Publications by authors named "Marija Jovanovic"

23 Publications

  • Page 1 of 1

Sagittal suture morphological variation in human archaeological populations.

Anat Rec (Hoboken) 2021 Mar 26. Epub 2021 Mar 26.

Department of Evolutionary Anthropology, University of Vienna, Vienna, Austria.

Cranial sutures join the many bones of the skull. They are therefore points of weakness and consequently subjected to the many mechanical stresses affecting the cranium. However, the way in which this impacts their morphological complexity remains unclear. We examine the intrinsic and extrinsic mechanisms of human sagittal sutures by quantifying the morphology from 107 individuals from archaeological populations spanning the Mesolithic to Middle ages, using standardized two-dimensional photographs. Results show that the most important factor determining sutural complexity appears to be the position along the cranial vault from the junction with the coronal suture at its anterior-most point to the junction with the lambdoid suture at its posterior-most point. Conversely, factors such as age and lifeways show few trends in complexity, the most significant of which is a lower complexity in the sutures of Mesolithic individuals who consumed a tougher diet. The simple technique used in this study therefore allowed us to identify that, taken together, structural aspects play a more important role in defining the complexity of the human sagittal suture than extrinsic factors such as the mechanical forces imposed on the cranium by individuals' diet.
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http://dx.doi.org/10.1002/ar.24627DOI Listing
March 2021

Mucoadhesive Gelatin Buccal Films with Propranolol Hydrochloride: Evaluation of Mechanical, Mucoadhesive, and Biopharmaceutical Properties.

Pharmaceutics 2021 Feb 18;13(2). Epub 2021 Feb 18.

Department of Materials Science and Engineering, Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11120 Belgrade, Serbia.

This study processes and characterizes propranolol hydrochloride/gelatin mucoadhesive buccal films. Two types of gelatin are used: Gelatin from porcine skin, type A (GA), and gelatin from bovine skin (GB). The influence of gelatin type on mechanical, mucoadhesive, and biopharmaceutical characteristics of buccal films is evaluated. Fourier-Transfer infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analysis show that GA with propranolol hydrochloride (PRH) in the film (GAP) formed a physical mixture, whereas GB with PRH (GBP) form a compound-complex. Results of mechanical testing (tensile test, hardness) revealed that GAP films exhibit higher elastic modulus, tensile strength, and hardness. A mucoahesion test shows that GBP has higher adhesion strength, while GAP shows higher work of adhesion. Both in vitro release study and in silico simulation indicated that processed films can provide effective drug transport through the buccal mucosa. In silico simulation shows improved bioavailability from buccal films, in comparison to the immediate-release tablets-indicating that the therapeutic drug dose can be markedly reduced.
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http://dx.doi.org/10.3390/pharmaceutics13020273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922149PMC
February 2021

Oral Health-Related Risk Factors Among Students in Southeast Serbia.

Med Sci Monit 2021 Feb 17;27:e929375. Epub 2021 Feb 17.

Department of Oral Medicine and Periodontology, Dental Clinic Medical Faculty, University of Niš, Niš, Serbia.

