Total costs of inpatient treatment for COVID-19 in a tertiary hospital in Serbia.

BACKGROUND: Our study aimed to identify the total costs of inpatient treatment for coronavirus disease 2019 (COVID-19) in a tertiary institution in Serbia, an upper-middle-income country in Southeast Europe. METHODS: An observational, retrospective, cost-of-illness study was performed from the perspective of the National Health Insurance Fund and included a cohort of 78 females and 118 males admitted to the COVID-19 ward units of a tertiary center during the first wave of the pandemic. RESULTS: The median of the total costs in the non-survivors subgroup (n =43) was 3,279.16 Euros [interquartile range (IQR): 4,023.34; range: 355.20-9,909.61) which is higher than in the survivors (n =153) subgroup 747.10 Euros (IQR: 1,088.21; 46.71-3,265.91). The cut-off value of 156.46 Euros regarding the total costs per day was estimated to have 95.3 % sensitivity and 91.5 % specificity for predicting patients' dismal prognosis, with the area under the curve (AUC) of 0.968 (95 % confidence interval: 0.940-0.996, p <0.001). CONCLUSIONS: Direct medical inpatient treatment costs for COVID-19 represent a significant economic burden. The link between increased costs and an ultimate unfavorable outcome should be further explored.HIPPOKRATIA 2022, 26 (2):62-69.

The Safety of Local Hormonal Treatment for Vulvovaginal Atrophy in Women With Estrogen Receptor-positive Breast Cancer Who Are on Adjuvant Aromatase Inhibitor Therapy: Meta-analysis.

Atrophic vaginitis is a relatively common adverse effect of aromatase inhibitors used as an adjunctive treatment for breast cancer. Vaginal estrogen therapy is a treatment option, but the safety of its use in estrogen receptor-positive breast cancer remains understudied. The aim of our study was to determine the safety of local hormonal treatment of vulvovaginal atrophy in women treated with aromatase inhibitors. Our meta-analysis was based on a systematic search of the literature and selection of high-quality evidence. The safety of local hormonal therapy of vaginal atrophy in women on aromatase inhibitors were summarized using calculators built by the authors; heterogeneity was assessed by the Cochrane Q test and I2 values. Several types of bias were assessed; publication bias was calculated by a funnel plot and the Egger regression. Eleven studies fulfilled the inclusion criteria for our study. After 8 weeks of local hormonal treatment, there was no change in the serum levels of luteinizing hormone and estradiol, whereas sex hormone binding globulins were low, and follicle stimulating hormone was almost doubled compared with the baseline. Adverse effect rates of vaginal discharge, facial hair growth, urinary tract or yeast infection, and vaginal or vulvar itching and/or irritation did not show significant changes in the sensitivity analysis, with exception of a single trial. Current evidence suggests that vaginal estrogen administration in postmenopausal women with a history of breast cancer is not associated with systemic absorption of sex hormones and may provide indirect evidence for the safety of their use.

The first comparative double-blind trial on efficacy and safety of ergotamine based five-component combination and sumatriptan in migraine without aura.

BACKGROUND: Dihydroergotamine or ergotamine are the most effective preparations for aborting acute attacks of migraine without aura. OBJECTIVE: The aim of our study was to compare the efficacy and safety of ergotamine based five-component drug combination and sumatriptan in the treatment of moderate to severe acute attacks of migraine without aura. METHODS: The study was designed as a randomized, double-blind, double-dummy, placebo-controlled, parallel arm, multi-center clinical trial. The enrolled patients having migraine without aura were randomized to one of the study arms, ergotamine based five-component drug combination or sumatriptan. RESULTS: In total, 201 patients were randomized to one of the treatment arms. Higher percentage of patients was completely free of the headache two hours after dose administration in the ergotamine-based medication group compared to the sumatriptan group, regardless whether all (51.12 % vs 33.70 %) or only repeated attacks were taken into account (50.91 % vs 23.73 %); the salvage therapy (diclofenac) utilization rate was also lower in the ergotamine-based medication group (relative risk 0.61). Photophobia, phonophobia, and osmophobia were reversed more frequently in the ergotamine-based medication group (51.12 % vs 33.70 %), and failure to abort an attack of the migraine without aura occurred more frequently in the group treated with sumatriptan (1.1 % vs 4.9 %). The headache intensity two hours after ingestion of the study medication increased more frequently with sumatriptan, while other adverse events were rare in both groups. CONCLUSIONS: This study demonstrated higher efficacy and similar safety of ergotamine based fixed drug combination in comparison to sumatriptan, when used in the treatment of an acute attack of the migraine. HIPPOKRATIA 2018, 22(1): 17-22.

