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Background: Serbia, as the largest market of the Western Balkans, has entered socioeconomic transition with substantial delay compared to most of Eastern Europe. Its health system reform efforts were bold during the past 15 years, but their results were inconsistent in various areas. The two waves of global recession that hit Balkan economies ultimately reflected to the financial situation of healthcare. Serious difficulties in providing accessible medical care to the citizens became a reality. A large part of the unbearable expenses actually belongs to the overt prescription of pharmaceuticals and various laboratory and imaging diagnostic procedures requested by physicians. Therefore, a broad national survey was conducted at all levels of the healthcare system hierarchy to distinguish the ability of cost containment strategies to reshape clinician’s mindsets and decision-making in practice. Aims: Assessment of healthcare professionals’ judgment on economic consequences of prescribed medical interventions and evaluation of responsiveness of healthcare professionals to policy measures targeted at increasing cost-consciousness. Study Design: Cross-sectional study. Methods: A nationwide cross-sectional survey was conducted through a hierarchy of medical facilities across diverse geographical regions before and after policy action, from January 2010 to April 2013. In the middle of the observed period, the National Health Insurance Fund (RFZO) adopted severe cost-containment measures. Independently, pharmacoeconomic guidelines targeted at prescribers were disseminated. Administration in large hospitals and community pharmacies was forced to restrict access to high budget-impact medical care. Economic Awareness of Healthcare Professionals Questionnaire–29 (EAHPQ-29), developed in Serbian language, was used in face-to-face interviews. The questionnaire documented clinician’s attitudes on: Clinical-Decision-Making-between-Alternative-Interventions (CDMAI), Quality-of-Health-Care (QHC), and Cost-Containment-Policy (CCP). The authors randomly and anonymously recruited 2000 healthcare experts, with a total of 1487 responding; after eliminating incomplete surveys, 649 participants were considered before and 651 after policy intervention. Results: Dentists (1.195±0.560) had a higher mean CDMAI score compared to physicians (1.017±0.453). The surgical group compared to the internist group had a higher total EAHPQ-29 score, CCP score and CDMAI score. Policy intervention had a statistically significant negative impact on the QHC score (F=4.958; df=1; p=0.027). There was no substantial impact of policy interventions on professional behavior and judgment with regard to the CDMAI, CCP, and total EAHPQ-29 scores. Conclusion: Although cost savings were forcibly imposed in practice, the effects on clinical decision-making were modest. Clinicians’ perceptions of quality of medical care were explained in a less effective manner due to the severely constrained resources allocated to the providers. This pioneering effort in the Balkans exposes the inefficiency of current policies to expand clinicians’ cost consciousness.

Antiepileptic drugs show clinically significant interactions among themselves as well as with other medications, because of a specific pharmacokinetic profile and relatively small therapeutic spectrum. The most significant clinical interactions of AE occur during their metabolism and distribution. In the combined antiepileptic therapy, it is very important to know the order of application of AE because of their influence on liver enzymes and the affinity to attach to plasma proteins. The AE with shorter half-time elimination have a greater potential for interaction which is why therapy monitoring is recommended. Populational pharmacokinetic analysis can provide significant information concerning interactions of AE with other medications. Vulnerable, pediatric population is under a special risk of developing interactions alongside patients with liver and kidney function damage.

Abstract The study aimed to estimate and compare the prevalence and type of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) between the STOPP/START original (v1) and updated version (v2) among older patients in various settings, as well as associated factors. The study included 440 patients attending a community pharmacy, 200 outpatients and 140 nursing home users. An increase in the prevalence of STOPP v2 (57.9%) compared to v1 (56.2%) was not statistically significant in the total sample and within each setting (p>0.05). A decrease in the prevalence of START v1 (55.8%) to v2 (41.2%) was statistically significant (p

Vitamin D is one of the keys to bone health, and the serum levels of this vitamin are a major concern for postmenopausal women. The aims of this study were to develop a population pharmacokinetic (PPK) model for the clearance of 25-hydroxy vitamin D in non-elderly postmenopausal women and to identify the factors which have a significant influence on its clearance. The study population consisted of postmenopausal women who had been referred for evaluation of bone mineral density (BMD) by DEXA (dual-energy x-ray absorptiometry) scanner. The population pharmacokinetics modeling was conducted using the ADVAN 1 subroutine from a non-linear mixed effects (NONMEM) program, and thirty-two covariates were assessed. A total of 75 serum concentrations were obtained from the same number of postmenopausal women and used for PPK analysis. The mean value of the participantsí age was 57.92 ± 3.93 years and their body weight was 69.76 ± 11.49 kg. A wide range of 25-hydroxy vitamin D concentrations was observed (from 3.41 to 61.92 ng/mL) with a mean value of 26.19 ± 10.95 ng/mL. A total of 32 covariates were examined and preliminary results suggested the influence of six covariates on 25-hydroxy vitamin D clearance. In the final PPK model, however, only one covariate was shown to have a significant impact on the clearance value -- the mean daily dietary intake dose of vitamin D (DD). These findings offer a preliminary basis on which to determine the level of vitamin D supplementation required by individual postmenopausal women. It could prove particularly important in achieving optimal serum levels of vitamin D in this vulnerable population. [ABSTRACT FROM AUTHOR]