BACKGROUND An association between insufficient or irregular oral hygiene with the occurrence of dental caries, gingival/periodontal diseases, and consequently general diseases has been established. The null hypothesis that there is no difference in the oral health status among students in a preclinical medical program and those who went through a clinical medical program was tested. The main objective of the study was to analyze oral health risk factors (oral hygiene practices, attitudes, and behavior) as well as their impact on oral health by using convenience sampling. MATERIAL AND METHODS We investigated risk factors for oral health conditions by examining oral hygiene practices, attitudes, and behaviors among the students in the medical program of the University of Niš, collecting data using questionnaires. The study included 396 students of medicine, dentistry, pharmacy, and vocational studies. Participants filled out the anonymous questionnaire. RESULTS In both groups, parents were mostly employed, with the representation of employed fathers significantly higher in student group 1 (P<0.05), which is also the only statistically significant difference between the groups. In terms of oral hygiene practices, students were most often trained by parents (68.69%). A very high percentage of students brushed their teeth every day (97.22%), and 54.55% did this twice a day. Of the total number of students, 78.28% thought that it was necessary to use interdental brushes/floss/toothpick. The duration of teeth cleaning was 3 minutes in 39.39%, whereas 55.30% thought that it should be longer than 3 minutes. The most common brushing movements were combined movements and were used by 60.35% of all students. Of all students, 253 (63.89%) never smoked, 182 (49.96%) regularly went to the dentist, and 141 (35.61%) visited the dentist 6 months ago. The majority of students, 265 (66.92%), obtained the greatest amount of information about oral and tooth care from their dentist, which was the case in both age groups. CONCLUSIONS This study highlights oral health risk factors among students at the University of Niš. It is essential to determine their oral health knowledge, as it is of great significance both to patients and to students. Also, these students will be the major providers of health services and will be responsible for public oral health promotion. It could help in reformation of the oral health education program. The results of this research indicate that it is necessary to educate preclinical students to solve oral health issues.
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http://dx.doi.org/10.12659/MSM.929375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898551PMC
February 2021

Contemporary management of severe symptomatic bicuspid aortic valve stenosis: the BiTri Registry.

J Cardiovasc Med (Hagerstown) 2021 Jun;22(6):492-495

Clinique Pasteur, Toulouse, France.

Aims: A greater number of patients with bicuspid aortic valves (BAV) may be identified and treated as indications for transcatheter aortic valve implantation (TAVI) are expected to expand to younger patients. We evaluated the contemporary frequency and management of symptomatic patients with stenotic BAV in a multicenter European registry.

Methods: Between November 2017 and February 2018, all consecutive patients admitted for symptomatic aortic stenosis across six high-volume European hospitals were prospectively enrolled in the BiTri registry.

Results: Of the 832 patients, 17% (n = 138) had a BAV. The most frequent BAV phenotypes were type 1 (left--right coronary cusps fusion 64%) and type 1 (right-noncoronary cusps fusion 17%). Type 0 and type 2 accounted for 12 and 2%, respectively. When compared with tricuspid patients (n = 694), BAV patients were younger, with lower surgical risk. The transthoracic echocardiography (TTE) identified BAV in 64% of patients. Multisliced computed tomography (MSCT) additionally completed the diagnosis in 20% of patients. Surgical inspection finally identified the remaining undiagnosed 16% of BAV. A combination of TTE and MSCT was the most common diagnosis method for BAV. Surgical aortic valve replacement (SAVR) was the predominant therapeutic option for BAV (70%) whilst TAVI was performed in 26%.

Conclusion: BAV is frequently observed in symptomatic patients with aortic stenosis. These patients are younger, have a lower risk profile and are predominantly treated with SAVR as compared with tricuspid patients. However, TAVI is performed in almost one-third of BAV patients in contemporary European practice. TTE combined with MSCT identified 84% of BAV.
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http://dx.doi.org/10.2459/JCM.0000000000001134DOI Listing
June 2021

A deep learning oriented method for automated 3D reconstruction of carotid arterial trees from MR imaging.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:2408-2411

The scope of this paper is to present a new carotid vessel segmentation algorithm implementing the U-net based convolutional neural network architecture. With carotid atherosclerosis being the major cause of stroke in Europe, new methods that can provide more accurate image segmentation of the carotid arterial tree and plaque tissue can help improve early diagnosis, prevention and treatment of carotid disease. Herein, we present a novel methodology combining the U-net model and morphological active contours in an iterative framework that accurately segments the carotid lumen and outer wall. The method automatically produces a 3D meshed model of the carotid bifurcation and smaller branches, using multispectral MR image series obtained from two clinical centres of the TAXINOMISIS study. As indicated by a validation study, the algorithm succeeds high accuracy (99.1% for lumen area and 92.6% for the perimeter) for lumen segmentation. The proposed algorithm will be used in the TAXINOMISIS study to obtain more accurate 3D vessel models for improved computational fluid dynamics simulations and the development of models of atherosclerotic plaque progression.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176532DOI Listing
July 2020

Understanding variability in the pharmacokinetics of atypical antipsychotics - focus on clozapine, olanzapine and aripiprazole population models.