Influence of regular reporting on local Pseudomonas aeruginosa and Acinetobacter spp. sensitivity to antibiotics on consumption of antibiotics and resistance patterns.

WHAT IS KNOWN AND OBJECTIVE: Regular surveillance of antimicrobial resistance is an important component of multifaceted interventions directed at the problem with resistance of bacteria causing healthcare-associated infections (HAIs) in intensive care units (ICUs). Our aim was to analyse antimicrobial consumption and resistance among isolates of Pseudomonas aeruginosa and Acinetobacter spp. causing HAIs, before and after the introduction of mandatory reporting of resistance patterns to prescribers. METHODS: A retrospective observational study was conducted between January 2011 and December 2015, at an interdisciplinary ICU of the Clinical Centre Kragujevac, Serbia. The intervention consisted of continuous resistance monitoring of all bacterial isolates from ICU patients and biannual reporting of results per isolate to prescribers across the hospital. Both utilization of antibiotics and density of resistant isolates of P. aeruginosa and Acinetobacter spp. were followed within the ICU. RESULTS AND DISCUSSION: Resistance densities of P. aeruginosa to all tested antimicrobials were lower in 2015, in comparison with 2011. Although isolates of Acinetobacter spp. had lower resistance density in 2015 than in 2011 to the majority of investigated antibiotics, a statistically significant decrease was noted only for piperacillin/tazobactam. Statistically significant decreasing trends of consumption were recorded for third-generation cephalosporins, aminoglycosides and fluoroquinolones, whereas for the piperacillin/tazobactam, ampicillin/sulbactam and carbapenems, utilization trends were decreasing, but without statistical significance. In the same period, increasing trends of consumption were observed for tigecycline and colistin. WHAT IS NEW AND CONCLUSION: Regular monitoring of resistance of bacterial isolates in ICUs and reporting of summary results to prescribers may lead to a significant decrease in utilization of some antibiotics and slow restoration of P. aeruginosa and Acinetobacter spp. susceptibility.

Translation of the Medical Fear Survey to Serbian: psychometric properties.

BACKGROUND: Medical Fear Survey (MFS) is an instrument designed for measuring fear of medical and related treatments. OBJECTIVE: Aim of the present study was MFS translation into Serbian, measurement of its psychometric properties and MFS validation using other Blood-injury-injections and related stimuli instruments that have been translated from English into Serbian. METHOD: After obtaining permission from the author of the original MFS, double forward translation from English to Serbian and backward translation to English were conducted in ten steps, according to International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Reliability, factorial analysis and concurrent validation of Serbian version of MFS were conducted on a sample of 485 medical or pharmacy students at University of Kragujevac, Serbia. RESULTS: Serbian version of MFS showed high internal consistency with a Cronbach's alpha 0.968 and good temporal stability after testing-and-retesting (Spearman's correlation coefficient 0.838, and intraclass correlation coefficient 0.877). Factorial analysis confirmed the same five factors demonstrated in the original English version: fear of mutilated bodies (10 items), fear of blood (11 items), fear of injections and blood draws (9 items), fear of sharp objects (10 items), and fear of medical examinations and physical symptoms (10 items). The total score of MFS correlated significantly with the total scores of Injection Phobia Scale-Anxiety (Spearman's correlation coefficient 0.391, p <0.001), Blood/Injection Fear Scale (Spearman's correlation coefficient 0.502, p <0.001) and Medical Avoidance Survey (Spearman's correlation coefficient 0.396, p <0.001). CONCLUSIONS: Serbian version of the 50-item MFS showed similar psychometric properties as the original English version of this scale, with the same factorial structure. It could be used for measurement of fear of medical and related treatments in Serbian socio-cultural milieu, preferably self-administered. Hippokratia 2016, 20(1): 44-49.