Abstract The results of the previous studies demonstrated an association between mycophenolic acid (MPA) exposure, serum albumin level (ALB), and adverse effects in kidney transplant patients. The aim was the identification of mathematical correlation and association between both, total and unbound MPA concentration in relation to ALB, body mass (BM), age and estimated glomerular filtration rate (eGFR) in stable kidney transplant recipients. Furthermore, investigation was conducted with the aim to clarify the role of salivary concentration (CSAL) of MPA in adverse effect profile. In order to analyze the association between total and salivary concentration of MPA in relation to ALB, BM, age and eGFR, a least squares method for determining the correlation between these parameters was performed. In addition, derived mathematical model based on experimental data can also be performed and simulated through the Monte Carlo (MC) approach. Adverse effects were grouped according to the nature of symptoms and scored by a previously published validated system. Numerically calculated values of CSAL from the models [CSAL = f(ALB, BM, age, eGFR, CP) = a00 + a10*(ALB, BM, age, eGFR) + a01*CP] were then compared with those from validation set of patients, where the best fitting model was for ALB [CSAL = 54.96–1.64*ALB +13.4*CP]. Adverse effects estimation showed the difference in esthetic score, positively correlated with CSAL in the lower ALB group (145.41 ± 219.02 vs. 354.08 ± 262.19; with statistical significance p = .014) and almost significant for gastrointestinal score (167.69 ± 174.79 vs. 347.55 ± 320.95; p = .247). The study showed that CSAL MPA may contribute to management of adverse effects, but these findings require confirmation of clinical utility.

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

Beside the traditional risk factors which have an effect on cardiovascular diseases, hemodialysis patients are exposed to metabolic factors, such as malnutrition, microinflammation and oxidative stress, along with mineral bone disorder. The aim of this study was to determine a three-year survival in patients undergoing chronic hemodialysis and to analyse correlation with parameters of mineral bone metabolism. During the three-year follow-up 186 patients were included, of which 115 men (61.83%) and 71 women, with a mean age 61.47±12.42. The exact date and the direct cause of death were recorded and mineral bone metabolism parameters were analysed. Out of 67 dead patients, 33 (49.25%) died from cardiovascular cause. Out of the total number of deaths in our study, only 11.9% of patients had a target PTH values. Patients with PTH>600 pg/ml are exposed to an increased risk from the overall mortality (RR=0.48, 95% CI (0.24-0.95), p=0.04), but also from cardiovascular mortality (RR=0.34, 95% CI (0.12-0.93), p=0.034) compared to patients with normal serum PTH. These patients have a statistically significant higher serum phosphorus in comparison with patients with normal PTH levels (1.72±0.42 vs. 1.39±0.36, p=0.032). Phosphorus above 2.10 mmol/L increases the relative risk for the overall mortality rate by 60% (RR=0.59, 95% CI (0.35-0.89), p=0.049). In our study, 2-fold higher risk of all-cause mortality (RR=2.00, 95% CI (0.92-4.36), p=0.048), and even 3-fold higher risk of cardiovascular mortality (RR=3.03, 95% CI (0.71-1.29), p=0.039) were found in patients with CaxP levels above 4.50 mmol2/L2. Three-year mortality rate of patients undergoing hemodialysis was 36.02%, while half of the patients died from cardiovascular disease. Patients with hyperparathyroidism and elevated calcium phosphorus product are at the highest risk, both for all-cause and cardiovascular mortality. Patients with hyperphosphatemia are at higher risk for all-cause mortality.

