right ventricular size stood out as a significant marker of disease severity.
Tijana Radonjić, Ognjen Milićević, Igor Jovanović, Marija Zdravković, Marija Dukić, Olga Milorad Mandić, Jelica Bjekić-Macut, Olivera Borko Marković, Zoran Todorović, Milica Brajković,et al.
MDPI AG
Background: This study aimed to calculate the frequency of elevated liver enzymes in hospitalized patients with coronavirus disease 2019 (COVID-19) infection and to test if liver enzyme biochemistry levels on admission could predict the computed tomography (CT) scan severity score of bilateral interstitial pneumonia. Methods: This single-center study comprised of 323 patients including their demographic data, laboratory analyses, and radiological findings. All the information was taken from electronic health records, followed by statistical analysis. Results: Out of 323 patients, 115 of them (35.60%) had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) over 40 U/L on admission. AST was the best predictor of CT scan severity score of bilateral interstitial pneumonia (R2 = 0.313, Adjusted R2 = 0.299). CT scan severity score in the peak of the infection could be predicted with the value of AST, neutrophils, platelets, and monocytes count (R2 = 0.535, Adjusted R2 = 0.495). Conclusion: AST, neutrophils, platelets, and monocytes count on admission can account for almost half (49.5%) of the variability in CT scan severity score at peak of the disease, predicting the extensiveness of interstitial pneumonia related to COVID-19 infection. Liver enzymes should be closely monitored in order to stratify COVID-19 patients with a higher risk of developing severe forms of the disease and to plan the beforehand step-up treatment.
Marija Zdravkovic, Viseslav Popadic, Slobodan Klasnja, Natasa Milic, Nina Rajovic, Anica Divac, Andrea Manojlovic, Novica Nikolic, Filip Lukic, Esma Rasiti,et al.
Frontiers Media SA
Introduction: The present study aimed to establish the role of lipid abnormalities and inflammatory markers for developing cardiovascular risk, as well as to address the importance of obesity as a common comorbidity in patients with obstructive sleep apnea (OSA).Methods: The study was conducted as a prospective cohort study including 120 patients with newly diagnosed OSA between 2019 and 2020, at University Clinical Hospital Center “Bezanijska kosa”, Belgrade, Serbia. The diagnosis was established by polysomnography. In all patients, sociodemographic data, respiratory, lipid, and inflammatory parameters were collected and complete echocardiographic study and 24-h blood pressure monitoring were performed.Results: The mean patient age was 55.7 ± 13.8 years. Study population was mostly male (70.0%) and obese (56.7%). At least 30 apneas or hypopneas per hour were present in 39.0% of patients. A strong positive correlation was found between OSA severity and BMI (r = 0.562, p &lt; 0.001), both associated with lipid, inflammatory and respiratory parameters, and cardiovascular profile of patients with OSA (p &lt; 0.05 for all). Echocardiographic study and 24-h blood pressure monitoring parameters were in turn correlated with lipid and inflammatory markers (p &lt; 0.05 for all).Conclusion: The results of this study support the important role of dyslipidemia and inflammation, as well as coexistence of obesity in the pathogenesis of numerous conditions linked with an increased risk of cardiovascular morbidity and mortality in patients with OSA.
Viseslav Popadic, Milica Brajkovic, Slobodan Klasnja, Natasa Milic, Nina Rajovic, Danica Popovic Lisulov, Anica Divac, Tatjana Ivankovic, Andrea Manojlovic, Novica Nikolic,et al.