Rewarming curves and derived parameters in the diagnosis of hand-arm vibration syndrome.

BACKGROUND: Exposure to hand-arm vibrations is a known cause of the Hand-arm vibration syndrome (HAVS), a progressive syndrome beginning with sensory loss and leading to gangrene, making timely diagnosis essential. OBJECTIVES: Assessment of the usefulness of 9 diagnostic parameters claimed as being of greatest value in the diagnosis of HAVS, and examination of the complementary diagnostic value of the curve shapes. METHODS: Three groups of subjects (HAVS cases, exposed workers without irreversible changes, and controls) were examined by cold provocation followed by thermographic imaging, obtainment of rewarming curves for four preselected regions and calculation of parameters. The discriminative value of individual parameters and the discriminative power of a combination of all the parameters were assessed. Qualitative curve shape analysis was included. RESULTS: The greatest individual discriminative ability is associated with RT (rewarming time to pre-cooling value, p < 0.001), Tmax (maximum temperature during the 10-minute recovery, p < 0.001), k (rewarming rate, p < 0.012) and RD (rewarming delay, p < 0.031). The discriminant analysis yielded one significant discriminant function (Wilks' lambda = 0.278, chi2 (18) = 48.67, p < 0.001, canonical R2 = 0.63). Four types of rewarming curves were identified. CONCLUSIONS: RT, Tmax, k and RD appear to be the most suitable individual parameters for group discrimination. When linearly combined, the parameters can be useful for discriminating HAVS cases from both Controls and Claimants, which constitutes the main task of an occupational health physician. Additional information is available from the qualitative assessment of the rewarming curve shape.

Contractile effects of endothelins on isolated human ureter.

The aim of our study was to investigate mechanism of action of endothelins 1, 2 and 3 on spontaneous activity, tone and intraluminal pressure of human ureter. Both longitudinal tension and intraluminal pressure were recorded from the isolated segments of proximal human ureter. Endothelins 1, 2 and 3 (5.35x10(-11) M - 5.05x10(-8) M) produced concentration-dependent tonic contraction and sustained increase in intraluminal pressure of isolated preparations of human ureter. Endothelins 1 and 3 produced also concentration-dependent inhibition of spontaneous, phasic contractions of the isolated preparations. Selective antagonist of ET(A) receptors BQ123 and selective antagonist of ET(B) receptors BQ788 produced significant inhibition of endothelin-1-induced tonic contraction (pA(2)=8.80 and 6.55, respectively) and increase in intraluminal pressure (pA(2)=8.68 and 7.02, respectively), while they did not affect endothelin-1-induced inhibition of spontaneous activity. Endothelin 1 produces increase in tone and intraluminal pressure of isolated human ureter acting on both ET(A) and ET(B) receptors, the first one being functionally more important. Only endothelins 1 and 3 inhibit spontaneous, phasic activity of human ureter, but this effect was not blocked by selective antagonists of ET(A) and ET(B) receptors.

Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis.

OBJECTIVE: The aim of the present study was to build population pharmacokinetic models for the clearance of carbamazepine (CBZ) in two separate populations of Serbian patients with epilepsy, children and adults. METHODS: Analysis was performed using 114 and 53 steady-state concentrations of CBZ collected from 98 children and 53 adult epileptic patients, respectively. Mean values of total body weight and age were 31 ± 13 kg and 8 ± 3 years in the population of children, and 67 ± 13 kg and 32 ± 15 years in the population of adults. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS: The derived final models of CBZ clearance were similar in the target populations. The most important factors which affected typical mean value of CBZ clearance in both populations studied were age of the patients and total daily dose; the CBZ clearance linearly followed increase of these factors. However, the influence of the patients' age was almost 3.4 times higher in the pediatric population than that in adults while the influence of total daily dose of CBZ is similar. On the other hand, final model in the adult population revealed also influence of concomitant therapy with phenobarbital (PB). The magnitude of this effect was +1.61 l h-1. The pharmacokinetic models obtained were validated in groups of 18 children and 13 adults with epilepsy. CONCLUSIONS: The derived models describe well CBZ clearance in terms of Serbian pediatric and adult epileptic patient characteristics, offering a basis for rational individualization of CBZ dosage regimens.