Drug Metab Rev 2020 02 3;52(1):1-18. Epub 2020 Feb 3.

Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Republic of Serbia.

Antipsychotic medicines are widely used for the management of psychotic symptoms regardless of the underlying diagnosis. Most atypical antipsychotics undergo extensive metabolism prior to excretion. Various factors may influence their pharmacokinetics, particularly elimination, leading to highly variable drug concentrations between individual patients following the same dosing regimen. Population pharmacokinetic approach, based on nonlinear mixed effects modeling, is a useful tool to identify covariates explaining pharmacokinetic variability, as well as to characterize and distinguish unexplained residual and between-subject (interindividual) variability. In addition, this approach allows the use of both sparsely and intensively sampled data. In this paper, we reviewed the pharmacokinetic characteristics of clozapine, olanzapine and aripiprazole, focusing on a population modeling approach. In particular, models based on a nonlinear mixed effects approach performed by software in order to identify and quantify sources of pharmacokinetic variability are presented. Population models were identified through systematic searches of PubMed and sixteen studies were selected. Some of the factors identified that significantly contribute to variability in elimination among clozapine, olanzapine, and aripiprazole are demographic characteristics, body weight, genetic polymorphism, smoking and in some cases drug interactions. Scientific research based on pharmacometric modeling is useful to further characterize sources of variability and their combined effect.
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http://dx.doi.org/10.1080/03602532.2020.1717517DOI Listing
February 2020

Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients.

J Crit Care 2020 02 5;55:116-121. Epub 2019 Nov 5.

Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Beograd, Serbia. Electronic address:

Purpose: The present study aimed to establish a population pharmacokinetic model of vancomycin, including adult critically ill septic patients, with normal and impaired renal function.

Materials And Methods: A prospective analysis of 146 concentrations from 73 adult critically ill septic patients treated with 1-h intravenous infusion of vancomycin were included in the study. A nonlinear mixed effects modeling (NONMEM) approach was applied for data analysis and evaluation of the final model. The influence of creatinine clearance calculated by the Cockcroft-Gault equation (CrCl), and other potential covariates on vancomycin clearance (CL) were evaluated.

Results: The final one-compartment pharmacokinetic model includes the effect of CrCl on CL. Population pharmacokinetic values for a typical subject were estimated at 0.024 l/h for CL dependent on renal function (CLCrCl), 1.93 l/h for residual portion of CL (not dependent on renal function), and 0.511 l/kg for volume of distribution (V). According to the final model, for patients with CrCl = 120 ml/min, the median vancomycin total CL is 4.81 l/h, while CrCl-dependent fraction accounts for approximately 60% of CL.

Conclusions: The developed population vancomycin model may be used in estimating individual CL for adult critically ill septic patients, and could be applied for individualizing dosage regimens taking into account the continuous effect of CrCl.
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http://dx.doi.org/10.1016/j.jcrc.2019.10.012DOI Listing
February 2020

Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis.

Eur J Pharm Sci 2020 Jan 15;141:105095. Epub 2019 Oct 15.

Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.

Purpose: The aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam.

Methods: In the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations.

Results: The final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values.

Conclusions: The developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.
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http://dx.doi.org/10.1016/j.ejps.2019.105095DOI Listing
January 2020

The modular organization of roe deer () body during ontogeny: the effects of sex and habitat.

Front Zool 2018 27;15:37. Epub 2018 Sep 27.

2Department of Evolutionary Biology, University of Belgrade, Institute for Biological Research "Siniša Stanković", Bulevar despota Stefana 142, Belgrade, Serbia.

Background: As a small artiodactyl, the roe deer ( L.) is characterized by biological plasticity and great adaptability demonstrated by their survival under a wide variety of environmental conditions. In order to depict patterns of phenotypic variation of roe deer body this study aims to quantify variation during ontogenetic development and determine how sex-specific reproductive investment and non-uniform habitat differences relate to phenotypic variation and do these differential investments mold the patterns of phenotypic variation through modular organisation.

