The Impact of Opioid Receptor Gene Polymorphism on Fentanyl and Alfentanil's Analgesic Effects in the Pediatric Perioperative Period.

Introduction: The polymorphism of the gene coding mu-opioid receptor (OPRM1) is one of the factors contributing to the variability in the response to opioid analgesics in children. The goal of this study is to investigate its role in association with postoperative acute pain in children of various ages. Methods: This prospective study analyzed 110 pediatric patients, after plastic or orthopedic surgery, who were genotyped and randomly assigned to receive fentanyl or alfentanil. Postoperative pain was rated using Numerical Rating Scale (0-10). All the patients were genotyped forOPRM1 118A>G (rs1799971) gene polymorphism. Results: School children under the age of 11 with the OPRM1 AA genotype were shown to have a higher BMI (p<0.05). Children over the age of 12 carrying G allele OPRM1, had increased postoperative pain sensitivity and intensity (3.28±1.95 vs 4.91±2.17; p<0.05), as compared to AA allele carriers. Discussion: OPRM1 118A>G polymorphism may explain the variation in the perception of postoperative pain in children over the age of 12 and may be a useful predictor for adjusting the dose of analgesics, but the dose is relative to the patient's needs regardless of his genetic characteristics. In younger children, carriers of polymorphic OPRM1 118G allele may be protected from obesity, due to diminished MOP expression.

Joint use of population pharmacokinetics and machine learning for optimizing antiepileptic treatment in pediatric population.

Purpose: Unpredictable drug efficacy and safety of combined antiepileptic therapy is a major challenge during pharmacotherapy decisions in everyday clinical practice. The aim of this study was to describe the pharmacokinetics of valproic acid (VA), lamotrigine (LTG), and levetiracetam (LEV) in a pediatric population using nonlinear mixed-effect modeling, while machine learning (ML) algorithms were applied to identify any relationships among the plasma levels of the three medications and patients' characteristics, as well as to develop a predictive model for epileptic seizures. Methods: The study included 71 pediatric patients of both genders, aged 2-18 years, on combined antiepileptic therapy. Population pharmacokinetic (PopPK) models were developed separately for VA, LTG, and LEV. Based on the estimated pharmacokinetic parameters and the patients' characteristics, three ML approaches were applied (principal component analysis, factor analysis of mixed data, and random forest). PopPK models and ML models were developed, allowing for greater insight into the treatment of children on antiepileptic treatment. Results: Results from the PopPK model showed that the kinetics of LEV, LTG, and VA were best described by a one compartment model with first-order absorption and elimination kinetics. Reliance on random forest model is a compelling vision that shows high prediction ability for all cases. The main factor that can affect antiepileptic activity is antiepileptic drug levels, followed by body weight, while gender is irrelevant. According to our study, children's age is positively associated with LTG levels, negatively with LEV and without the influence of VA. Conclusion: The application of PopPK and ML models may be useful to improve epilepsy management in vulnerable pediatric population during the period of growth and development.

Pharmacokinetics and machine learning in epilepsy Abstract: Nowadays, combined antiepileptic therapy is the best option for a number of pediatric patients. Furthermore, there are no standard procedures in the therapy management of this complex treatment. Besides therapeutic monitoring, the population pharmacokinetic (PopPK) approach and machine learning (ML) are useful sources of information regarding the optimization of therapy. The aim of this study was to describe the pharmacokinetics of valproic acid (VA), lamotrigine (LTG), and levetiracetam (LEV) in a pediatric population using nonlinear mixed-effect modeling, while ML algorithms were applied to identify any relationships among the plasma levels of the three medications and patients' characteristics. The study included 71 pediatric patients of both genders, aged 2­18 years, on combined antiepileptic therapy. Population pharmacokinetic (PopPK) models were developed separately for VA, LTG, and LEV. Based on the estimated pharmacokinetic parameters and the patients' characteristics, three ML approaches were applied (principal component analysis, factor analysis of mixed data, and random forest). According to our study, children's age is positively associated with LTG levels, negatively with LEV and without influence from VA. However, the gender of patients has no influence on drug plasma concentration. Findings demonstrated that the application of PopPK and ML models may be useful to improve epilepsy management in vulnerable pediatric population during the period of growth and development.

