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A poor correlation was found between daily CBZ dose and serum concentrations in the elderly patients (r=0.2, P=0.25). Probably statistically significant difference in the median values of the CBZ metabolic rate constant (P<0.001) between elderly and relatively young epileptic patients was found. Our results showed that age-related influences in CBZ pharmacokinetics in elderly patients should be considered in the optimal planning of CBZ dosage regimens. Most elderly patients with epilepsy will usually need CBZ dosages lower than those based on the median population PK parameter values obtained from younger patients. The present population model is also uniquely well suited for the new 'multiple model' design of dosage regimens to hit target therapeutic goals with maximum precision.

Therapeutic drug monitoring (TDM) of valproate (VAL) is important in the optimization of its therapy. The aim of the present work was to evaluate the ability of TDM using model-based, goal-oriented Bayesian adaptive control for help in planning, monitoring, and adjusting individualized VAL dosing regimens. USC*PACK software and routine TDM data were used to estimate population and individual pharmacokinetics of two commercially available VAL formulations in epileptic adult and pediatric patients on chronic VAL monotherapy. The population parameter values found were in agreement with values reported earlier. A statistically significant (P < 0.001) difference in median values of the absorption rate constant was found between enteric-coated and sustained-release VAL formulations. In our patients (aged 0.25-53 years), VAL clearance declined with age until adult values were reached at about age 10. Because of the large interindividual variability in PK behavior, the median population parameter values gave poor predictions of the observed VAL serum concentrations. In contrast, the Bayesian individualized models gave good predictions for all subjects in all populations. The Bayesian posterior individualized PK models were based on the population models described here and where most patients had two (a peak and a trough) measured serum concentrations. Repeated consultations and adjusted dosage regimens with some patients allowed us to evaluate any possible influence of dose-dependent VAL clearance on the precision of total VAL concentration predictions based on TDM data and the proposed population models. These nonparametric expectation maximization (NPEM) population models thus provide a useful tool for planning an initial dosage regimen of VAL to achieve desired target peak and trough serum concentration goals, coupled with TDM soon thereafter, as a peak-trough pair of serum concentrations, and Bayesian fitting to individualize the PK model for each patient. The nonparametric PK parameter distributions in these NPEM population models also permit their use by the new method of 'multiple model' dosage design, which allows the target goals to be achieved specifically with maximum precision. Software for both types of Bayesian adaptive control is now available to employ these population models in clinical practice.

This approach permits one to individualize drug therapy for patients even when only sparse therapeutic drug monitoring (TDM) data are available. Future individual CBZ serum level predictions were acceptable from a clinical point of view (mean absolute error = 13.2 +/- 9.7%). The optimal sampling strategy approach helped to design an optimal cost-effective TDM protocol for CBZ therapy management.

What is Known and Objective Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepines and/or valproates by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for valproate (VPA) and post – induction carbamazepine (CBZ) behaviour as well as for combined therapy with CBZ plus another “old” antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data “works”, and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post-induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. Methods Four groups of TDM data were analyzed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors and weighted prediction errors were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. Results and Discussion This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient-specific maximum aposteriori probability (MAP) Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residuals and weighted residuals were close to a Normal distribution (Kolmogorov – Smirnov test, p>0.05) and their mean values did not differ statistically significantly from zero (no statistically significant bias, p>0.05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (p<0.05). Prediction of serum levels further into the future was less precise than those closer to the present for a 1.5 to 3.5-year observation period. No bias in predictions was associated with the time horizons. What is New and Conclusion Our validation res...

Background: The microrheological disorders of red blood cells in obesity is often missed by the researchers. This study aimed to report an experimental investigation on laboratory animals with developed obesity and to find out the effect of meldonium on the erythrocytes.Methods: A total of 95 healthy male-rats of Vistar line were taken into the investigation, 29 animals had experienced no impacts and allocated as the control group, while 64 rats which had developed obesity induced by a cardioangionefopathogenic semisynthetic diet into the obesity group. These rats were casually divided into an experimental (34 rats) group and the control group (30 rats). The rats of the experimental group in the next ten days were intragastrically injected with meldonium for 80 mg/kg. The biochemical, hematological and statistical methods of investigation were used in this study.Results: During the formation of obesity and the use of meldonium, the body weight of the rats were gradually decreased to the normal level. On the obese rat's group receiving meldonium, the content of the lipids peroxidation products in erythrocytes progressively decreased.  and reached the level of the healthy control rats group. Moreover, there was a decrease in the number of erythrocytes-discocytes accompanied by an increase in the reversible and irreversible changes. These values were returned to the level of the healthy control rats group at the end of the observation. This pattern was observed in the total number of erythrocytes aggregate and free erythrocytes.Conclusion: The application of meldonium eliminates the existing erythrocytes abnormal microrheological features in the rats with recently developed obesity.

Background and Aim: Left ventricular myocardial remodeling could play an important role in the progression of chronic heart failure (CHF) syndrome in dogs with mitral valve endocardiosis. The aim of this study was to evaluate the left ventricular myocardial remodeling in dogs with mitral valve endocardiosis and to study the dependence of the incidence of this pathological phenomenon on the functional class (FC) of progression of the CHF syndrome. Materials and Methods: A total of 108 afflicted dogs and 36 clinically healthy dogs were examined using transthoracic echocardiography. The following structural and geometric parameters of the left ventricular remodeling were evaluated: Myocardial mass and its index, sphericity index at the end of systole and diastole, end-systolic and end-diastolic relative wall thickness, and integral remodeling index. Results: In all clinically healthy dogs, a normal type of the left ventricular chamber geometry was revealed, whereas, in dogs with mitral valve endocardiosis, the normal geometry of the left ventricle occurred in 56.4%, eccentric hypertrophy in 24.1%, concentric remodeling in 10.2%, and concentric hypertrophy in 9.3% of the cases. In patients with endocardiosis, there was no dilatation type of cardiac remodeling observed. Conclusion: When compared to the clinically healthy animals, the dogs with mitral valve endocardiosis presented with indicators of structural and geometric remodeling, such as increased myocardial mass, myocardial mass index, and sphericity index at the end of systole and diastole, as well as relatively reduced integral systolic index of remodeling and systolic relative thickness of the walls of the heart. The parameters of the left ventricular myocardial remodeling correlated significantly with the FC of CHF syndrome.