Frontiers Media SA
Introduction: Obstructive sleep apnea (OSA) is a serious condition linked with various metabolic disorders and associated with increased all-cause and cardiovascular mortality. Although the potential mechanisms of pathophysiological processes related to OSA are relatively well known, the data regarding the correlation between obstructive sleep apnea, dyslipidemia, and systemic inflammation are still inconclusive.Methods: The study was conducted as a retrospective cohort study including 328 patients with newly diagnosed obstructive sleep apnea during the period between April 2018, and May 2020, in University Clinical Hospital Center “Bezanijska kosa”, Belgrade, Serbia. Polysomnography was performed in all patients according to the protocol. Numerous demographic, antropometric, laboratory, and clinical data were correlated to Apnea-Hypopnea Index (AHI) as a dependent variable, with a particular review on the relation between lipid abnormalities, inflammatory parameters, and obstructive sleep apnea severity. Multivariate logistic regression model was used to assess predictors of severe OSA (AHI ≥30 per hour).Results: A total of 328 patients were included in the study. The mean age of the patients was 54.0 ± 12.5 years and more than two-thirds were male (68.8%). The majority of the patients had an AHI of at least 30 events per hour. Patients with severe OSA were more frequently male, obese, hypertensive and hyperlipidemic, and had increased neck circumference (both male and female patients). One hundred and thirty-two patients had metabolic syndrome. Patients with severe OSA more frequently had metabolic syndrome and significantly higher levels of glucose, creatinine, uric acid, AST, ALT, CK, microalbumine/creatinine ratio, triglyceride, total cholesterol, HDL, total cholеsterol to HDL‐C ratio, CRP, and ESR. In the multivariate linear regression model with AHI (≥30 per hour) as a dependent variable, of demographic and clinical data, triglycerides ≥1.7 mmol/L and CRP &gt;5 mg/L were significantly associated with AHI≥30 per hour.Conclusion: The present study on 328 patients with newly diagnosed obstructive sleep apnea revealed significant relation of lipid abnormalities, inflammatory markers, and other clinically important data with obstructive sleep apnea severity. These results can lead to a better understanding of the underlying pathophysiological processes and open the door to a new world of potentially useful therapeutic modalities.
Aleksandra Milovančev, Milovan Petrović, Višeslav Popadić, Tatjana Miljković, Slobodan Klašnja, Predrag Djuran, Aleksandra Ilić, Mila Kovačević, Anastazija Stojšić Milosavljević, Milica Brajković,et al.
MDPI AG
Acute coronary syndrome (ACS) in patients with COVID-19 is triggered by various mechanisms and can significantly affect the patient’s further treatment and prognosis. The study aimed to investigate the characteristics, major complications, and predictors of mortality in COVID-19 patients with ACS. All consecutive patients hospitalized from 5 July 2020 to 5 May 2021 for ACS with confirmed SARS-Co-2 were prospectively enrolled and tracked for mortality until 5 June 2021. Data from the electronic records for age and diagnosis, matched non-COVID-19 and COVID-19 ACS group, were extracted and compared. Overall, 83 COVID-19 ACS patients, when compared to 166 non-COVID ACS patients, had significantly more prevalent comorbidities, unfavorable clinical characteristics on admission (acute heart failure 21.7% vs. 6.6%, p < 0.01) and higher rates of major complications, 33.7% vs. 16.8%, p < 0.01, and intrahospital 30-day mortality, 6.7% vs. 26.5%, p < 0.01. The strongest predictors of mortality were aortic regurgitation, HR 9.98, 95% CI 1.88; 52.98, p < 0.01, serum creatinine levels, HR 1.03, 95% CI 1.01; 1.04, p < 0.01, and respiratory failure therapy, HR 13.05, 95% CI 3.62; 47.01, p < 0.01. Concomitant ACS and COVID-19 is linked to underlying comorbidities, adverse presenting features, and poor outcomes. Urgent strategies are needed to improve the outcomes of these patients.