Irrational antibiotic consumption, especially in the case when there is no appropriate indication for its usage, may be one of the most crucial global issues for public health care, leading to bacterial resistance and the increase of indirect medical expenses. According to the report of the European program for the monitoring of the antibiotic consumption, Serbia is on the fifth place among the countries which are not members of EU. The goal of this work is the evaluation of antibiotic consumption in the Clinical Centre Niš, from 2007 to 2013, with the focus on the monitoring of the cephalosporins utilization, as they are one of the most prescribed groups of antibiotics in the tertiary health care. The utilization of antibiotics in the Clinical Center Niš in the observed period was obtained from the computerized database of the Department of Pharmacotherapy and expressed as defined daily dose (DDD) per 100 bed/days (DBD). Our results showed that there was an increase in antibiotic use of the whole group of cephalosporins and penicillin as well as a reduction of quinolones consumption within the observed period. Our analysis showed that ceftriaxone was the most frequently prescribed cephalosporin, followed by cefuroxime. Although antibiotic therapy and prophylaxis in our hospital are in keeping with the recommended guidelines, the obtained results may suggest that cephalosporin consumption, and especially ceftriaxone consumption is higher than in other European countries.

Self-medication represents the use of medicines and herbal remedies with the purpose of treating or preventing a disease the symptoms of which are recognized by the patients themselves. Drugs that are intended for self-medication and do not require a prescription are called “over-the-counter medicines” (OTC) products. The aim of the paper was to evaluate self-medication in the adult population in the Niš region and determine the potential factors affecting the level and the quality of self-medication. A total of 300 respondents, divided into three age categories, were interviewed: aged 18 to 30, 31 to 65 and over 65. Self-medication is the most common in the respondents aged 18 to 30 (98%). The analysis of the data revealed a statistically significant difference among groups at the level of trust in doctors and their own expertise/awareness of the disease as the main reasons for self-medication. There was a statistically significant difference among the groups regarding media influence on the selection of drug (p

Carvedilol is a nonselective beta blocker/alpha-1 blocker, which is used for treatment of essential hypertension, chronic stable angina, unstable angina and ischemic left ventricular dysfunction. The aim of this study was to describe carvedilol population pharmacokinetic (PK) analysis as well as the validation of analytical procedure, which is an important step regarding this approach. In contemporary clinical practice, population PK analysis is often more important than standard PK approach in setting a mathematical model that describes the PK parameters. Also, it includes the variables that have particular importance in the drugs pharmacokinetics such as sex, body mass, dosage, pharmaceutical form, pathophysiological state, disease associated with the organism or the presence of a specific polymorphism in the isoenzyme important for biotransformation of the drug. One of the most frequently used approach in population PK analysis is the Nonlinear Modeling of Mixed Effects - NONMEM modeling. Analytical methods used in the data collection period is of great importance for the implementation of a population PK analysis of carvedilol in order to obtain reliable data that can be useful in clinical practice. High performance liquid chromatography (HPLC) analysis of carvedilol is used to confirm the identity of a drug and provide quantitative results and also to monitor the efficacy of the therapy. Analytical procedures used in other studies could not be fully implemented in our research as it was necessary to perform certain modification and validation of the method with the aim of using the obtained results for the purpose of a population pharmacokinetic analysis. Validation process is a logical terminal phase of analytical procedure development that provides applicability of the procedure itself. The goal of validation is to ensure consistency of the method and accuracy of results or to confirm the selection of analytical method for a given sample and drug. This study confirmed the importance of using valid analytical procedure for the purpose of carvedilol population pharmacokinetic analysis. Identification of demographic, pathophysiological and other factors that may influence the population carvedilol PK parameters gives the physician the possibility of a more comprehensive overview of the patient and better optimization of the therapeutical regimen.

The insulin resistance is present when the concentration of insulin is normal and biological response is decreased. The most frequent metabolic change that was detected during anti-hypertension therapy is a change in the insulin resistance. Beta-blockers are generally accompanied by the deterioration of metabolic control in patients with diabetes. It is considered that using certain beta-blockers in hypertension therapy in patients with diabetes mellitus type 2 (DM type 2) can significantly influence the insulin resistance. Taking into consideration the latest knowledge on pharmaco-dynamics of insulin analogues and beta -blockers, by observing the parameters of glycoregulation, it would be of great interest and practical significance to determine the following influence of beta - blockers and their selectivity on the insulin resistance in patients with DM type 2 and hypertension. The research was conducted at the Endocrinology Clinic of the Clinical Centre Niš, and it included 60 patients with diagnosed diabetes mellitus type 2. After collecting anamnesis data, clinical and laboratory research performance, all patients were divided into two therapy groups: first group, 30 patients that were administered the therapy based on insulin glargine and second group, 30 patients that were administered the therapy based on insulin glargine and blocker divided into two therapy subgroups: 15 patients that were administered the therapy based on insulin glargine and carvedilol and 15 patients that were administered the therapy based on insulin glargine and metoprolol. Higher values of glycaemia and glycolised haemoglobin were found in patients receiving therapy based on beta–blocker (p