Potentially inappropriate prescribing among older patients and associated factors: comparison of two versions of STOPP/START criteria

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<0.001) in the total sample and within each setting (p<0.05). Drug indication (32.9%) and fall-risk medications (32.2%) were most commonly identified for STOPP v2, while cardiovascular system criteria (30.5%) were the most frequently detected for START v2. The number of medications was the strongest predictor for both STOPP v1 and v2, with odds ratio values of 1.35 and 1.34, respectively. Patients' characteristics associated with the occurrence of STOPP and START criteria were identified. According to both STOPP/START versions, the results indicate a substantial rate of potentially inappropriate prescribing among elderly patients. The prevalence of PIMs was slightly higher with the updated version, while the prevalence of PPOs was significantly lower

Plasma advanced oxidation products as an additional tool in assessment of post-infarction heart failure.

OBJECTIVE: To define which oxidative stress markers could be used as diagnostic tools in the assessment of post-infarction heart failure (HF). METHODS: This observational study enrolled patients with HF that were divided into three subgroups (ejection fraction [EF] ≥ 50%; EF 40-49%; EF < 40%) and age- and sex-matched healthy control subjects. The plasma concentrations of advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances, catalase activity and free thiols were determined in all participants. RESULTS: The study enrolled 81 patients with HF and 68 healthy control subjects. There were significant differences in the values ​​of oxidative stress markers between patients and controls. Oxidative stress parameters did not differ between the subgroups of patients, except for AOPP, which was significantly higher in the EF < 40% group. Univariate and multivariate logistic regression analyses showed an association between AOPP and HF in the EF ≥ 50% group, while receiver operating characteristic (ROC) curve analysis identified a cut-off value of 60.89 µmol/l for AOPP. CONCLUSIONS: Based on the ROC curve analysis of AOPP and the higher significance in the multivariate analyses for patients with EF ≥ 50%, these current results suggest that AOPP could be a useful additional tool in the assessment of post-infarction HF.

Utility of salivary mycophenolic acid concentration monitoring: Modeling and Monte Carlo validation approach.

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.

Antibiotic utility and susceptibility changes of multidrug-resistant Escherichia coli and Klebsiella spp: 5-year experience in a tertiary healthcare centre.

OBJECTIVES: Multiple studies have identified cross-sectional relationships between antibiotic use and bacterial resistance. The aim of this study was to analyse the susceptibility of multidrug-resistant (MDR) and non-MDR (nMDR) isolates of Escherichia coli and Klebsiella spp to cephalosporins: ceftazidime (CTZ), ceftriaxone (CTX), cefepime (CEF) and fluoroquinolones: ciprofloxacin (CIP) and levofloxacin (LEV) in a tertiary healthcare centre from 2014 to 2018. In addition, we aimed to evaluate a correlation between the antibiotic utility and susceptibility of the selected enterobacteria. METHODS: Antibiotics consumption and antimicrobial resistance were monitored in a tertiary care university hospital from 2014 to 2018. Utilisation of antibiotics in the observed period was expressed as defined daily dose (DDD) per 100 bed/days (DBD). Bacterial susceptibility was reported as the percentage of susceptible results among all tested isolates from all patient samples. In further analysis, bacterial strains were considered as MDR or nMDR species. An MDR bacterial strain was defined as one with acquired non-susceptibility to at least one agent in three or more antimicrobial categories. RESULTS: Our results suggest that cephalosporins were the most used antibiotics, followed by fluoroquinolones, during the entire observed period 2014-2018. Our findings show that MDR isolates of E. coli had an increasing trend in susceptibility in relation to CTX (p=0.005), whereas a decreasing trend was observed for MDR isolates of E. coli susceptibility towards CIP and LEV (p<0.001). Klebsiella spp susceptibility for MDR isolates showed a decreasing trend in relation to CEF (p<0.001) and both fluoroquinolones (p<0.001). A significant negative association between CEF consumption and Klebsiella spp MDR isolates susceptibility was observed (p=0.045). CONCLUSION: Implementation of antimicrobial stewardship programmes with early detection and close monitoring of MDR bacterial strains of E. coli and Klebsiella spp may be a crucial step in reducing the menace of antimicrobial resistance, which is now a global problem.