Gallbladder emptying in patients with major depression: a case series.

INTRODUCTION: Although several adverse effects of antidepressants on the gastrointestinal tract have been described (bleeding, constipation, dolichocolon), their influence on gallbladder motility was not investigated.The aim of our study was to investigate the effects of selected antidepressants on gallbladder emptying in patients with major depression. METHODS: The study was set up as an open clinical trial, with the same intervention (ingestion of test meal provoking gallbladder emptying) undertaken in 112 patients with major depression. There were 30 patients not taking antidepressants (the control group), 25 patients taking amitriptyline, 30 patients taking maprotiline, and 27 patients taking fluoxetine. The volume of gallbladder in the study patients was measured by ultrasonography before the test meal, and 15, 30, 45 and 60 min after the meal. RESULTS: 1 h after ingestion of the study meal, the amitriptyline group showed incomplete gallbladder emptying (F=10.829, df=3, p=0.000; mean residual volume 11.0±6.1 mL), while in the control, maprotiline and fluoxetine groups emptying of gallbladder was complete (mean residual volumes 5.0±3.3 mL, 5.6±3.7 mL and 5.7±2.3 mL, respectively). DISCUSSION: In patients with cholecystitis, it would be wise to use antidepressants which do not impair gallbladder emptying, like maprotiline or fluoxetine, and to avoid amitriptyline.

Factors influencing valproate pharmacokinetics in children and adults.

OBJECTIVE: The aim of the present study was to build population pharmacokinetic models for the clearance of valproate (VPA) in 2 separate populations of Serbian patients with epilepsy, children and adults. METHODS: Analysis was performed using 65 and 63 steady-state concentrations of VPA collected from 58 children and 60 adult epileptic patients, respectively. Mean values for total body weight and age were 27.07 ± 13.08 kg and 7.21 ± 3.63 years in the pediatric population, and 69.67 ± 15.60 kg and 33.97 ± 16.41 years in the adult population. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS: The derived final models show that VPA clearance increased with total body weight of patients in both populations. However, the carbamazepine comedication was the main determinant of the final model in children whereas phenobarbitone comedication was the most important factor in the adult population. The magnitudes of these effects were +0.159 lh-1 and +0.539 lh-1 for carbamazepine and phenobarbitone, respectively. A significant decrease in interindividual and intraindividual variability was observed in the target populations. The pharmacokinetic models obtained were validated in groups of 15 epileptic patients, each showing good predictive performance of the model. CONCLUSIONS: The derived models describe well VPA clearance in terms of characteristics of Serbian pediatric and adult epileptic patients, offering a basis for rational individualization of VPA dosage regimens.

Population pharmacokinetics of tacrolimus in kidney transplant patients.

OBJECTIVE: The purpose of this study was to derive population pharmacokinetics (PPK) model of tacrolimus clearance, identify and describe factors that influence it in Serbian kidney transplant patients. METHODS: Population pharmacokinetics analysis was performed using nonlinear mixed-effects model (NONMEM) program from Serbian adult kidney transplant patients receiving triple immunosuppressive therapy, including oral tacrolimus. Details of drug dosage history, sampling time and tacrolimus concentration in 63 patients (44 males and 19 females), 27 - 57 years old (age mean 40.88 +/- 7.01 years) were collected retrospectively. Effects of several covariates on tacrolimus clearance were tested: total body weight, gender, age, posttransplantation days, hemoglobin count, CRP, alanine aminotransferase/aspartate aminotransferase, total daily dose of tacrolimus, co-medication with cotrimoxasole, omeprazole, mycophenolate mofetil and prednisone (> 25 mg). RESULTS: Typical mean value of tacrolimus clearance, estimated by the base model (without covariates), in our population was 1.03 l h-1. The final model showed that tacrolimus clearance increased with total daily dose and concomitant administration of high-dose prednisone (> 25 mg). The magnitude of prednisone effect was + 1.16 l h-1. Final model was validated in a group of 17 patients, showing good predictive performance. CONCLUSIONS: The derived model describes well tacrolimus clearance in terms of characteristics of Serbian kidney transplant patients, offering basis for rational individualization of tacrolimus dosing regimens.