Results: Patterns of phenotypic correlation among body traits change during the ontogeny of roe deer, with differential influence of sex and habitat type. Modularity was found to be a feature of closed habitats with trunk+forelimbs+hindlimbs as the best supported integration/modularity hypothesis for both sexes. The indices of integration and evolvability vary with habitat type, age and sex where increased integration is followed by decreased evolvability.

Conclusion: This is the first study that quantifies patterns of correlation in the roe deer body and finds pronounced changes in correlation structure during ontogeny affected by sex and habitat type. The correlation structure of the roe deer body is developmentally written over the course of ontogeny but we do not exclude the influence of function on ontogenetic changes. Modularity arises with the onset of reproduction (subadults not being modular) and is differentially expressed in males and females from different habitats. Both adult males and females show modularity in primordial, closed habitats. Overall, all these findings are important as they provide support to the idea that modularity can evolve at the population level and change fast within a species.
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http://dx.doi.org/10.1186/s12983-018-0283-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161383PMC
September 2018

Expectations, concerns, and needs of patients who start drugs for chronic conditions. A prospective observational study among community pharmacies in Serbia.

Eur J Gen Pract 2018 Dec 22;24(1):19-25. Epub 2017 Nov 22.

b Department of Pharmacotherapy and Pharmaceutical Care , University of Groningen , Groningen , The Netherlands.

Background: During the initiation of treatment of a chronic disease, patients may have varying interests, expectations, concerns, and reasons to stop treatment, influencing compliance with prescribed treatment. Thus, healthcare professionals are expected to integrate these needs into medicines management.

Objectives: To determine what information is important to patients; assess predictors of patients' interests, expectations, concerns, reasons to stop therapy; evaluate drug-related problems following initiation of therapy and summarize how pharmacists resolve them during patient-pharmacist counselling.

Methods: In 2014, a four-month study was performed in Serbian community pharmacies, as part of the Pharmaceutical Care Quality Indicators Project led by the European Directorate for the Quality of Medicines & Healthcare. Seventy community pharmacists were asked to participate in the study. Pharmacists recruited adult patients who consented to participate in the study and who initiated treatment, lasting at least six months. Patients completed an open-ended questions form. After two-to-four weeks, a patient-pharmacist consultation was performed.

Results: Forty-four community pharmacists (response rate 62.9%) sent back the completed forms from 391 patients (response rate 67.1%). The total number of dispensed drugs was 403. In terms of drug safety, 29.4% of patients sought information, 32.5% expressed concerns, and 28.1% of patients cited it as a reason to discontinue treatment. During the first weeks of therapy, 18% of patients experienced practical problems, while 27.3% reported adverse drug reactions.

Conclusion: Safety issues are a major focus of patients' prescribed new medicines for long-term treatment.
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http://dx.doi.org/10.1080/13814788.2017.1388778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774285PMC
December 2018

Differentiation between progression and pseudoprogresion by arterial spin labeling MRI in patients with glioblastoma multiforme.

J BUON 2017 Jul-Aug;22(4):1061-1067

Clinical Center of Serbia, Radiology and MRI Center, Belgrade, Serbia.

Purpose: To compare arterial spin labeling (ASL) perfusion technique with the clinically established dynamic susceptibility contrast-enhanced (DSC) perfusion weighted-imaging (PWI), and to determine its value in routine MRI evaluation of disease progression in patients with glioblastoma multiforme (GBM).

Methods: A prospective intraindividual study was performed in 31 patients with histologically proven GBM who had clinical and/or radiological deterioration after treatment, including surgery, radiotherapy and therapy with temozolomide. Conventional brain protocol with ASL and DSC techniques was performed on 3T MRI unit. Cerebral blood flow (CBF) and cerebral blood volume (CBV) maps were analyzed by means of regions of interest (ROI). Each ROI average value was normalized to the contralateral normal brain parenchyma ROI value. Neuroradiologists analyzed CBF and CBV maps separately, and classified patients into progression or pseudoprogression group. Radiological diagnosis was confirmed by clinical-radiological follow-up for at least three months after patient deterioration.