Zoran Todorović, Sonja Vučković, and Nevena Divac
Centre for Evaluation in Education and Science (CEON/CEES)
The School of Medicine at the University of Belgrade celebrates its centennial anniversary. The Institute of Pharmacology and Toxicology, founded in 1924, played an important role in the School's life and development. It is not just about the scientific achievements, but above all, the exceptional personalities of our predecessors. If they spent their academic careers somewhere else, they would certainly have been among the most respected researchers in the world. The courage to stay in the turbulent Balkans and maintain successful communication with colleagues from abroad deserves respect and admiration. One German and one Serb, professors Arnold Holste and Radivoje Pavlović, the latter with severely impaired sight, did an extraordinary job. They established a distinct pharmacological school, equipped research labs and provided their students with generous support despite the adverse circumstances (two world wars and persistent economic crisis, above all). Their younger associates, future professors Dimitrijević and Bogdanović, followed in the footsteps of their predecessors. Their example and sacrifice oblige us to keep pace with the extremely rapid development of pharmacology in the world.
Siniša Đurašević, Aleksandra Ružičić, Iva Lakić, Tomislav Tosti, Saša Đurović, Sofija Glumac, Snežana Pejić, Ana Todorović, Dunja Drakulić, Sanja Stanković,et al.
MDPI AG
A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality in faecal-induced peritonitis (FIP) in rats. We postulated that the same mechanism that is responsible for the otherwise strong anti-inflammatory effects of meldonium could be the culprit of the increased mortality. In the present study, we applied the LPS-induced model of sepsis to explore the presence of any differences from and/or similarities to the FIP model. When it comes to energy production, despite some shared similarities, it is evident that LPS and FIP models of sepsis differ greatly. A different profile of sympathoadrenal activation may account for this observation, as it was lacking in the FIP model, whereas in the LPS model it was strong enough to overcome the effects of meldonium. Therefore, choosing the appropriate model of sepsis induction is of great importance, especially if energy homeostasis is the main focus of the study. Even when differences in the experimental design of the two models are acknowledged, the role of different patterns of energy production cannot be excluded. On that account, our results draw attention to the importance of uninterrupted energy production in sepsis but also call for much-needed revisions of the current recommendations for its treatment.
Jaroslav Nádeníček, Eva Voslářová, Veronika Vojtkovská, Zoran Todorović, and Vladimír Večerek
University of Veterinary and Pharmaceutical Sciences
The aim of the study was to assess the impact of social isolation of rats in the post-weaning period using behavioural tests aimed at assessing cognitive function, anxiety, and depressive-like behaviours. The monitoring was performed in male Wistar rats which were housed after weaning either individually (n = 8) or in pairs (n = 8) for 33 days. In the open field, rats kept in isolation reared less often (P < 0.05) than pair-housed rats. In the elevated plus-maze test, pair-housed rats entered the open arm more frequently (P = 0.002) and stayed in the closed arm less often (P = 0.019) compared to rats housed in isolation. In the forced swim test, climbing was seen more frequently (P = 0.016) in pair-housed rats whereas immobility was more common (P = 0.006) in rats housed individually. In the novel object recognition test, the pair-housed rats preferred (P = 0.014) the novel object whereas there was no difference (P = 0.107) in time spent by exploring familiar and novel objects in rats housed in isolation. Furthermore, juvenile rats housed for 33 days in isolation showed higher (P = 0.003) body weight gain during the monitored period than rats housed for the same period in pairs. Our findings are important not only in terms of assessing the impact of rat housing on their mental and physical development but also in terms of the accurate interpretation of the results of other experiments where the rat is used as a model organism.