The contractile effects of endothelins on isolated isthmic segment of human oviduct at the luteal phase of the menstrual cycle.

The purpose of this study was to investigate the effects of endothelins (ET) 1, 2 and 3 on isolated isthmic segments of the human oviduct at the luteal phase of menstrual cycle. Fallopian tubes were taken from 21 patients and the isthmic segments were mounted in an organ bath longitudinally. Tension of the isolated preparations was recorded with an isometric transducer. ET-1 and ET-2 triggered concentration-dependent tonic contractions of the isolated isthmic segment and inhibited rhythmic activity, while ET-3 caused no effect. Furthermore, the selective ET(A) antagonist BQ-123 and the selective ET(B) antagonist BQ-788 inhibited the ET-1 effects on both tone and spontaneous rhythmic contractions. These results suggested that during the luteal phase of the menstrual cycle, both ET(A) and ET(B) receptors participate in contractile effects of endothelins on isthmic segment of fallopian tubes, probably regulating the length of time the oocyte remains in the oviduct ampulla.

Arterial embolization of uterine fibroids.

PURPOSE: the aim of this study was to analyze outcomes in a series of patients with symptomatic uterine fibroids who had undergone endovascular arterial embolization. METHODS: analysis included 36 patients with uterine fibroids and average age of 38.5 years, with bilateral endovascular embolization of fibroid-feeding arteries. Solitary uterine fibroids were present in 20 (56%) patients, and multiple in 16 (44%) patients. The patients were followed up to one year after embolization. RESULTS: in the subgroup of patients with solitary uterine fibroids, 6 months after the embolization, the volume of uterine fibroids was reduced to 50% in 16 patients, and to 38% in 4 patients. After one year, the volume of uterine fibroids was reduced to 50% in all 36 patients. In the subgroup of patients with multiple uterine fibroids, 6 months after the embolization, the volume of uterine fibroids was reduced to 50% in 10 patients, and to 36% in 6 patients. After one year, the volume of uterine fibroids was reduced to 50% in 14 patients, while in 2 patients the reduction of the volume remained 36%. After one year, all patients became symptomless. CONCLUSION: the results of this case series show high efficacy of endovascular embolization of uterine fibroids: with a minimally invasive treatment, the volume of uterine fibroids is halved and symptoms disappear, obviating the need for a surgical intervention.

Population pharmacokinetics of lamotrigine in patients with epilepsy.

OBJECTIVE: The purpose of this study was to derive a population pharmacokinetics (PPK) model of lamotrigine clearance as well as to identify and describe factors that influence it in Serbian patients with epilepsy. METHODS: A total of 40 steady-state serum concentrations from 38 adult and pediatric patients with epilepsy, collected during routine therapeutic drug monitoring, were used for the analysis. To determine the influence of different covariates on the estimate of lamotrigine clearance we built a non-linear mixed-effects one-compartment model with the first order elimination and without absorption. RESULTS: Typical mean value of lamotrigine clearance, estimated by the base model (without covariates), in our population was 1.15 l h-1. The final model showed that lamotrigine clearance increased with total body weight, daily dose and concomitant administration of carbamazepine, and decreased with concomitant administration of valproate. The magnitude of carbamazepine and valproate effect was +1.13 l h-1 and -1 l h-1, respectively. The final model was validated in a group of 15 epileptic patients, showing good predictive performance. CONCLUSIONS: The derived model describes well lamotrigine clearance in terms of characteristics of Serbian patients, offering basis for rational individualization of lamotrigine dosing regimens.

Etiology of a short-term mortality in the group of 750 patients with 920 episodes of status epilepticus within a period of 10 years (1988-1997).