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach.

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.

Assessment of pharmacokinetic mycophenolic acid clearance models using Monte Carlo numerical analysis.

Previously, we performed population pharmacokinetic analysis and indicated age, mycophenolate mofetil (MMF)/mycophenolic acid (MPA) daily dose, and presence of nifedipine in patient therapy as significant predictors of MPA apparent clearance (CL/F) variability. This study aimed to determine the reliability of previously published population pharmacokinetic models derived from similar studies. Furthermore, this study investigated correspondence between chosen population models from the literature.By means of the Monte Carlo simulation method, pharmacokinetic models from different studies are simulated and analysed in the range of standard deviations of measured system parameters as well as the range of observed model parameters taken from the comparison studies.The 1000 numerical simulations were performed for every analysed model in order to calculate the most possible MPA CL/F values according to the expected values from the performed experiment. Fitting our results with other models showed how the presence of nifedipine makes difference in MPA CL/F values.By testing the data from selected studies into our model, a similar range of expected CL/F values was obtained, which may confirm the validity of our model. The results of our population pharmacokinetic study are partially applicable in models by other researchers.

Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience.

BACKGROUND AND OBJECTIVE: Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS: The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS: The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION: The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.

Traditional uses of autochthonous medicinal and ritual plants and other remedies for health in Eastern and South-Eastern Serbia.

ETHNOPHARMACOLOGICAL RELEVANCE: River and mountain regions in Eastern and South-Eastern Serbia are geographically interesting and, historically they represent an important resource of plants used as food, spices and as remedies for treating many diseases. Different cultures have lived in these regions for ages. They have used wild plants and the methods of their preparation and application, which has remained throughout the history and now is passed on from generation to generation. The aim of the study is a survey of herbal drug uses for the specific ailment categories and their comparison between the two research regions. METHODS: Semi-structured anonymous ethnobotanical interviews were conducted. The interviews took place in the River Timok region and Mountain Svrljig region as they make two of the most interesting centers of plant biodiversity. Volunteers in the Timok region were 64 median age and in the Svrljig region - 73 median age. People were interviewed about the local names of plants, the preparation process and about which disease the plants were used for. RESULTS AND DISCUSSION: 161 Respondents from 10 Timok and 10 Svrljig municipality villages were interviewed and 2199 use-reports were recorded. The results of the ethnobotanical research showed 195 plant taxa from the Timok and Svrljig regions. In the Timok region, the recorded species were classified into 47 families and in the Svrljig region they were classified into 64 families. Out of 195 taxa used for medicinal purposes, only 52 species are also included in the European Pharmacopoeia 9.0. The most commonly used plants in Timok region were Hypericum spp., Matricaria chamomilla, Mentha x piperita, Urtica dioica, Juglans regia, while the residents of Svrljig region most frequently used Satureja montana, Sambucus nigra, Polygonum aviculare, Marrubium vulgare and Teucrium chamaedrys. Different statistical analyzes showed that Vlachs used more medical specimens per person than Serbs in the Timok region. The study demonstrated that female informants treated more body organs with medical species per person than male informants. There was a significant difference between the male and female respondents of the Svrljig region in terms of organ systems for which they used certain plant species. CONCLUSION: The ethnopharmacological study showed a great importance of medicinal plants in the daily life of local communities. According to the analysis, it can be concluded that the village population of the Timok and Svrljig regions use medicinal plants to treat digestive tract problems rather than seeking professional medical attention in health facilities. The aerial part and rhizome of Elymus repens are used for digestive problems in both the Timok and Svrljig regions, and the use of this plant in for the treatment of digestive tract problems is not mentioned in the similar studies conducted in the Balkan region. Also, it can be observed that the population of the two different regions mainly use different herbal drugs to treat the same systems. The reason for that is the availability of certain plants that grow in the two different areas - river and mountain area.

