Population pharmacokinetics of tamsulosine in patients with benign prostatic hyperplasia.

PURPOSE: The study aimed to determine the typical clearance and volume of distribution values of tamsulosin in patients with benign prostatic hyperplasia (BPH), and to identify factors with a measurable impact on the drug's elimination. METHODS: This open-label, single-arm population pharmacokinetic study involved 65 adult men with BPH who had been on tamsulosin therapy for at least seven days. The steady-state serum concentrations of tamsulosin were measured using liquid chromatography-tandem quadrupole mass spectrometry. Population pharmacokinetic parameters, their variability, and influencing factors were estimated based on a two-compartment pharmacokinetic model using NONMEM software. RESULTS: The estimated tamsulosin clearance in BPH patients was 0.719 L/h, and the steady-state volume of distribution was 32 L. Neither renal nor liver function parameters had a statistically significant effect on tamsulosin clearance. However, a positive correlation was observed between hemoglobin levels and tamsulosin clearance in the BPH patient cohort. CONCLUSION: Our investigation reveals significant associations between tamsulosin pharmacokinetics and specific characteristics of patients with lower urinary tract symptoms (LUTS) due to BPH. The study highlights that tamsulosin clearance is associated with hemoglobin levels in patients with LUTS/BPH. This study underscores the importance of considering patient-specific factors when managing BPH treatment with tamsulosin, emphasizing associations rather than causative relationships.

Exposure to Stress and Burnout Syndrome in Healthcare Workers, Expert Workers, Professional Associates, and Associates in Social Service Institutions.

Background and Objectives: Workplace burnout syndrome is often as sociated with particular aspects of certain job positions, especially those that entail working with people with special needs. The burnout syndrome in healthcare jobs is a serious problem that has grown into an epidemic among healthcare workers and associates. The aim of this research is to assess the presence of stress and burnout syndrome at work with healthcare workers, expert workers, professional associates, and associates in social service institutions in Belgrade. Materials and Methods: This research was conducted in the form of a cross-sectional study of a representative sample in social institutions in Belgrade. It was conducted from March to the end of June of 2023. The sample of the study had 491 participants. The questionnaires used were a structured instrument with social-demographic and social-economic characteristics, workplace characteristics, lifestyle characteristics, and the following questionnaires: DASS-21, Copenhagen, Brief Resilience Scale, and Brief Resilient Coping Scale. Results: The end results indicate the following to be significant risk factors for the occurrence of workplace burnout syndrome: overtime (OR = 2.62; CI = 1.50-4.56), BRS average score (OR = 0.28; CI = 0.17-0.44), DASS21 D heightened depression (OR = 2.09; CI = 1.1-4.04), DASS21 A heightened anxiety (OR = 2.38; CI = 1.34-4.21), and DASS21 S heightened stress (OR = 2.08; CI = 1.11-3.89). The only protective risk factor that stood out was the self-assessment of health levels (OR = 0.60; CI = 0.42-0.85). Conclusion: Overtime is a significant factor associated with workplace burnout. Apart from it, other significant factors associated with workplace burnout were heightened depression, anxiety, and stress levels.

Hypovitaminosis D in infants: Evidence that increased intake of vitamin D reduces the incidence of allergic and respiratory disorders.

AIM: The study assessed the relationship between vitamin D status in infants and the presence of allergic and/or respiratory disorders. MATERIALS AND METHODS: The study cohort comprised 81 hospitalized infants presenting at the Pediatric Clinic, University Clinical Center Kragujevac, Serbia, between January 2011 and June 2016. RESULTS: The age of the infants ranged from 29 days to 12 months. All infants received prophylactic doses of vitamin D3 of 400 IU/daily until the end of the first year of life regardless of whether they are fed with adapted infant formula (n = 20) or breast milk (n = 37) or concurrently both (n = 24), up to the 5th month of life. The mean level of plasma 25(OH)D was 29.65 ng/mL. Hypovitaminosis D (mean serum level of 25(OH)D < 30 ng/mL) was found in n = 38 infants of which 6 presented with severe vitamin D deficiency (level below 10 ng/mL), 13 presented with vitamin D deficiency (level between 10 and 20 ng/mL) and 19 had vitamin D insufficiency (levels between 20 and 30 ng/mL). The median vitamin D serum level in infants with allergic disease (n = 16) was 32.35 ng/mL and in infants with respiratory disease (n = 65) 28.99 ng/mL. CONCLUSION: Daily vitamin D3 supplementation with 400 IU in infants until the end of the first year of life is too low to provide optimal defense against respiratory and/or allergic conditions.

