This review continues a series of reviews on the analysis of compounds with cardioprotective properties in a number of biaromatic structures, which include a range of sodium channel blockers. Among voltage-gated sodium channels, the Nav1.5 isoform is the most abundant in the heart. Sodium channel blockers have historically been called "class I antiarrhythmics". Among the compounds of this type, a biaromatic structure mainly have the Nav1.5 late current blockers belonging to the Id subclass of antiarrhythmic drugs. Leader molecules from this subgroup, such as ranolazine, GS-458967, and F15845, reduce action potential recovery time and suppress trigger activity induced by early post-depolarization. They are effective for the treatment of stable angina and ventricular tachycardia.

Relevance. As part of the conducted open non-randomized phase I clinical trial the pharmacokinetics (PK) of the first Russian novel antiplatelet agent Angipur (nonpeptide glycoprotein IIb/IIIa receptor inhibitor) was studied.

Aim of the research was to evaluate PK parameters of Angipur in healthy volunteers after single dose ascending infusions.

Methods. 20 male healthy volunteers were enrolled in this phase I trial. Angipur (0.02% concentrate solution for infusion) was administered to every subject in single doses 0.015, 0.05, 0.09 mg/kg for 3 consecutive days. PK parameters were evaluated.

Results. After single intravenous administration of doses 0.015, 0.05, 0.09 mg/kg to healthy volunteers the peak plasma concentration of Angipur was reached at the end of the infusion, and then the plasma concentration rapidly decreased 15 minutes after the end of the infusion followed by slow decrease for 12 hours. Dose proportionality for key PK parameters was established. After single infusions of doses 0.015, 0.05, 0.09 mg/kg mean AUC_0-t was 27.11, 92.04 and 180.39 ng× h/ml; mean AUC_0-¥ – 37.03, 125.76 and 239.61 ng×h/ml; mean С_max – 12.44, 46.1 and 92.48 ng/ml; mean V_d – 304.01, 299.67 and 252.96 l; mean Т_1/2 – 6.72, 6.84 and 6.06 h; Сl – 32.19, 32.29 and 31.55 l/h; k_el – 0.1073, 0.1109 and 0.1257 l/h; MRT – 8.94, 8.93 and 8.18 h.

Conclusion. Pharmacokinetics of Angipur in studied doses demonstrated linearity, rapid reaching of С_max immediately after the infusion and the high distribution of the drug in tissues and biological fluids of the human organism..

The article presents the results of studying the pharmacokinetics and enzymatic stability of a new pharmacologically active compound GZK-111– N-phenylacetyl-glycyl-L-proline ethyl ether in comparison with noopept – N-phenylacetyl-L-prolyl-glycine ethyl ether in rats. It has been shown that both compounds are intensively metabolized in the body of experimental animals, while one of the main active metabolites of both compounds is cyclo-L-prolylglycine (CPG), which has similar neurotropic activity, but the intensity and speed of its formation during metabolic transformations is significantly more pronounced in GZK-111 compared to noopept. The significance of CPG in the realization of the main neurotropic effects of the studied compounds in the experiment in rats is shown.

Background. Alkylating drugs have been used in tumor chemo therapy for many decades, and the search for effective compounds continues.

The aim of the study was to study the activity of the developed new compound – 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol) in comparison with lomustine (CCNU) from the nitrosoalkylurea group, which is similar in chemical structure, in the model of intracranially transplanted Ehrlich's tumor and sarcoma 180 in mice.

Methods. According to the developed technique, 64 female mice of the BALB/c line were punctured in the skull under anesthesia and inoculated with tumor cells of Ehrlich's carcinoma or sarcoma 180 in 0.9 % sodium chloride solution. After 24 hours, the test substances were administered at the maximum tolerated doses – chlonisol (20 mg/kg, i.p.) and lomustine (50 mg/kg, orally), once. The effect was compared with the control (solvent injection).

Results. Chlonisol significantly increased the median overall survival (MOS) of animals after intracranial transplantation of both Ehrlich's tumor (by 39 %) and sarcoma 180 (by 84 %) compared with control (p<0.0001). Chlonisol reduced the risk of death in mice by 73 % compared to control in Ehrlich tumor transplantation and by 83 % in sarcoma 180 (p<0.0001). In contrast, lomustine did not show a significant therapeutic effect in intracranial transplantation of both tumors.