PURPOSE: To determine the etiology of short-term mortality in patients with status epilepticus (SE). METHODS: 920 episodes of SE were recorded among 750 patients in a 10-year period. According to the clinical assessment, sequence of events that led to death in a particular case showed two major causes of death: (1) underlying disease, and (2) complications caused by convulsions, therapy or coma. RESULTS: Among 920 episodes of SE, 120 (13%) patients passed away. 79 patients (65.8%) died due to the underlying disease and 27 patients (22.5%) died of the combination caused by complications of underlying disease, convulsions, therapy, and/or coma. Among remaining 14 patients (11.7%), underlying disease was not the cause of death. Those 14 patients suffered complications caused by convulsions, therapy, and coma which caused death in four; therapy and coma in three; therapy in three; coma in two; and convulsions and coma in two patients, in the order already mentioned. CONCLUSIONS: Among approximately 9 out of 10 patients with SE, death was the result of underlying disease. Although with very few patients, additional factors could provoke fatal complications of SE. In case of 1 among 10 patients complications caused by coma, therapy, and/or convulsions were the immediate cause of death. In case of such patients timely and adequate treatment could prevent death.

Pharmacokinetic modeling of valproate from clinical data in Serbian epileptic patients.

The aim of this study was to define a population pharmacokinetic model that could estimate the clearance of valproate (VPA) in a Serbian epileptic population. For the analysis, 97 steady-state concentrations of VPA were used, collected from 93 patients with epilepsy during routine clinical care in our hospital. To build a final model, we selected the ADVAN1 program subroutine from the NONMEM library for estimating the drug clearance (CL) and determining the influence of different covariates. This is a one-compartment model with first-order elimination and without absorption. Estimation of the predictive performances of the final model was performed on a validation set consisting of 20 epileptic patients. Typical mean value of CL of VPA estimated by the base model in our population was 0.368 l h(-1). The results of the final model show that the CL of VPA increased linearly with total body weight (TBW) and patients' age, while carbamazepine (CBZ) comedication did not affect it significantly. Interindividual variability (coefficient of variation) for CL was 27.2%. Residual error, including intraindividual variability, was 29.68%. The results of the validation process and the analysis of prediction errors suggest a good predictive performance of the final population model. The defined model describes CL of VPA in terms of specific Serbian patient characteristics, using serum concentration data obtained from routine therapeutic drug monitoring.

Contractile effect of acetylcholine on isolated isthmic segment of fallopian tubes.

The Fallopian tubes are sparsely innervated with cholinergic nerve fibers. Acetylcholine is released from these nerves and contracts the smooth muscles of the tubes. The aim of our study was to investigate the effect of acetylcholine on the isthmic segment of the Fallopian tubes using selective antagonists in different hormonal settings. We investigated the effects of acetylcholine on the isolated isthmus of Fallopian tubes taken from 83 patients during abdominal hysterectomy with adnexectomy. Twenty-eight patients were in the follicular phase, 36 were in the luteal phase of the menstrual cycle, and 19 patients were in menopause. Selective and non-selective muscarinic and nicotinic receptor antagonists were used. Acetylcholine (1.8-658.6 micro M) produced concentration-dependent tonic contraction of isthmus taken from the patients in the follicular phase, the luteal phase and menopause. The nicotinic receptor antagonist mecamylamine (6.5 micro M) and local anesthetic lidocaine (230.8 micro M) did not alter the effect of acetylcholine. While M(1) and M(2)-selective muscarinic receptor antagonists pirenzepine (1.6 micro M) and methoctramine (0.9 micro M) did not show specific effect, atropine (0.01 micro M) and the selective M(3)-receptor antagonist p-fluoro-hexahydro-sila-difenidol (pFHHSiD; 0.2 micro M) effectively blocked contractions caused by acetylcholine (maximal pA(2) values 9.74 and 7.54, respectively). The affinity of pFHHSiD for muscarinic receptors was highest in the follicular phase. The results of our study suggest the existence of functional M(3) muscarinic receptors in the isthmus of the Fallopian tubes, located on the smooth muscle cells.