Population Pharmacokinetic Modeling to Inform Sertraline Dosing Optimization in Patients with Depression.

Sertraline is one of the most prescribed antidepressants, but its pharmacokinetic (PK) properties are still not completely characterized. Using nonlinear mixed-effects modeling, we examined factors influencing sertraline PK variability in outpatients with major depressive disorder. Blood samples from 53 male and female adults treated with sertraline orally were collected at a steady state. Various demographic and clinical covariates were tested by stepwise regression procedure. We found that sertraline clearance is significantly influenced by serum concentrations of its main metabolite N-desmethylsertraline, whereas clearance of N-desmethylsertraline is affected by both creatinine clearance and drug daily dose. These results were confirmed by the reduction of points dispersion in goodness-of-fit plots for their predicted versus measured concentrations and with bootstrapping analyses. This finding can serve to inform sertraline dosing optimization, especially when changes in kidney function occur in treated individuals, to prevent adverse drug reactions and maximize therapeutic benefits.

The significant role of dietary intake of vitamin D in non-menopausal women health.

Optimal vitamin D status is very important for reflecting not only bone but overall woman's health. The aim of the study was to determine pharmacokinetic variability of 25-hydroxy vitamin D, to reveal and quantify the most significant factors that affect its variability in the population of healthy non-menopausal women using the population pharmacokinetic (PopPK) approach. The study population consisted of 74 healthy reproductive women aged from 35 to 50 years, without the use of any supplement. A population pharmacokinetics analysis was conducted using a nonlinear mixed-effects model software. A total of 35 factors were assessed: demographic, clinical, biochemical data and lifestyle factors. The average age and bodyweight of our participants were 40.11 ± 4.35 years 65.30 ± 6.80 kg, respectively. The observed mean serum concentration of 25-hydroxy vitamin D was 26.51 ± 13.49 ng/mL with a wide range of 6.97 to 59.89 ng/mL. Development final PopPK model of the clearance of 25-hydroxy vitamin D showed that only the average daily dose of vitamin D intake from food had a significant influence, with a magnitude of its effects of 0.00401. These results could help when individualizing vitamin D intake in the form of supplements, especially during the wintertime, in healthy reproductive women.

Effects of Supplementation in Vitamin D3 Deficient or Insufficient Children with Allergic Diseases.

Background and Objectives: Although vitamin D insufficiency or deficiency is prevalent in children with allergic diseases, recommendations for supplementation dosing regimens are imprecise and variable in the literature, because clinical trials aiming to determine optimal doses were scarce in the past. This study aimed to investigate supplementation of vitamin D3 that may achieve therapeutically effective but not toxic serum levels in a subpopulation of children with allergic diseases and concomitant hypovitaminosis D. Materials and Methods: The retrospective, observational study with a cross-sectional design included 94 children suffering from allergic diseases and having vitamin D deficiency/insufficiency who were prescribed high-dose vitamin D3 supplementation by a pediatrician for at least 6 weeks and not more than 9 weeks. Serum levels of the major metabolite of vitamin D (25-(OH)D) were determined in all children twice: before and two weeks after the end of vitamin D3 supplementation. Results: An increase in serum level of the 25-(OH)D after supplementation was significant. However, if the subjects had higher serum levels of the 25-(OH)D before the supplementation, and if the supplementation lasted 8 instead of 6 weeks, the absolute increase in serum level of the 25-(OH)D was lower. Patients taking corticosteroids as inhalation or intranasally had a more intense effect of vitamin D3 supplementation, i.e., the absolute increase in levels of 25-(OH)D was higher than in patients not using such medication. Conclusions: Vitamin D deficiency and insufficiency in children with allergic diseases can be treated with maximal recommended doses of vitamin D3 for a short period of time, especially if they were prescribed with inhalation or intranasal corticosteroids.