Conclusion. The high activity of chlonisol in comparison with lomustine gives reason to consider it as a potential cytostatic agent in the treatment of nervous system tumors.

Anti-inflammatory potency of 5-hydroxypyrimidine derivatives SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypirimidine) and SNK-578 (hydrochloride 2-isobutyl-4,6-dimethyl-5-hydroxypirimidine) was evaluated on the model of complete Freund`s adjuvant (CFA)-induced exudative inflammation in experiment on 60 outbreed male rats weighing 180–200 g in comparison with prednisolone. Prednisolone, SNK-411 and SNK-578 were injected twice: in 24 and 2 hours in before the injection of CFA. Prednisolone was administered in dose of 10 mg/kg, SNK-411 in doses of 25 mg/kg and 40 mg/kg, SNK-578 in doses of 10 mg/kg and 25 mg/kg. Paw and ankle joint edema were registered 24 hours after subplantar injection of CFA in right hind foot. Prednisolone administration in dose of 10 mg/kg decreased paw and ankle joint edema, SNK-578 in dose of 25 mg/kg decreased exudative edema of the paw, SNK-411 in dose of 40 mg/kg decreased paw and ankle joint edema. Acquired data correlates with previously obtained results that 5-hydroxypirimidine derivatives have antiallergenic effect on the model of systemic anaphylaxis in experiment on guinea pigs.

GIZh-298 is a new derivative of 4-phenylpyrrolidone with anticonvulsant and nootropic effects. A selective and sensitive HPLC-MS technique for the quantitative determination of GIZh-298 in rat blood plasma has been developed and validated. The linearity of the technique was confirmed by a high correlation coefficient (>0.99). Recovery of GIZh-298 from blood plasma averaged 73.4 ±3.4 %. Accuracy during one working cycle and between cycles was < 4.01%, precision < 8.03 %. The study of the stability of GIZh-298 revealed that the target compound is stable in a biomatrix at room temperature (4 h), when it is in a thermostatically controlled autosampler (8 °C) during an analytical experiment, with prolonged storage at -50 ° C for 30 days, and also if it is subjected to several freeze-thaw cycles (3 cycle). The pharmacokinetics of GIZh-298 in rat blood plasma after a single intravenous injection at a dose of 60 mg/kg was studied.

The effect of picamilon (50 mg/kg/day), tropoxin (10 mg/kg/day) and LK-933 (9,3 mg/kg/day) on the behavior of CD-1 mice phenotypes with different attention stability in the "closed enriched cross maze" test after 6 days of intraperitoneal administration was studied. It was shown for the first time that in mice with native attention deficit drugs with nootropic and cerebrovascular activity improved attention. Observed effect was combined with changings of exploratory behavior parameters, motor activity and anxiety in both mice subpopulations. Obtained results allow to make an assumption about further experimental study of drugs with cerebrovascular properties in the attention deficit disorder model proposed by the authors.

Relevance. Interpretation of the preclinical trials data is fundamental importance. The correctness of extrapolation of data obtained from animals to humans is due to the qualitative and quantitative diversity of the systems tested the recorded parameters and approaches to their interpretation, as well as statistical methods in determining the possible risk to humans.

Aim. Comparative assessment of the safety and tolerability parameters obtained during the preclinical and clinical trials of the Reamberin® (LLC «POLYSAN») and the development of approaches to improving clinical trial planning processes for assessing safety and tolerability, taking into accounts the results of preclinical studies.

Materials and methods. A comparative analysis of the safety parameters that arose during a clinical study involving healthy volunteers and deviations from the control levels of clinical and laboratory parameters established at the stage of a preclinical study on outbred rats and rabbits of the chinchilla breed of a drug with an international non-proprietary name (INN): meglumine sodium succinate (trade name (TN) Reamberin® (LLC «POLYSAN»)).

Results. Unidirectional deviations from normal (control) values were established. Isolated cases of adverse events among healthy volunteers (increased activity of hepatic transaminases, changes in blood pressure) were identified. This facts didn't correlate with the preclinical study. The number of comparable indicators in laboratory animals, for which statistically significant differences were established between the experimental and control groups, significantly exceeded the number of signs in the form of adverse events among healthy volunteers.