The partnership between renalase and ejection fraction as a risk factor for increased cardiac remodeling biomarkers in chronic heart failure patients.

Objective: Heart failure (HF) represents a huge socio-economic burden. It has been demonstrated, experimentally, that renalase, a newly discovered protein, prevents cardiac hypertrophy and adverse remodeling, which is seen in HF. We postulated the following aims: to investigate associations of renalase with biomarkers of cardiac remodeling: galectin-3, soluble suppression of tumorigenicity, (sST2), growth differentiation factor 15 (GDF-15) and syndecan-1, myocardial stretch (BNP) and cardio-renal axis (cystatin C) in HF patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) to determine whether renalase, in combination with left ventricular ejection fraction (LVEF), represents a risk factor for plasma elevation in biomarkers.Methods: We classified HF patients (n = 76) according to LVEF (preserved/reduced), applied a median plasma renalase (113 ng/mL) as a cut-off value (low/high) and created four subgroups of HF patients: HFpEF/low renalase (n = 19), HFrEF/low renalase (n = 19), HFrEF/high renalase (n = 32) and HFpEF/high renalase (n = 6). A control group (n = 35) consisted of healthy volunteers.Results: Plasma concentrations of evaluated biomarkers were determined using an ELISA technique and were highest in HF patients with reduced EF (p < .001, respectively), and renalase's positive correlations were obtained relating to all biomarkers: galectin-3 (r = 0.913; p < .001), sST2 (r = 0.965; p < .001), GDF-15 (r = 0.887; p < .001), syndecan-1 (r = 0.922; p < .001), BNP (r = 0.527; p < .001) and cystatin C (r = 0.844; p < .001) and strong and negative correlation with LVEF (r = -0.456, p < .001). Increased renalase, regardless of the EF (preserved/reduced), was shown to be an independent risk factor for an increase in all evaluated cardiac remodeling biomarkers, p < .001, respectively. However, increased renalase and reduced EF was the only independent risk factor for BNP and cystatin C elevation, p < .001, respectively. Results after multivariable adjustments (age/gender) were identical.Conclusion: When elevated plasma renalase and HF are present, regardless of EF being reduced or preserved, that represents a significant risk factor for increase in cardiac remodeling biomarker plasma concentrations. However, only elevated renalase and reduced EF demonstrated significance as a risk factor for BNP and cystatin C plasma elevation. Renalase may be considered a promising molecule for the improved predictive abilities of conventional biomarkers and is worthy of further investigation.

Cardiac Remodeling Biomarkers as Potential Circulating Markers of Left Ventricular Hypertrophy in Heart Failure with Preserved Ejection Fraction.