Population pharmacokinetic analysis of bisoprolol in type 2 diabetic patients with hypertension.

PURPOSE: Given that it has been reported that type 2 diabetes mellitus may affect the pharmacokinetics of a large number of drugs and that there are still no published population pharmacokinetic (PopPK) analyses in routinely treated patients with hypertension and type 2 diabetes mellitus as comorbid condition, the aim of this study was to determine PK variability of bisoprolol in 70 Serbian patients using the PopPK approach. METHODS: PopPK analysis was conducted using a nonlinear mixed effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In our patients, a total daily dose of bisoprolol ranged from 1.25 to 10 mg. The drug was administrated orally as a single daily dose or in two divided doses per day. RESULTS: A wide range of the drug concentrations were noted (1-103 ng/mL) in the population consisted of the adult patients with type 2 diabetes mellitus. From a total of 21 separately assessed covariates, our results indicated that only creatinine clearance could have a potential impact on the variability of the clearance of bisoprolol. CONCLUSION: Routine assessment of renal function should be carried out before the initiation of treatment with bisoprolol in order to individualize the dose and to prevent possible accumulation and adverse drug reactions.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

Population pharmacokinetics of 25-hydroxy vitamin D in children with asthma
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OBJECTIVES: Asthma and vitamin D deficiency are widespread in the pediatric and adolescent population. The aim of this study was to develop a population pharmacokinetic (PPK) model and to evaluate the most important factors that can significantly affect clearance of 25-hydroxy vitamin D in asthmatic children using PPK analysis. MATERIALS AND METHODS: The study population included school children and adolescents from 7 to 18 years of age of both sexes. PPK analysis was performed by non-linear mixed-effects modeling (NONMEM), and 19 covariates were assessed. Goodness-of-fit plots, validation set and bootstrap analysis were conducted to confirm predictive performance of the final model. RESULTS: A total of 60 patients were included in the basic NONMEM data set for PPK modeling with a mean age of 10.2 years and body weight of 41.3 kg. The final pharmacokinetic model for the clearance of 25-hydroxy vitamin D included as covariates intake of vitamin D from foods (DD), hereditary predisposition to asthma (HPA) and the ratio of forced expiratory volume in first second and forced vital capacity (FEV1/FVC ratio). A validation set consisted of 14 separate patients with similar characteristics to the basic data set. The final model was confirmed by internal and external validation and also through goodness-of-fit plots. CONCLUSION: These results could be of help for individualization of vitamin D supplementation doses in this vulnerable population.
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CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy.

PURPOSE: The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations -3860G > A and -163C > A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients. METHODS: The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for -3860G > A and -163C > A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used. RESULTS: CYP1A2 polymorphism -163C > A was found at the frequency of 65.0 %, while -3860G > A was not detected. The correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in carriers of -163C/C and C/A genotypes (r = 0.68, p = 0.0004). The equation that described population clearance (CL) was CL (l/h) = 0.176 + 0.0484 * SEX + 0.019 * CYP1A2 + 0.000156 * DD, where SEX has a value of 1 if male and 0 if female, CYP1A2 has a value of 1 if -163A/A and 0 if -163C/C or C/A, and DD is the total carbamazepine daily dose (mg/day). CONCLUSIONS: CYP1A2 -163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, -163C > A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance.

Population Pharmacokinetics of Bisoprolol in Hemodialysis Patients with Hypertension.

The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis.

Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults.

OBJECTIVES: The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. METHODS: Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 ± 1.82 years and 21.31 ± 2.69 kgm-2, respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. RESULTS: In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 x DD + 0.618 x PHO. CONCLUSIONS: The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults.

Variability of mycophenolic acid elimination in the renal transplant recipients ­ population pharmacokinetic approach.