Results: High linear correlation existed between DSC-PWI and ASL in the tumor ROI (r=0.733; p<0.001). 92% of ASL CBF maps were informative. ASL detected all lesions as well as DSC MRI. Both techniques provided perfusion values closely correlated.

Conclusion: ASL allows distinction between GBM progression and pseudoprogression, and it can be used as reliable alternative to DSC-PWI.
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July 2019

Impact of community pharmacists' interventions on asthma self-management care.

Res Social Adm Pharm 2018 06 25;14(6):603-611. Epub 2017 Jul 25.

Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia.

Background: Asthma self-management is aimed to improve the quality and effectiveness of asthma care by supporting the patients to manage their illness by themselves.

Objective: The aim of the study was to evaluate the impact of pharmacist-delivered counselling on patients knowledge and beliefs about the medicines, adherence level, and asthma control.

Methods: A prospective intervention study was conducted in community pharmacies. A total of 90 patients completed the study. Four questionnaires were used: (1) Beliefs about medicines questionnaire (BMQ), (2) Knowledge of asthma and asthma medicine (KAM), (3) Asthma control test (ACT), and (4) 8-item Morisky medication adherence scale questionnaire (MMAS-8). Questionnaires were completed at baseline and 3 months later.

Results: Low level of adherence and poor asthma control were determined initially. Better asthma control was significantly associated with higher adherence level, lower concerns regarding the medication use, and knowledge of triggers. Statistically significant improvement was found after 3 months in patients knowledge of asthma and its medications, their attitude towards medications (decrease in harm, overuse and concern; increase in necessity score), asthma control score (increased from 19 to 20, p < 0.05) and level of adherence (MMAS-8 score decreased from 3 to 2 p < 0.05). Better asthma control was achieved in 60% of patients. Sixteen patients (18%) were transferred from poor to well-controlled asthma, implying no need for patients' referral to the doctor and no additional cost for the health system.

Conclusions: Improved disease control could be a result of enhanced knowledge and understanding of the disease-medication relationship, improved inhalation technique, and support on patients' adherence. Acquired knowledge and skills, as well as improved attitude, empowered patients to take a more active part in asthma management. Education in further patients' follow-up should consider topics tailored to the patients' characteristics, needs, and prior counselling schedule with issues discussed.
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http://dx.doi.org/10.1016/j.sapharm.2017.07.007DOI Listing
June 2018

Elderly polypharmacy patients' needs and concerns regarding medication assessed using the structured patient-pharmacist consultation model.

Patient Educ Couns 2017 Sep 1;100(9):1714-1719. Epub 2017 May 1.

Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, The Netherlands.

Objective: To evaluate elderly polypharmacy patients' needs and concerns regarding medication through the Structured Patient-Pharmacist Consultation (SPPC).

Methods: Older patients on chronic treatment with ≥5 medications were asked to fill in the SPPC form at home. A consultation with the community pharmacist, structured according to patient's answers, followed within 2-4 weeks. Logistic regression associated patients' individual treatment with care issues and consultation outcomes.

Results: Out of 440 patients, 39.5% experienced problems, and 46.1% had concerns about medication use. 122 patients reported reasons for discontinuing treatment. The main outcome of the consultation was a better understanding of medication use (75.5%). Side effects and/or non-adherence were identified in 50% of patients, and 26.6% were referred to the doctor. Atrial fibrillation, COPD, anticoagulants, benzodiazepines, and beta agonists/corticosteroids were associated with problems during medication use. Patients with diabetes improved their understanding of medication use significantly.

Conclusion: Patients on benzodiazepines, anticoagulants, and beta agonists/corticosteroids, with atrial fibrillation and/or COPD, may have a higher potential for non-adherence. Counseling patients based on the SPPC model may be particularly useful for patients with diabetes.

Practice Implications: The SPPC model is a useful tool for counseling based on patient needs.
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http://dx.doi.org/10.1016/j.pec.2017.05.001DOI Listing
September 2017

Evaluation of drug-related problems in older polypharmacy primary care patients.

J Eval Clin Pract 2017 Aug 29;23(4):860-865. Epub 2017 Mar 29.

Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, the Netherlands.

Aims And Objectives: Targeting older patients with predictive factors for drug-related problems (DRPs) could make clinical medication reviews more cost-effective. The aim of this study was to identify the number, type, and potential predictive factors for DRPs in older polypharmacy patients.

Methods: Community pharmacists performed clinical medication reviews and documented DRPs, types of interventions, and their implementation in older patients.

Results: Three hundred eighty-eight medication reviews were analyzed, 964 DRPs (average 2.5 ± 1.9), and 1022 interventions (average 2.6 ± 2.0) were identified. The overall implementation rate of interventions was 70.1%, the highest was observed in interventions aiming to resolve the lack of therapy monitoring (86.8%). Patients with ≥12 medications had an increased risk of ≥5 DRPs (P < .001). Asthma was associated with lack of adherence (P = .002), lack of aspirin, statins, and proton pump inhibitors use with additional therapy needed (P = .002-.004). Predictive factors for drug interactions were antihypertensive medications and/or medications with narrow therapeutic index (P < .05). Lack of efficacy was associated with diabetes (P = .006). Nonsteroidal anti-inflammatory drugs were risk factors for inappropriate drug selection (P = .002). Lack of monitoring was associated with hypertension (P = .013), whereas benzodiazepines (P < .001) and aspirin (P = .021) were overused.

Conclusion: Patients with asthma, hypertension, and diabetes and lack of statin, antithrombotic agent, and/or proton pump inhibitor use were associated with higher risks for DRPs.
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http://dx.doi.org/10.1111/jep.12737DOI Listing
August 2017

Extracellular ATP induces graded reactive response of astrocytes and strengthens their antioxidative defense in vitro.

J Neurosci Res 2017 04 7;95(4):1053-1066. Epub 2016 Oct 7.

Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia.

It is widely accepted that adenosine triphosphate (ATP) acts as a universal danger-associated molecular pattern with several known mechanisms for immune cell activation. In the central nervous system, ATP activates microglia and astrocytes and induces a neuroinflammatory response. The aim of the present study was to describe responses of isolated astrocytes to increasing concentrations of ATP (5 µM to 1 mM), which were intended to mimic graded intensity of the extracellular stimulus. The results show that ATP induces graded activation response of astrocytes in terms of the cell proliferation, stellation, shape remodeling, and underlying actin and GFAP filament rearrangement, although the changes occurred without an apparent increase in GFAP and actin protein expression. On the other hand, ATP in the range of applied concentrations did not evoke IL-1β release from cultured astrocytes, nor did it modify the release from LPS and LPS+IFN-γ-primed astrocytes. ATP did not promote astrocyte migration in the wound-healing assay, nor did it increase production of reactive oxygen and nitrogen species and lipid peroxidation. Instead, ATP strengthened the antioxidative defense of astrocytes by inducing Cu/ZnSOD and MnSOD activities and by increasing their glutathione content. Our current results suggest that although ATP triggers several attributes of activated astrocytic phenotype with a magnitude that increases with the concentration, it is not sufficient to induce full-blown reactive phenotype of astrocytes in vitro. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.23950DOI Listing
April 2017

Application of Counter-propagation Artificial Neural Networks in Prediction of Topiramate Concentration in Patients with Epilepsy.

J Pharm Pharm Sci 2015 ;18(5):856-62

Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia...

Purpose: The application of artificial neural networks in the pharmaceutical sciences is broad, ranging from drug discovery to clinical pharmacy. In this study, we explored the applicability of counter-propagation artificial neural networks (CPANNs), combined with genetic algorithm (GA) for prediction of topiramate (TPM) serum levels based on identified factors important for its prediction.

Methods: The study was performed on 118 TPM measurements obtained from 78 adult epileptic patients. Patients were on stable TPM dosing regimen for at least 7 days; therefore, steady-state was assumed. TPM serum concentration was determined by high performance liquid chromatography with fluorescence detection. The influence of demographic, biochemical parameters and therapy characteristics of the patients on TPM levels were tested. Data analysis was performed by CPANNs. GA was used for optimal CPANN parameters, variable selection and adjustment of relative importance.