Soluble suppressor of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor (GDF)-15 and syndecan-1 represent biomarkers of cardiac remodeling, involved in heart failure (HF) progression. We hypothesize that their plasma concentrations, together with brain natriuretic peptide (BNP), are different in HF stratified by ejection fraction (EF), demonstrating correlations with echocardiographic parameters that indicate left ventricular (LV) hypertrophy; LV mass index (LVMI) and posterior wall and septum diameters. HF patients (n = 77) were classified according to EF: reduced EF < 40% (HFrEF), mid-range EF = 40-49% (HFmrEF), preserved EF > 50% (HFpEF). We found that plasma concentrations of four cardiac remodeling biomarkers were highest in HFrEF and lowest in HFpEF, p < 0.001. In HFpEF, remodeling biomarkers independently correlated with LVMI: sST2 (p = 0. 002), galectin-3 (p < 0.001), GDF-15 (p = 0.011), and syndecan-1 (p = 0.006), whereas galectin-3 correlated after multivariable adjustments (p = 0.001). Independent correlates of septum and posterior wall diameters, in HFpEF, were sST2 (p = 0.019; p = 0.026), galectin-3 (p = 0.011; p = 0.009), GDF-15 (p = 0.007; p = 0.001), and syndecan-1 (p = 0.005; p = 0.002). In HFrEF, only sST2, adjusted, correlated with LVMI (p = 0.010), whereas BNP correlated with LVMI (p = 0.002) and EF (p = 0.001). GDF-15 correlated with diastolic dysfunction in HFpEF (p = 0.046) and HFrEF (p = 0.024). Cardiac remodeling biomarkers are potential circulating indicators of LV hypertrophy in HFpEF, which may ensure timely recognition of disease progression among high-risk patients.

Association of Plasma Renalase and Left Ventricle Mass Index in Heart Failure Patients Stratified to the Category of the Ejection Fraction: A Pilot Study.

Heart failure represents a growing health problem, with increasing morbidity and mortality globally. According to the mechanisms involved in the pathogenesis of heart failure, many biomarkers have been proposed for the timely diagnosis and prognostication of patients with heart failure, but other than natriuretic peptides, none of them has gained enough clinical significance. Renalase, a new protein derived from kidneys was demonstrated to metabolize catecholamines and to have a cardioprotective role. The aim of the study was to determine whether renalase and brain natriuretic peptide (BNP) concentration could be used to differentiate heart failure patients stratified to the category of the ejection fraction and whether plasma renalase could be used as a biomarker for left ventricle hypertrophy in all subgroups of heart failure patients. We included patients diagnosed with heart failure and stratified them to the three subgroups according to the ejection fraction. Regarding echocardiographic parameters, HFmrEF had an intermediate profile in between HFrEF and HFpEF, with statistical significance in most evaluated parameters. BNP concentration was significantly different in all three subgroups (p < 0.001), and renalase was statistically higher in HFrEF (p = 0.007) compared to the HFmrEF and HFpEF, where its results were similar, without statistical significance. Renalase plasma concentration was demonstrated to be highly and positively associated with left ventricle mass index in HFrEF (p = 0.029), as well as increased plasma concentration of BNP (p = 0.006). In the HFmrEF group of patients, body mass index was positively associated with LVMI (p = 0.05), while in the patients with HFpEF, diabetes mellitus was demonstrated to have a positive association with LVMI (p = 0.043). These findings suggest that renalase concentration may be measured in order to differentiate patients with reduced ejection fraction. Plasma renalase concentrations positively correlated with left ventricle hypertrophy in patients with reduced ejection fraction, being strongly associated with increased left ventricular mass index.

The predictive value of Klotho polymorphism, in addition to classical markers of CKD-MBD, for left ventricular hypertrophy in haemodialysis patients.

PURPOSE: Cardiovascular events are the major reasons for mortality in haemodialysis patients. Fibroblast growth factor 23 (FGF23), Klotho protein and G-395A Klotho gene polymorphism have been associated with effects on the cardiovascular system. Our study investigates the interrelationship between Klotho protein gene variations, mineral-bone metabolism and left ventricular hypertrophy in patients undergoing chronic haemodialysis programme. MATERIALS AND METHODS: Patients (n = 142) were genotyped for G-395A Klotho gene. Components of mineral-bone metabolism, classical and non-classical (FGF23, Klotho and vitamin D) as well as echocardiographic examination were determined. Predictive models were designed to determine the significance of Klotho gene variations and mineral-bone metabolism components for left ventricle hypertrophy (LVH). RESULTS: A-allele carriers were longer on haemodialysis (p = 0.033), and had higher phosphorus levels (p = 0.016) while the level of Klotho protein was significantly lower (p = 0.001) compared to non-A-allele carriers. The best gains were achieved upon addition of allele A, and all three new markers; the AUC made significant improvement from 0.596 to 0.806 (p < 0.001), and improved net reclassification for 82.1% (95% CI 42.9-121.3%). CONCLUSIONS: The genetic background of A-allele carriers of the G-395A Klotho gene polymorphism increases the susceptibility patients to haemodialysis. A-allele carriers are at a higher risk for the development of cardiovascular complications. The addition of non-classical to classical mineral metabolism components improves prediction power to LVH.