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.

Antimicrobial treatment in invasive infections caused by Gordonia bronchialis: systematic review.

Background: Corynebacterium, Nocardia, Rhodococcus, Mycobacterium, as well as Gordonia genera belongs to the genus Gordonia, Actinomycetia class. Gordonia bronchialis is a nitrate-reducing, urease-producing, non-motile, force aerobe with a rod-like figure that is known to arrangement into sessile, cord-like groups. This systematic review aimed to establish whether and what invasive infections in humans were caused by Gordonia bronchialis, and to evaluate outcomes of administered antibiotic treatment. Methods: We have registered this systematic review in PROSPERO database of systematic reviews and meta-analyses with the number CRD42022369974. Results: A total of 24 publications were included (22 case reports and two case series) with 28 individual cases. The oldest patients had 92 years, and the youngest patients had 13 years. Clinical signs of infection were present in six patients (21%). All isolates were susceptible to ciprofloxacin, imipenem, and amikacin. Vancomycin was the most frequently used antibiotic with nine cases followed by ciprofloxacin, ceftriaxone, and amoxicillin/clavulanic acid. Conclusion: Although there are no standardized recommendations to date, successful treatment with a favorable outcome has most often been carried out with fluoroquinolones, vancomycin with or without aminoglycosides, as well as carbapenems.

Population pharmacokinetics of bisoprolol in patients with chronic heart failure.

PURPOSE: The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF). METHODS: Parameters associated with the plasma concentrations of bisoprolol at steady-state were analyzed in 61 patients (mean age 66.21 ± 9.49 years; mean total body weight 8.90 ± 12.26 kg) with CHF using non-linear mixed-effect modeling (NONMEM). A validation set of 17 patients with heart failure was used to estimate the predictive performance of the pharmacokinetic model. RESULTS: The typical mean value for bisoprolol clearance (CL), estimated by the base model (without covariates), in our population was 11.4 l h(-1). In the full model, covariates such as bisoprolol total daily dose (DD) and creatinine clearance were included. The final regression model for the clearance of bisoprolol was the following: CL (l h(-1)) = 4.68 + 0.859 * DD. CONCLUSION: The derived PK model describes the clearance of bisoprolol in patients with CHF, showing that the total daily dose of bisoprolol is the most important covariate. This finding will provide the basis for future PK studies on beta blockers in this specific patient population and lead to better overall management of heart failure.

Antimicrobial treatment of Erysipelatoclostridium ramosum invasive infections: a systematic review.

The aim of this systematic review was to determine the causal role of Erysipelatoclostridium ramosum in specific invasive infections in humans, and to assess the clinical outcome of antibiotic therapy used to treat them. Several electronic databases were systematically searched for clinical trials, observational studies or individual cases on patients of any age and gender with a systemic inflammatory response syndrome (SIRS) due to E. ramosum isolated from body fluids or tissues in which it is not normally present. Only reports identifying E. ramosum as the only microorganism isolated from a patient with SIRS were included. This systematic review included 15 studies reporting 19 individual cases in which E. ramosum caused invasive infections in various tissues, mainly in immunocompromised patients. E. ramosum was most often isolated by blood cultures and identified by specific biochemical tests. Severe infections caused by E. ramosum were in most cases effectively treated with antibiotics, except in two patients, one of whom died. More than one isolate of E. ramosum exhibited 100% susceptibility to metronidazole, amoxicillin/clavulanate and piperacillin/tazobactam. On the other hand, individual resistance of this bacterium to penicillin, ciprofloxacin, clindamycin, imipenem and ertapenem was reported. This systematic review confirmed the clinical relevance of E. ramosum as a cause of a number of severe infections mainly in immunocompromised inpatients. Metronidazole and meropenem appear to be the antibiotics of choice that should be used in combination or as monotherapy to treat E. ramosum infections, depending on the type and severity of the infection.

Contemporary surgical management of drug-resistant focal epilepsy.

