The Kv1.5 potassium channel provides an ultra-rapid delayed rectifier potassium current, I_Kur, that acts selectively in human atrial cells. This makes selective Kv1.5 blockade a promising approach to control atrial arrhythmias without the adverse ventricular effects associated with classical hERG-subtype potassium channel blockers (Kv11.1). This review considers all currently known Kv1.5-channel blockers with a biaromatic structure and data on their biological properties. For many of the Kv1.5-selective compounds studied, the ability to prevent the development of atrial arrhythmias without affecting ventricular refractoriness was confirmed.

Relevance. Alcoholic cardiomyopathy (ACMP) is the leading cause of mortality in chronic disease, which is largely associated with an increased risk of developing malignant diseases of the cardiovascular disease. Search for new drugs, including those exhibiting pronounced antiarrhythmic activity, supposed relevance. Objective. To study the effect of combination therapy with fabomotizole and ALM-802 on atrial depolarization in a translational model of alcoholic cardiomyopathy in rats. Methods. The sequence of depolarization of the atrial epicardium was studied in rats in a translational model of alcoholic cardiomyopathy, which received a combination of fabomotizole and compound ALM-802 daily for 28 days after the end of 24 weeks of alcoholization, or pyrogen-free water intraperitoneally. Results. As a result of the 28-day combined action of fabomotizole and the compound ALM-802 in animals with alcoholic cardiomyopathy, additional areas of early activation in the area of lacunae of the pulmonary veins that form during the 24-week period of alcoholization disappear, the risk of atrial arrhythmias is minimized, and sequential propagation.

The antiarrhythmic activity of bis-alkoxyphenyltriazaalkanes 1 and bis-alkoxyphenyldiazaalkanes 2 was analyzed in a model of reperfusion arrhythmia in rats. It was found that the key requirements for the compounds activity in this model are the use of 2,3,4 trimethoxyphenyl aromatic pharmacophores and the presence of a central nitrogen atom in the linker. The most active compounds were ALM-802 (trihydrochloride N¹–(2,3,4-trimethoxybenzyl)-N²– {2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine) and ALM-811 (N¹-(2,3,4-trimethoxybenzyl)-N³-{3-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,3-propanediamine trihydrochloride), which significantly prevented the development of ventricular tachycardias and/or ventricular fibrillation.

The experimental study of the pharmacokinetic characteristics of a new pyrrole derivative of carnosine, pyrrolylcarnosine, was carried out. Based on the results of the experiment, the basic pharmacokinetic parameters of the drug are expected. The tissues and organs bioavailability was studied. The tropism of pyrrolylcarnosine to the organs of elimination and the ability of pyrrolylcarnosine to penetrate into the heart muscle tissue were shown.

The aim. The primary objective of the study was to evaluate the effect of food on the bioavailability of Aterixen^® 100 mg tablet after single oral dose under fasting or fed conditions. The secondary objective was to evaluate the pharmacokinetic parameters, safety, and tolerability of Aterixen^® 100 mg tablet after single oral dose under fasting or fed conditions. Materials and methods. Healthy male and female volunteers aged 18 to 45 years were included in the study. Due to lack of data about intra-individual variability of the main pharmacokinetic parameters of the active substance in Aterixen^® (XC221GI, 1-[2-(1-Methylimidazol-4-yl)-ethyl]perhydroazin-2,6-dione), an adaptive group sequential approach was used in the study. At Stage I, 24 volunteers were randomized into 2 groups (12 in each group): Group 1 (sequence AAB) received treatment A (administration of the drug under fasting conditions) during period I, treatment A during period II and treatment B (administration of the drug under fed conditions) during period III, Group 2 (sequence BBA) received therapy B during period I, therapy B during period II, and therapy A during period III. In each study period, serial blood samples were collected before and throughout 12 h after administration of the study drug. The quantification of the active substance XC221GI in plasma samples was performed using a validated high-performance liquid chromatography method with mass spectrometric detection. Safety evaluation was performed on the basis of frequency and severity of adverse events (AEs) and serious adverse events (SAEs), which were registered based on complaints, physical examination, laboratory tests, and electrocardiography (ECG). Drug tolerability was evaluated in terms of proportion of volunteers who prematurely discontinued participation in the study due to AE/SAE. Results. 24 randomized volunteers completed the study in compliance with the approved study protocol. The averaged pharmacokinetic curves profiles of XC221GI had similar shapes under fasting and fed conditions. Confidence intervals for the ratio of the geometric means for the primary parameters (AUC_(0-t) and C_max) of XC221GI and AUC_(0-∞) were within the 80-125 % acceptance interval, while a small in absolute value, but statistically significant differences were noted in time until C_max is reached. Throughout the study, 2 volunteers reported AEs (low RBC count, low hemoglobin concentration, and low hematocrit value) after receiving the study drug under fed conditions. All reported AEs were mild. The relationship between AEs and the study drug product was assessed by investigator as doubtful. Conclusion. The results of this study indicate that food does not affect the bioavailability of Aterixen^® 100 mg, tablets, and the single oral dose of 100 mg was safe and well tolerated by healthy volunteers.