Adverse effects of mycophenolic acid in renal transplant recipients: gender differences.

Background Mycophenolic acid is widely used immunosuppressive drug, associated with adverse effects which increase patient morbidity and decrease medication adherence. Objective To evaluate the adverse effects in renal transplant recipients under mycophenolate treatment with respect to gender. Setting University Clinical Centre of Nis, Clinic of Nephrology, Serbia. Method This research included 96 renal transplant recipients, who received immunosuppressive regimen, based on tacrolimus or cyclosporin A, prednisone and mycophenolic acid. The high-performance liquid chromatography method combined with protein precipitation was used for the analysis of mycophelate concentration in human plasma. Drug concentration and dose-adjusted concentration were determined with respect to the patients' gender. An adverse effect scoring system developed by nephrologists within the University of Buffalo Nephrology/Transplant Program was used to monitor adverse effects of therapy. Main outcome measure Individual and scores of adverse effects in relation to the dosing regimen and gender. Results Results showed statistically lower dose and concentrations in men compared to the women in our investigation group. Also, female patients demonstrated higher mean scores (cumulative and subscores) within the same dosing regimens of mycophenolic acid. The gastrointestinal score was significantly higher in women who received a dose greater than 720 mg compared to men (0.20 ± 0.12 vs 0.12 ± 0.12). Women demonstrated higher individual adverse effects such as diarrhea and skin changes (41.7 vs 17.0; p = 0.038 and 62.5 vs 30.2; p = 0.037, respectively). Conclusions The results of our research showed that recipients' gender may play an important role in pharmacokinetic profile of mycophenolic acid, suggesting that women had higher concentration of mycophenolic acid and more serious side effects.

Current Biochemical Monitoring and Risk Management of Immunosuppressive Therapy after Transplantation.

Immunosuppressive drugs play a crucial role in the inhibition of immune reaction and prevention of graft rejection aswell as in the pharmacotherapy of autoimmune disorders. Effective immunosuppression should provide an adequate safety profile and improve treatment outcomes and the patients' quality of life. High-risk transplant recipients may be identified, but a definitive prediction model has still not been recognized. Therapeutic drug monitoring (TDM) for immunosuppressive drugs is an essential, but at the same time insufficient tool due to low predictability of drug exposition and marked pharmacokinetic variability. Parallel therapeutic, biochemical and clinical monitoring may successfully optimize and individualize therapy for transplanted recipients, providing optimal medical outcomes. Modern pharmacotherapy management should include new biomarkers with better sensitivity and specificity that can identify early cell damage. The aim of this study was to point out the importance of finding new biomarkers that would enable early detection of adverse drug events and cell damage in organ transplant recipients. We wanted to confirm the importance of routine biochemical monitoring in improving the safety of immunosuppressive treatment.

Renalase Assessment With Regard to Kidney Function, Lipid Disturbances, and Endothelial Dysfunction Parameters in Stable Renal Transplant Recipients.

