The article considers the main methodological methods of therapeutic drug monitoring (TDM) of psychotropic drugs. Analytical methods that allow performing these studies have been described. It has been given the interpretation, examples and brief results of two studies of TDM of antipsychotic drugs made in FSBSI “Mental Health Research Center” and Psychiatric hospital No.14 in Moscow.

The aim of the present study is a comparative assessment of the echocardiographic characteristics in female and male mongrel rats. In experiments on anesthetized rats (ketamine 100 mg / kg, iv), it was shown that in female rats, the size and volume of the left ventricle are smaller than in males, but compared with males, their left ventricular ejection fraction, which characterizes its inotropic function, is statistically significantly higher.

The investigation purpose. N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine (ALM-802 compounds) cardioprotective effect has been studied in rat models of subendocardial ischemia caused by isoproterenol and dobutamine. Material and methods. Acute subendocardial myocardial ischemia in anesthetized rats (urethane 1300 mg/kg, i.p.) was caused by infusion of isoproterenol (20 µg/kg/min i.v.) or dobutamine (80 µg/kg/min i.v.). Results. It was shown that in anesthetized rats, isoproterenol and dobutamine caused almost the same ST-segment depression in the II standard ECG lead. The compound ALM-802 (2 mg/kg i.v.), administered 2 minutes before the infusion start of isoproterenol or dobutamine, equally prevented the occurrence of ischemic changes on the ECG. Conclusion. The non-selective beta-adrenomimetic isoproterenol and the selective β1-adrenomimetic dobutamine cause subendocardial ischemia of the same intensity in anesthetized rats. The compound ALM-802 has a pronounced anti-ischemic effect on both models.

Background. The arsenal of antitumor drug therapy for melanoma brain metastases is limited. The search and study of new agents capable to penetrate the blood-brain barrier and provide a therapeutic effect against intracranial tumors remains an unmet clinical need. The aim is to evaluate the antitumor activity of the domestic derivative of nitrosoalkylureas, chlonisol, in mice with intracranially transplanted syngeneic B16 melanoma. Methods. The experiment was carried out in 18 female inbred C57BL/6 mice. After intracranial tumor transplantation, performed according to modified technique, the animals were randomized into two groups: I. Control (n = 10) – the animals were injected with normal saline 10 ml/kg intraperitoneally; II. Chlonisol (n = 8) – the animals were treated with the test compound at a dose of 15 mg/kg in normal saline intraperitoneally. The single administration of normal saline and chlonisol was performed 24 hours after tumor transplantation. The end point of the study was overall survival (OS) of the animals. Results. Compared with the control group, administration of chlonisol significantly increased the median OS of mice from 13 to 18 days (log rank test, p = 0.0005). Chlonisol significantly decreased the risk of death by 71 % compared with the control group (HR = 0.29; 95 %CI 0.10–0.82). By the 15th day after intracranial transplantation of B16 melanoma, all 10 mice in the control group died from intracerebral tumors (100 %), whereas in the chlonisol group only 2 out of 8 (25 %) mice died (Fisher's exact test, p = 0.0015). Conclusion. Despite the exploratory nature of the present study, it provides a good starting point for further research of chlonisol in brain tumors.

It is known that the alcoholic cardiomyopathy (ACMP) is the main reason for lethality from chronic alcoholism. For ACMP the risk of development of malignant violations of a heart rhythm which result approximately at 40% of such patients is sudden heart death is extremely high. Materials and methods. Experiments were made on the ACMP translational model developed by us which is formed at rats by the end of the 24th week of compulsory reception of 10 % of ethanol solution. For studying the mechanisms which are the responsible of antiarrhythmic action of a fabomotizole dihydrochloride used a complex of morphohistological, electrophysiological and molecular researches. Results. It is shown that against the background of systematic therapy fabomotizole dihydrochloride (15 mg/kg, i.p.) daily within 28 days after 24 weeks of alcoholization, in comparison with alcoholized control the fat dystrophy of a myocardium significantly decreases and the threshold of electric fibrillation of heart ventricles is restored. According to results of molecular researches, a fabomotizole dihydrochloride significantly suppresses revealed in control alkoholized animals the abnormal mRNA expression of key receptor genes and proteins responsible for maintenance in cardiomyocytes of a homeostasis of ions of Ca++ and regulation of their rhythmic activity: regulatory proteins Epac1 (p = 0.021), Epac2 (p = 0.018), CaM (p = 0.00001) and also RyR2 (p = 0.031), IP3R2 (p = 0.006) receptors. Conclusion. The obtained results suggest that antiarrhythmic action of a fabomotizole dihydrochloride in the conditions of ACMP is connected with its ability to suppress abnormal activity of regulatory proteins Epac2 and RyR2, IP3R2 receptors.

The study used the method of cobalt epilepsy, which allows rats with long-term implanted electrodes in the cortical and subcortical structures of the brain to monitor the dynamics of the formation and migration of Epi-foci for a long time. It was found that in the control at the 1st stage of development of the Epi system, Epi activity is most pronounced in the electrocorticograms of the ipsilateral cortex, and at the 2nd, stable stage of development of the Epi system – in the contralateral cortex and subcortical structures. The compound GIZH-290 (the original structural analogue of levetiracetam) reduces the number of Epi discharges and their duration at the 2nd, stable stage of the development of the Epi system. The target structure of the GIZH – 290 compound was the hippocampus. The compound GIZH -290 selectively statistically significantly reduces both the number and duration of Epi – discharges only in the hippocampus and does not affect the foci of epileptic activity in the ipsi-and contralateral cortex and hypothalamus.

Relevance. BCRP is an efflux transporter protein that plays an important role in the pharmacokinetics of a wide range of drugs. The BCRP activity in vitro experiments is assessed by the transport of transporter protein substrates (methotrexate, etc.) across the bilipid membrane of cells overexpressing
BCRP, for example, Caco-2 cells. The aim is to develop and validate a method for the quantitative determination of the BCRP substrate, methotrexate, in the transport medium of Caco-2 cells by HPLC-MS/MS. Methods. The work was performed on an Ultimate 3000 HPLC chromatograph (ThermoFisher, USA) with a TSQ Fortis tandem mass-selective detector (ThermoFisher, USA). The conditions of chromatographic analysis were as follows: column UCT Selectra C18 4.6 mm * 100 mm 5um, 100A, Selectra C18 Guard Cartridges SLC-18GDC46-5UM, separation temperature 35 °С, flow rate 0.3 ml/min, injected sample volume - 2 μl, analysis time - 10 min. Used a gradient elution: the ratio of the solution of 0.1 % formic acid and acetonitrile was at 0 min 75 and 25 %; 0.4 min 60 and 40 %; 6 minutes 20 and 80 %; 8 minutes 75 and 25 %. Under these conditions, the retention time of methotrexate is 3.11 minutes. Detection conditions: methotrexate - positive ionization mode, 455.15 m / z → 308.125 m / z, collision energy 22.99 V, source fragmentation 5, CID gas pressure 2 mTorr. The extraction of methotrexate from the transport medium (Hanks solution with 25 mM Hepes and 1% dimethyl sulfoxide) after incubation with Caco-2 cells for 3 h was carried out with a mixture of methanol + water in a ratio of 1: 1. Results. The developed method was validated according to the following parameters: selectivity, linearity, accuracy, precision, limit of quantitative determination, sample transfer, sample stability. The confirmed analytical range of the method was 60 -10,000 nmol / L in the transport medium. Conclusions: a method for the quantitative determination of methotrexate in the transport medium of Caco-2 cells by HPLC-MS / MS was developed and validated.