Imbalance of glucose homeostasis in the mother-placenta-fetus system in case of gestational diabetes mellitus (GDM) leads to pre- and postnatal abnormalities in offspring. Lack of universally recognized GDM-model complicates the search for pathogenetic means to prevent and correct abnormalities in offspring. A model using food load (high-calorie diet) in combination with low doses of diabetogen streptozotocin (HCD-STZ model) seems to be one of the closest in causes, mechanisms of development and clinical findings. Hence, the aim was to work out and assess the suitability of HCD-STZ model of GDM in order to register abnormalities in the offspring and determine the possibility of their pharmacological correction. Rats and its fetuses were the objects of the study. Modeling of GDM involved keeping rats on a high-calorie diet (NCD) for at least 10 weeks followed by a single injection of low-dose STZ on the first day of gestation. The hyperglycemia characteristic of GDM is recorded in less than 40 % of animals in HCD group combined with streptozotocin at a dose of 25 mg/kg. This fact does not allow a reliable assessment of abnormalities of antenatal and postnatal development of offspring. Thus, the model used is not promising for finding means of pharmacological correction of the effect of GDM on offspring.

Relevance. To conduct a preclinical evaluation of the effectiveness of antidiabetic drugs, models simulating the pathogenesis and main manifestations of diabetes mellitus (DM) in humans are needed. The streptozotocin (STZ) model, which has received the most widespread use in the experiment, does not allow reproducing the stepwise multifactorial development of type 2 diabetes. Goal. To develop a model of type 2 diabetes using a high-carbohydrate diet in combination with a subthreshold dose of STZ in Wistar rats, characterized by hyperglycemia and insulin resistance. Methods. The animals of the control group (n = 20) received water as a drink, and the experimental group (n = 20) received a 10 % solution of fructose. After 14 days, 10 animals from each group were injected with STZ at a dose of 35 mg/kg. The blood glucose level was determined weekly. To assess insulin resistance, a oral glucose tolerance test was performed before and after the administration of STZ. Results. It was found that keeping rats on a high-carbohydrate diet for two weeks leads to a violation of glucose tolerance, which indicates insulin resistance. The introduction of STZ at a subthreshold dose of 35 mg/kg to animals on a standard diet causes an increase in the glycemic drop to 13.2 mmol/l, while the same dose of STZ against the background of a high-carbohydrate diet causes an increase in the level of hyperglycemia to 22.9 mmol/l and increases insulin resistance. Conclusion. The synergism of a high-carbohydrate diet and low doses of STZ makes it possible to obtain a model of type 2 diabetes mellitus that reproduces not only basal hyperglycemia, but also impaired glucose tolerance, which more fully corresponds to the process of developing type 2 diabetes in humans.

One way to analyze the activity of the ABCB1 protein is to assess the accumulation of its substrate fexofenadine (F.) inside the test cells. The goal is to develop and validate a method for the quantitative analysis of F. in Caco-2 cell lysate using HPLC-MS/MS. Materials and methods. Caco-2 cell lysate was used as a matrix. The analysis was performed on an "Ultimate 3000" chromatograph with a TSQ Fortis triple quadrupole mass detector, a UCT Selectra C18 4.6 mm*100 mm 5 µm column in a gradient elution mode. The mobile phase rate was 0.3 ml/min, the sample volume was 20 µl, the ionization mode was positive, and the internal standard was amantadine (ng/ml). Sample preparation — precipitation of cell lysate protein with acetonitrile. The method was validated for the following parameters: selectivity, linearity, lower limit of quantitation (LLOQ), correctness, precision, sample transfer and sample stability. Results. Chromatograms of the blank lysate of Caco-2 cells showed no peaks with retention times characteristic of F. (5.70 min) and amantadine (3.58 min). NPKO F. was 0.5 ng/ml. F.'s transfer did not exceed 20% of NPKO, and amantadine — 5%. Based on the results of the analysis of three series of calibration standards (0.5; 1; 1.5; 5; 10; 25; 40; 50 ng/ml), linear regression equations were obtained, the correlation coefficients exceeded 0.99. Accuracy and precision were assessed within and between cycles by analyzing F. solutions in the matrix (0.5; 1.5; 25 and 40 ng/ml) within three cycles. The parameters did not exceed 20% for LLPO and 15% for other points. The stability of F. solutions (1.5 and 40 ng/ml) in the lysate was analyzed during storage at room temperature, after 3-fold freezing-thawing, storage at -80 °C for 60 days, after sample preparation and being in the autosampler for 24 hours. The accuracy was within 15% of the nominal values. Conclusions. A method for the quantitative determination of F. in Caco-2 cell lysate using HPLC-MS/MS has been developed and validated.