BACKGROUND: Renal transplant dysfunction has been shown to be independent predictor for premature cardiovascular disease and mortality. Renalase, a flavoprotein secreted by several tissues, including the kidney, has been found to regulate sympathetic tone and blood pressure. The purpose of this secondary analysis was to explore relationships among parameters of endothelial dysfunction, lipids, glomerular filtration rate, and renalase in 2 groups: renal transplant patients with controlled hypertension and healthy volunteers. METHODS: In the parent study, 73 renal transplant recipients and 32 age- and gender-matched controls were enrolled. A fasting sample for endothelial, lipid, and renalase values, along with other clinical parameters, was obtained. RESULTS: We found statistically significant inverse correlation between renalase and estimated glomerular filtration rate ( r = -0.552, P < .001), positive correlation between renalase and creatinine ( r = 0.364, P = .003), total cholesterol ( r = 0.578, P < .001), low-density lipoprotein cholesterol ( r = 0.261, P = .046), and non-high-density lipoprotein cholesterol ( r = 0.327, P = .01). Renalase inversely correlated with hemoglobin ( r = -0.232, P = .032) and positively with white blood cells ( r = 0.233, P = .032). There was a significant difference in plasma renalase with regard to chronic kidney disease stages ( F = 13.346, P < .001) but did not correlate with C-reactive protein. Renalase did not correlate with any of parameters of endothelial dysfunction, C-reactive protein, neither with some demographic data (gender, age, time or type of transplantation, risk factors). There were no differences in renalase concentration with regard to antihypertensive therapy. CONCLUSION: Renalase strongly and inversely correlated with kidney function, positively with creatinine and lipid disturbances. Due to that it is very likely that renalase levels are determined mostly by renal function.

Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function.

The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation.

Herbal self-medication use in patients with diabetes mellitus type 2.

BACKGROUND/AIM: A considerable number of patients suffering from diabetes mellitus (DM) turn to self-medication using medicinal plants, preparations, and medicine. The aim of this study was to investigate self-medication using medicinal plants and the potential influence of health care professionals' advice or media information regarding the use of herbal dietary supplements with hypoglycemic effect in a population of patients with type 2 DM. MATERIALS AND METHODS: This research, in the form of an analytic cross-sectional study, was conducted in 6 pharmacies in the territory of Nis, Serbia, during October 2013. The criterion set for the study was to include patients diagnosed with type 2 diabetes who used pharmacotherapy in addition to herbal supplements. RESULTS: Surveyed women showed a statistically significant difference in the frequency of using herbal supplements compared to men (P < 0.001). More frequent symptoms of hypoglycemia were reported in the group of diabetic respondents who used herbal dietary supplements (P < 0.05). The media was most responsible for influencing decisions about self-medication that included the use of herbal dietary supplements. CONCLUSION: The role of health professionals is indispensable and very important, especially when the media is a potential cause of seeking self-medication.

The assessment of renalase: searching for the best predictor of early renal dysfunction by multivariate modeling in stable renal transplant recipients.

BACKGROUND: Renal transplant dysfunction has been shown to be an independent risk factor for cardiac, non-cardiovascular, and all-cause mortality in post-transplantation follow-up. MATERIAL AND METHODS: We enrolled 73 renal transplant recipients who were more than 12 months post-renal transplant surgery, had stable graft function, and were on standard immunosuppression. The purpose of the study was to observe the relation between renal dysfunction and endothelial dysfunction parameters (nitrates, asymmetric and symmetric dimethylarginine, and endothelial nitric oxide synthase), and renalase, and to hypothesize the best predictor of early renal dysfunction by multivariate modeling. The other aim was to observe differences with regard to immunosuppression. RESULTS: Non-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate in transplant recipients with increased renalase concentration (p=0.026); age-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate with increased renalase concentration (p=0.042), also after multivariable adjustment (p=0.032). Increased plasma endothelial nitric oxide synthase concentration was a protective factor for glomerular filtration rate (p=0.011). After adjustment for age (p=0.045), and after multivariate modeling, endothelial nitric oxide synthase was shown to be a protective factor for glomerular filtration rate (p=0.014). Significant differences in immunosuppression were found in plasma renalase in patients maintained on cyclosporine (p=0.027). CONCLUSIONS: Renalase was shown to be strong predictor of decreased glomerular filtration rate and was significantly higher in the group of patients on cyclosporine. Endothelial nitric oxide synthase was identified as a strong protective factor for kidney function.