Results: Data for training included 88 measured TPM concentrations, while remaining were used for validation. Among all factors tested, TPM dose, renal function (eGFR) and carbamazepine dose significantly influenced TPM level and their relative importance were 0.7500, 0.2813, 0.0625, respectively. Relative error and root mean squared relative error (%) and their corresponding 95% confidence intervals for training set were 2.14 [(-2.41) - 6.70] and 21.5 [18.5 - 24.1]; and for test set were -6.21 [(-21.2) - 8.77] and 39.9 [31.7 - 46.7], respectively.

Conclusions: Statistical parameters showed acceptable predictive performance. Results indicate the feasibility of CPANNs combined with GA to predict TPM concentrations and to adjust relative importance of identified variability factors in population of adult epileptic patients.
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http://dx.doi.org/10.18433/j33031DOI Listing
September 2016

Low-dose ribavirin treatments attenuate neuroinflammatory activation of BV-2 Cells by interfering with inducible nitric oxide synthase.

Anal Cell Pathol (Amst) 2015 27;2015:923614. Epub 2015 Aug 27.

Department of Neurobiology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Boulevard Despot Stefan 142, Belgrade 11060, Serbia.

Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.
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http://dx.doi.org/10.1155/2015/923614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564589PMC
June 2016

Optimal Ancient DNA Yields from the Inner Ear Part of the Human Petrous Bone.

PLoS One 2015 18;10(6):e0129102. Epub 2015 Jun 18.

Institute for Biochemistry and Biology, Faculty for Mathematics and Natural Sciences, University of Potsdam, Karl-Liebknechtstr. 24-25, 14476 Potsdam Golm, Germany; Department of Biology, University of York, Wentworth Way, Heslington, York, United Kingdom.

The invention and development of next or second generation sequencing methods has resulted in a dramatic transformation of ancient DNA research and allowed shotgun sequencing of entire genomes from fossil specimens. However, although there are exceptions, most fossil specimens contain only low (~ 1% or less) percentages of endogenous DNA. The only skeletal element for which a systematically higher endogenous DNA content compared to other skeletal elements has been shown is the petrous part of the temporal bone. In this study we investigate whether (a) different parts of the petrous bone of archaeological human specimens give different percentages of endogenous DNA yields, (b) there are significant differences in average DNA read lengths, damage patterns and total DNA concentration, and (c) it is possible to obtain endogenous ancient DNA from petrous bones from hot environments. We carried out intra-petrous comparisons for ten petrous bones from specimens from Holocene archaeological contexts across Eurasia dated between 10,000-1,800 calibrated years before present (cal. BP). We obtained shotgun DNA sequences from three distinct areas within the petrous: a spongy part of trabecular bone (part A), the dense part of cortical bone encircling the osseous inner ear, or otic capsule (part B), and the dense part within the otic capsule (part C). Our results confirm that dense bone parts of the petrous bone can provide high endogenous aDNA yields and indicate that endogenous DNA fractions for part C can exceed those obtained for part B by up to 65-fold and those from part A by up to 177-fold, while total endogenous DNA concentrations are up to 126-fold and 109-fold higher for these comparisons. Our results also show that while endogenous yields from part C were lower than 1% for samples from hot (both arid and humid) parts, the DNA damage patterns indicate that at least some of the reads originate from ancient DNA molecules, potentially enabling ancient DNA analyses of samples from hot regions that are otherwise not amenable to ancient DNA analyses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472748PMC
April 2016

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

Eur J Clin Pharmacol 2015 Feb 9;71(2):183-90. Epub 2014 Nov 9.

Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, 11000, Serbia,

Purpose: The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients.

Methods: In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model.

Results: According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F.

Conclusions: Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.
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http://dx.doi.org/10.1007/s00228-014-1778-7DOI Listing
February 2015

Role of cystatin C and renal resistive index in assessment of renal function in patients with liver cirrhosis.