Snezana Mugosa, Ivan Radosavljevic, Majda Sahman, Natasa Djordjevic, and Zoran Todorovic
Walter de Gruyter GmbH
Abstract This study aimed to investigate the possible influence of genetic and non-genetic factors on the incidence of clopidogrel adverse drug reactions (ADRs) in cardiology patients, including the most important CYP2C19 alleles, namely *2 and *17, as well as compliance, dose, drug interactions, and clinical factors. A total of 102 clopidogrel-treated adult Caucasian patients hospitalized at the Cardiology Department of the Clinical Center of Montenegro were enrolled in the study. Data on clinical outcomes of interest were obtained by intensive monitoring ADRs during hospitalization and one year after hospital discharge. Genotyping for CYP2C19*2 and *17 was conducted using the real-time polymerase chain reaction method. ADRs were characterized using the Rawlins and Thompson classification and the World Health Organization criteria. Causality was assessed using the Naranjo probability scale. ADRs to clopidogrel were observed in 9 of 102 patients (8.8%). The observed frequencies of CYP2C19*2 and *17 were 13.2 and 25.5%, respectively. Our study, which is the first to report the frequency of CYP2C19 polymorphism in the Montenegrin population, as well as to link the pharmacovigilance of clopidogrel with CYP2C19 gene variability, shows that the incidence of ADRs of clopidogrel in cardiac patients is high and depends on CYP2C19 polymorphisms, comedication/drug interactions, and gastrointestinal comorbidity.
Siniša Đurašević, Maja Stojković, Jelena Sopta, Slađan Pavlović, Slavica Borković-Mitić, Anđelija Ivanović, Nebojša Jasnić, Tomislav Tosti, Saša Đurović, Jelena Đorđević,et al.
Springer Science and Business Media LLC
AbstractAcute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, we investigated the effects of a 4-week meldonium pre-treatment (300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that meldonium ameliorates I/R-induced liver inflammation and injury, as confirmed by liver histology, and by attenuation of serum alanine- and aspartate aminotransferase activity, serum and liver high mobility group box 1 protein expression, and liver expression of Bax/Bcl2, haptoglobin, and the phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells. Through the increased hepatic activation of the nuclear factor erythroid 2-related factor 2, meldonium improves the antioxidative defence in the liver of animals subjected to I/R, as proved by an increase in serum and liver ascorbic/dehydroascorbic acid ratio, hepatic haem oxygenase 1 expression, glutathione and free thiol groups content, and hepatic copper-zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Based on our results, it can be concluded that meldonium represent a protective agent against I/R-induced liver injury, with a clinical significance in surgical procedures.
Siniša Đurašević, Aleksandra Ružičić, Iva Lakić, Tomislav Tosti, Saša Đurović, Sofija Glumac, Slađan Pavlović, Slavica Borković-Mitić, Ilijana Grigorov, Sanja Stanković,et al.
MDPI AG
Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches.
Siniša Đurašević, Snežana Pejić, Ilijana Grigorov, Gorana Nikolić, Dragana Mitić-Ćulafić, Milan Dragićević, Jelena Đorđević, Nevena Todorović Vukotić, Neda Đorđević, Ana Todorović,et al.
MDPI AG
Thioacetamide (TAA) is widely used to study liver toxicity accompanied by oxidative stress, inflammation, cell necrosis, fibrosis, cholestasis, and hepatocellular carcinoma. As an efficient free radical’s scavenger, C60 fullerene is considered a potential liver-protective agent in chemically-induced liver injury. In the present work, we examined the hepatoprotective effects of two C60 doses dissolved in virgin olive oil against TAA-induced hepatotoxicity in rats. We showed that TAA-induced increase in liver oxidative stress, judged by the changes in the activities of SOD, CAT, GPx, GR, GST, the content of GSH and 4-HNE, and expression of HO-1, MnSOD, and CuZnSOD, was more effectively ameliorated with a lower C60 dose. Improvement in liver antioxidative status caused by C60 was accompanied by a decrease in liver HMGB1 expression and an increase in nuclear Nrf2/NF-κB p65 ratio, suggesting a reduction in inflammation, necrosis and fibrosis. These results were in accordance with liver histology analysis, liver comet assay, and changes in serum levels of ALT, AST, and AP. The changes observed in gut microbiome support detrimental effects of TAA and hepatoprotective effects of low C60 dose. Less protective effects of a higher C60 dose could be a consequence of its enhanced aggregation and related pro-oxidant role.
