On the mechanism of the antiarrhythmic action of fabomotizole hydrochloride in alcoholic cardiomyopathy

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.

Cardioprotective effects of compound ALM-802 on subendocardial ischemia models

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.

Development and validation of the method for the quantitative determination of methotrexate in a transport medium by HPLC-MS/MS

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 overexpressingBCRP, 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.

Determination of Serum/Plasma Concentrations of Psychotropic Drugs in Therapeutic Drug Monitoring

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.

Study of the electrophysiological mechanisms of anticonvulsant action of the original levetiracetam analog the compound GIZH-290

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.

Evaluation of the antitumor activity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol) in C57BL/6 mice with intracranially transplanted B16 melanoma

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.

Comparative evaluation of echocardiographic characteristics of the heart left ventricle in female and male rats

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.

Pharmacokinetic relationships in psychotropic drugs effects

The review discusses relationships between pharmacokinetic parameters and effects of psychotropic drugs, both in preclinical studies and clinical practice. The identification of such correlations can serve as a basis for understanding the complex system of relationships between pharmacokinetic and pharmacodynamic mechanisms in the manifestation of the action of this group of drugs and allows us to use the data of pharmacokinetic studies to optimize therapeutic approaches in medical practice.

Computer analysis of the emotional modality of 20 million publications in PUBMED database indicates ways to increase the effectiveness of pharmacotherapy by identifying pseudoscientific publications aimed at negative emotional "pumping" of doctors

The search for original publications on fundamental and clinical medicine that would produce results of the highest scientific quality represents an urgent need for every medical researcher. Such publications are essential, in particular, for the development of reliable treatment standards. The Englishlanguage resources PUBMED and EMBASE are essential to help in solving this problem. However, there is an obvious problem in assessing the quality of the studies found. The paper formulates a method for analyzing the texts of biomedical publications, which is based on an algorithmic assessment of the emotional modality of medical texts (so-called sentiment analysis). The use of the topological theory of data analysis made it possible to develop a set of high-precision algorithms for identifying 16 types of sentiments (manipulative turns of speech, research without positive results, propaganda, falsification of results, negative personal attitude, aggressiveness of the text, negative emotional background, etc.). On the basis of the developed algorithms, a point scale for assessing the sentiment quality of research was obtained, which we called the "β-score": the higher the β-score, the less the evaluated text contains manipulative language constructions. As a result, the ANTIFAKE system (http://antifake-news.ru) was developed to analyze the sentiment-quality of Englishlanguage scientific texts. An analysis of ~ 20 million abstracts from PUBMED showed that publications with low sentiment quality (β-score <0, that is, that the prevalence of manipulative constructions over meaningful ones) is only 19 %. In the overwhelming majority of thematic headings (27,090 out of 27,840 headings of the MESH system PUBMED), a positive dynamics of sentiment quality of the texts of publications is shown by years). At the same time, as a result of the study, 249 headings were identified with sharply negative dynamics of sentiment quality and with a pronounced increase in manipulative sentiments characteristic of the "yellow" English-language press. These headings include tens of thousands of publications in peer-reviewed journals, which are aimed at (1) legalizing ethically unacceptable practices (euthanasia, perversions, so-called "population control", etc.), (2) discrediting psychiatry as a science, (3) media the war against micronutrients and (4) discrediting evidence-based medicine under the guise of developing the so-called "international standards of evidence-based medicine". In general, the developed system of artificial intelligence allows researchers to filter out pseudoscientific publications, the text of which is overloaded with emotional manipulation and which are published under the guise of "evidence-based standards".

The acute toxicity study GIZH-290 in mice

Acute toxicity testing is a commonly accepted procedure for preclinical testing of the safety of potential drugs. The compound GIZh-290, which is a derivative of 4-phenylpyrrolidone– 2,6 - dimethylanilide (2-oxo-4-phenylpyrrolidine-1-yl) acetic acid and has a nootropic and anticonvulsant effect, was studied. The results obtained after a single oral and intraperitoneal administration to mice allow us to attribute GIZH-290 to the 4th class of toxicity – "lowtoxic substances". The study revealed the neurotoxic effects of GIZH-290, which may be due to the main pharmacological activity of the compound used in sublethal doses.