World J Gastroenterol 2014 Jun;20(21):6573-9

Đorđe Ćulafić, Miloš Štulić, Danijela Miletić, Dragana Mijač, Milica Stojković, Clinic of Gastroenterology and Hepatology, Clinical Center of Serbia, and School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.

Aim: To evaluate the clinical significance of cystatin C and renal resistive index for the determination of renal function in patients with liver cirrhosis.

Methods: We conducted a study of 63 patients with liver cirrhosis. A control group comprised of 30 age and gender-matched healthy persons. Serum cystatin C was determined in all study subjects and renal Doppler ultrasonography was made. Estimated glomerular filtration rate from serum creatinine (GFRCr) and cystatin C (GFRCys) was calculated.

Results: We confirmed significant differences in values of cystatin C between patients with different stages of liver cirrhosis according to Child-Pugh (P = 0.01), and a significant correlation with model of end stage liver disease (MELD) score (r s = 0.527, P < 0.001). More patients with decreased glomerular filtration rate were identified based on GFRCys than on GFRCr (P < 0.001). Significantly higher renal resistive index was noted in Child-Pugh C than in A (P < 0.001) and B stage (P = 0.001). Also, a significant correlation between renal resistive index and MELD score was observed (r s = 0.607, P < 0.001). Renal resistive index correlated significantly with cystatin C (r s = 0.283, P = 0.028) and showed a negative correlation with GFRCys (r s = -0.31, P = 0.016).

Conclusion: Cystatin C may be a more reliable marker for assessment of liver insufficiency. Additionally, cystatin C and renal resistive index represent sensitive indicators of renal dysfunction in patients with liver cirrhosis.
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http://dx.doi.org/10.3748/wjg.v20.i21.6573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047343PMC
June 2014

Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients.

Ann Pharmacother 2014 Aug 8;48(8):992-997. Epub 2014 May 8.

Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia.

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance.

Objective: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients.

Methods: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL).

Results: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P < 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels.

Conclusions: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful.
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http://dx.doi.org/10.1177/1060028014534397DOI Listing
August 2014

Population pharmacokinetics of topiramate in adult patients with epilepsy using nonlinear mixed effects modelling.

Eur J Pharm Sci 2013 Nov 25;50(3-4):282-9. Epub 2013 Jul 25.

Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia. Electronic address:

The objective of the study was to develop population pharmacokinetic model of topiramate (TPM) using nonlinear mixed effects modelling approach. Data were collected from 78 adult epileptic patients on mono- or co-therapy of TPM and other antiepileptic drugs, such as carbamazepine (CBZ), valproic acid, lamotrigine, levetiracetam, phenobarbital and pregabalin. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography with fluorescence detection. A one-compartment model with first order absorption and elimination was used to fit the concentration-time TPM data. Volume of distribution of TPM was estimated at 0.575 l/kg. The influence of demographic, biochemical parameters and therapy characteristics of the patients on oral clearance (CL/F) was evaluated. Daily carbamazepine dose (DCBZ) and renal function estimated by Modification of diet in renal disease (MDRD) formula significantly (p<0.001) influenced CL/F and were included in the final model: CL/F · (l/h)=1.53(l/h) · [1+0.476 · DCBZ(mg/day)/1000(mg/day)] · EXP[0.00476 · [MDRD(ml/ min)-95.72(ml/min)]]. Increase of CL/F with DCBZ and MDRD was best described by linear and exponential models. Mean TPM CL/F during CBZ co-therapy was 2.46 l/h, which is higher for 60.8% than in patients not co-treated with CBZ. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by adequate plots and indicated satisfactory precision. This model allows individualisation of TPM dosing in routine patient care, especially useful for patients on different CBZ dosing regimen.
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http://dx.doi.org/10.1016/j.ejps.2013.07.008DOI Listing
November 2013

Getting the balance right: Established and emerging therapies for major depressive disorders.

Neuropsychiatr Dis Treat 2010 Sep 7;6:343-64. Epub 2010 Sep 7.

Department of Pharmacokinetics, Faculty of Pharmacy, University of Belgrade, Serbia.

Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938284PMC
http://dx.doi.org/10.2147/ndt.s10485DOI Listing
September 2010
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