Zoran Todorović, Siniša Đurašević, Maja Stojković, Ilijana Grigorov, Slađan Pavlović, Nebojša Jasnić, Tomislav Tosti, Jelica Bjekić Macut, Christoph Thiemermann, and Jelena Đorđević
MDPI AG
Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.
Nina Đukanović, Slobodan Obradović, Marija Zdravković, Siniša Đurašević, Maja Stojković, Tomislav Tosti, Nebojša Jasnić, Jelena Đorđević, and Zoran Todorović
MDPI AG
Lipids play an essential role in platelet functions. It is known that polyunsaturated fatty acids play a role in increasing platelet reactivity and that the prothrombotic phenotype plays a crucial role in the occurrence of major adverse cardiovascular events. The ongoing increase in cardiovascular diseases’ incidence emphasizes the importance of research linking lipids and platelet function. In particular, the rebound phenomenon that accompanies discontinuation of clopidogrel in patients receiving dual antiplatelet therapy has been associated with changes in the lipid profile. Our many years of research underline the importance of reduced HDL values for the risk of such a rebound effect and the occurrence of thromboembolic events. Lipids are otherwise a heterogeneous group of molecules, and their signaling molecules are not deposited but formed “on-demand” in the cell. On the other hand, exosomes transmit lipid signals between cells, and the profile of such changes can be monitored by lipidomics. Changes in the lipid profile are organ-specific and may indicate new drug action targets.
Lucia Martinelli, Vanja Kopilaš, Matjaž Vidmar, Ciara Heavin, Helena Machado, Zoran Todorović, Norbert Buzas, Mirjam Pot, Barbara Prainsack, and Srećko Gajović
Frontiers Media SA
Wearing face masks is recommended as part of personal protective equipment and as a public health measure to prevent the spread of coronavirus disease 2019 (COVID-19) pandemic. Their use, however, is deeply connected to social and cultural practices and has acquired a variety of personal and social meanings. This article aims to identify the diversity of sociocultural, ethical, and political meanings attributed to face masks, how they might impact public health policies, and how they should be considered in health communication. In May 2020, we involved 29 experts of an interdisciplinary research network on health and society to provide their testimonies on the use of face masks in 20 European and 2 Asian countries (China and South Korea). They reflected on regulations in the corresponding jurisdictions as well as the personal and social aspects of face mask wearing. We analyzed those testimonies thematically, employing the method of qualitative descriptive analysis. The analysis framed the four dimensions of the societal and personal practices of wearing (or not wearing) face masks: individual perceptions of infection risk, personal interpretations of responsibility and solidarity, cultural traditions and religious imprinting, and the need of expressing self-identity. Our study points to the importance for an in-depth understanding of the cultural and sociopolitical considerations around the personal and social meaning of mask wearing in different contexts as a necessary prerequisite for the assessment of the effectiveness of face masks as a public health measure. Improving the personal and collective understanding of citizens' behaviors and attitudes appears essential for designing more effective health communications about COVID-19 pandemic or other global crises in the future. To wear a face mask or not to wear a face mask? Nowadays, this question has been analogous to the famous line from Shakespeare's Hamlet: “To be or not to be, that is the question.” This is a bit allegorical, but certainly not far from the current circumstances where a deadly virus is spreading amongst us... Vanja Kopilaš, Croatia.
Marija Zdravkovic, Viseslav Popadic, Slobodan Klasnja, Vedrana Pavlovic, Aleksandra Aleksic, Marija Milenkovic, Bogdan Crnokrak, Bela Balint, Milena Todorovic-Balint, Davor Mrda,et al.