Introduction: Seizures, which could not be controlled by drug therapy, have profound negative influence on the quality of life of the affected person. If with clear locus of origin and accompanied by loss of consciousness, drug-resistant epilepsy could be treated by surgery.Areas covered: The aim of this article was to review current status of epilepsy surgery through description of the most important operative methods and narrative comparison of their benefits and harms. In total 1154 articles were retrieved from MEDLINE, SCOPUS, EBSCO, and SCINDEKS databases, and 78 included in the review. The review included systematic reviews, meta-analyses, clinical trials, observational studies on humans, case series, and case reports.Expert opinion: Sophisticated diagnostic methods nowadays offer much more precise localization of epileptogenic focus and detailed planning of a surgical procedure which will make minimal damage of neural pathways and structures essential for movements, speech, cognition, and emotions. Advent of perioperative care, and improved diagnostics and surgical techniques resulted with significant drop in rates of postoperative complications, long-term neurological deficit, and mortality in the last decade, while seizure freedom rate and quality of life increased.

Clinical Pharmacokinetics of Second-Generation Triazoles for the Treatment of Invasive Aspergillosis and Candidiasis.

Second-generation triazoles were developed in response to the quest for more efficacious and safer therapeutic options for the treatment of severe systemic aspergillosis and candidiasis. These agents include voriconazole, posaconazole, isavuconazole, and ravuconazole. The aim of this review was to present and compare the pharmacokinetic characteristics of second-generation triazoles for the treatment of invasive aspergillosis and candidiasis, emphasizing their clinical implications. The MEDLINE, Scopus, EBSCO, Google Scholar, and SCIndeks databases were searched using advanced search options, including the names of second-generation triazoles and pharmacokinetic terms as keywords. The intravenous administration of voriconazole, posaconazole, and isavuconazole results in stable pharmacokinetics of these drugs, with mostly predictable variations influenced by common and usually known factors in routine clinical settings. The high oral bioavailability of isavuconazole and, to some extent, voriconazole makes them suitable for intravenous-to-oral switch strategies. Except for intravenous voriconazole (due to the accumulation of the toxic vehicle hydroxypropyl betadex), dose reduction of second-generation triazoles is not needed in patients with renal failure; patients with hepatic insufficiency require dose reduction only in advanced disease stages. The introduction of therapeutic drug monitoring could aid attempts to optimize the blood concentrations of triazoles and other drugs that are known to or that possibly interact, thus increasing treatment efficacy and safety. There is a need for new studies that are designed to provide useful data on second-generation triazole pharmacokinetics, particularly in special circumstances such as central nervous system and ocular infections, infections in newborns and infants, and in subjects with genetic polymorphisms of metabolizing enzymes.

Pharmacokinetic modeling of carbamazepine based on clinical data from Serbian epileptic patients.

The purpose of this study was to perform population pharmacokinetic (PPK) analysis on carbamazepine and to determine the population model of clearance of this drug in terms of individual patient characteristics. A total of 107 steady-state serum concentrations from 97 adult and pediatric epileptic patients, collected during routine clinical care, were used for the analysis. To determine the influence of different covariates on the estimate of carbamazepine clearance we used the non-linear mixed effects modeling (NONMEM) software package with ADVAN1 subroutine. This is a one-compartment model with first-order elimination and without absorption. The typical mean value for carbamazepine clearance, estimated by the base model (without covariates), in our population was 3.43 l/h. The final results of our analysis show that carbamazepine clearance increased nonlinearly with total body weight and age, and linearly with concomitant administration of valproate. The magnitude of the effect of valproate was +0.874 l/h. The interindividual variability (coefficient of variation) for clearance and the residual variability (including intraindividual variability), described by an exponential error model, were 16.76% and 31.14%, respectively. The results of this PPK analysis were validated in a group of 16 epileptic patients and suggested good predictive performance of the final model. The derived model describes carbamazepine clearance in terms of characteristics of Serbian patients, using minimal data obtained from routine clinical care of epileptic patients. This is the basis for future pharmacokinetic studies on a specific epileptic population, which will lead to better overall management of epilepsy in Serbia.