Immunosuppressive medicines are characterized by specific pharmacokinetic profile which requires therapy monitoring by means of measuring their blood concentrations. Therapy monitoring, by means of determining blood concentration of the medicine, enables application of an optimal individual immunosuppressive therapy. Due to its variable pharmacokinetics, and small therapeutic index and potential interaction with numerous other medicines, the post-operative monitoring of immunosuppressive medicines is an essential element of therapy protocol for renal transplantation patients. Therapy monitoring represents an efficient way to reduce adverse effects of immunosuppressive medicines and to prevent transplantation rejection, by means of adapting the doses in renal transplantation patients. Determining the concentration of immunosuppressive medicines is of special importance in the modified dosing for patients with renal insufficiency. Pharmacokinetic analysis is important for proper interpretation of immunosuppressive medicines' blood concentrations. The interpretation of the received results must be multidisciplinary, considering that there are numerous factors of variability of patients and immunosuppressive medicines.

Beside excretory role in elimination of many drugs, there is intensive metabolism and secretion in kidney, which is essential for normal functioning of many organs and systems.The use of drugs in renal failure is associated with doubled risk of side and toxic effects. That is the reason why meticulously modificated dosing of drugs eliminating or metabolized by kidney is essential, particularly drugs with small therapic wideness and drugs which cumulate.

The syndrome of chronic renal failure (CRF) is already known for more than 150 years. Current research in this domain changed our understanding in epidemiology, aetiology, prevention of disease progression, classifications, definition, and adequate treatment of comorbid conditions in predialytic period. With data collection and registration on CRF patients it is obvious an increase in prevalence and incidence of patients with CRF in the world. The diabetic nephropathy is the most common disease leading in 40% of cases to terminal CRF. In the follow up of these patients the most important goal is slowing down the disease progression with low protein diet (0,6-0,8 g/kg BW/day) and vigorous blood pressure control (target values: 120-135/75-85 mmHg). The adequate therapy of anaemia and secondary hyperparathyroidism including predialytic use of erythopoietin and vitamin D significantly slow down the progression of CRF and postpones the beginning of dialytic treatment. Numerous comorbid conditions present in predialytic period fasten the progression of CRF. The most common are of cardiovascular origin (congestive heart failure and coronary artery disease). Those cardiovascular comorbid conditions have an impact on CRF progresion as well as on the outcome in dialytic therapy. The most common causes of cardiovascular comorbidity are hypertension, anemia and secondary hyperparathyroidism, all of which should be treated in predialytic period. Of special concern is use of nephrotoxic drugs, particularly nephrotoxic antibioticsaminoglycosides. The optimal timing of creation of permanent vascular access and vaccination against hepatitis B in predialytic period are cost-effective and have an impact on quality of dialysis.

The substitution of human tissues by similar material obtained from other humans or animals has been one of the most ancient dreams but has only recently become a reality. Successful renal transplantation is the treatment of choice for most end stage renal disease (ERDS) patients, improving quality of life and increasing survival as compared with longterm dialysis treatment. The purpose of this article is to explain the process of transplantation by discussing the development of this method in region, postoperative course, potential complications and benefits. A brief overview of immunosuppression will also be discussed as well as future prospects including measure of improving the results and increasing the numberof renal transplants.

The pharmacotherapeutic attitude that the statins are optimal hypo-lipemic medicaments in treating the increased serum cholesterol is generally accepted. Regarding the fact that in the lipid profile of the patients with the terminal kidney inefficiency the hypercholesterolemia dominates at the peritoneal dialysis, the therapeutic efficiency and the fluvastatin forbearance are examined.In the study the one-way blind, placebo controlled method of the clinic examination is used in the study. The research is carried out at the Institute for Nephrology and Hemodialysis of the Clinic Center, Nis, in 30 patients at the CAPD (14 men and 16 women, of average age 52,8±11,23 and dialyzing duration of 2,26±0,95 years). The patients are treated with fluvastatin, namely, 20 mg once a day, in the evening, for 6 months. The control placebo group was made up of20 patients at the CAPD with similar clinic characteristics. The lipid status also comprised determination and monitoring of cholesterol (C), triglyceride (TG), lipoproteins of high density (HDL) and lipoprotein of small density (LDL).During the six months of its application, fluvastatin has led to a statistically considerably important reduction of cholesterol (p 0,001), LDL (p