Hindawi Limited
Introduction. Risk stratification is an important aspect of COVID-19 management, especially in patients admitted to ICU as it can provide more useful consumption of health resources, as well as prioritize critical care services in situations of overwhelming number of patients. Materials and Methods. A multivariable predictive model for mortality was developed using data solely from a derivation cohort of 160 COVID-19 patients with moderate to severe ARDS admitted to ICU. The regression coefficients from the final multivariate model of the derivation study were used to assign points for the risk model, consisted of all significant variables from the multivariate analysis and age as a known risk factor for COVID-19 patient mortality. The newly developed AIDA score was arrived at by assigning 5 points for serum albumin and 1 point for IL-6, D dimer, and age. The score was further validated on a cohort of 304 patients admitted to ICU due to the severe form of COVID-19. Results. The study population included 160 COVID-19 patients admitted to ICU in the derivation and 304 in the validation cohort. The mean patient age was 66.7 years (range, 20–93 years), with 68.1% men and 31.9% women. Most patients (76.8%) had comorbidities with hypertension (67.7%), diabetes (31.7), and coronary artery disease (19.3) as the most frequent. A total of 316 patients (68.3%) were treated with mechanical ventilation. Ninety-six (60.0%) in the derivation cohort and 221 (72.7%) patients in the validation cohort had a lethal outcome. The population was divided into the following risk categories for mortality based on the risk model score: low risk (score 0–1) and at-risk ( score > 1 ). In addition, patients were considered at high risk with a risk score > 2 . By applying the risk model to the validation cohort ( n = 304 ), the positive predictive value was 78.8% (95% CI 75.5% to 81.8%); the negative predictive value was 46.6% (95% CI 37.3% to 56.2%); the sensitivity was 82.4% (95% CI 76.7% to 87.1%), and the specificity was 41.0% (95% CI 30.3% to 52.3%). The C statistic was 0.863 (95% CI 0.805-0.921) and 0.665 (95% CI 0.598-0.732) in the derivation and validation cohorts, respectively, indicating a high discriminative value of the proposed score. Conclusion. In the present study, AIDA score showed a valuable significance in estimating the mortality risk in patients with the severe form of COVID-19 disease at admission to ICU. Further external validation on a larger group of patients is needed to provide more insights into the utility of this score in everyday practice.
Viseslav Popadic, Slobodan Klasnja, Natasa Milic, Nina Rajovic, Aleksandra Aleksic, Marija Milenkovic, Bogdan Crnokrak, Bela Balint, Milena Todorovic-Balint, Davor Mrda,et al.
Hindawi Limited
Introduction. Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. Methods. We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. Results. The mean patient age was 65.6 years (range, 29–92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6–18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12–28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. Conclusion. In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.
Snezana Mugosa, Zoran Todorovic, Jelena Cukic, Majda Sahman-Zaimovic, and Natasa Djordjevic
Walter de Gruyter GmbH
Abstract Clopidogrel is an antiplatelet drug that displays significant interindividual variability in treatment response. Its bioavailability depends on the function of P-glycoprotein (P-gp), which is coded by a highly polymorphic ABCB1 gene. Thus, the aim of this study was to investigate the effect of ABCB1 genetic polymorphism on clopidogrel efficacy and safety and to determine the frequency distribution of its most common single nucleotide polymorphisms (SNPs) in 106 Montenegrin cardiology patients. Clopidogrel efficacy and safety were followed up during 1 year after hospitalization, with the lack of efficacy and adverse drug reactions observed in 11 (10.4%) and 8 patients (7.5%), respectively. Genotyping for ABCB1 SNPs rs1128503 (1236C > T), rs2032582 (2677G > A/T), and rs1045642 (3435C > T) was performed by the real-time PCR method, and the variant alleles were detected with the frequencies of 42.9, 44.8, and 52.8%, respectively. No significant association was observed between any of the examined genotypes and clopidogrel efficacy (p = 0.253) or safety (p = 0.424). Due to small sample size, co-treatment with other drugs, and other genetic factors not taken into account, we believe the absence of correlation between ABCB1 genotypes and indicators of clopidogrel efficacy and safety in this study should be apprehended conditionally, and that larger and better-controlled studies are warranted.