The effect of early and late pharmacological correction with GABA derivatives of psychoemotional state of offspring of rats with experimental preeclampsia

Experimental preeclampsia has a negative effect on the psychoemotional state of offspring. Early and late pharmacological correction with derivatives of GABA, such as succicard, salifen and phenibut, reduced anxiety, manifestations of obsessive-compulsive disorder, and depression in offspring of the rats with EP pregnanc

Evaluation of hepatotoxic properties of pyrimidine derivatives

The aim of the study was to evaluate the hepatotoxic properties of new pyrimidine derivatives 3-[2-(1-naphthyl)-2- oxoethyl]-6-bromoquinazoline-4(3H)-oh (VMA–13–06), 3-(2-tert-butyl-2-oxoethyl)quinazoline-4(3H)-one (VMA-13- 11) and 3-(2-isopropyloxy-2-oxoethyl)quinazoline-4(3H)-oh (VMA-13-12). Material and methods. The study was carried out on male rats, which were divided into four groups: control receiving an intragastrically distilled water and experimental groups of animals receiving intragastrically suspended in distilled water pyrimidine compounds VMA- 13-06, VMA-13-11 and VMA-13-12 at doses of 1/10 of the molecular weight (39, 24 and 24 mg/kg respectively) for 60 days. In order to assess possible toxic damage to the liver, blood biochemical parameters were evaluated: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase activity, total protein, albumin, total and free bilirubin content. Results. There were no statistically significant changes in total protein, albumin, total and free bilirubin after administration of VMA–13–06 and VMA–13–11 in comparison with the control group. The VMA–13–12 compound contributed to an increase in total and free bilirubin content by 43 % (p < 0.01) and 90 % (p < 0.01), while the increase in the concentration of total protein and albumin did not have any statistical significance. The analysis of enzyme parameters also indicates the absence of hepatocyte damage with the introduction of VMA- 13-06 and VMA-13-11: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase activity did not change. VMA–13–12 administration led to an increase in enzyme activity in comparison with the control: alanine aminotransferase – by 59 % (p < 0.01), aspartate aminotransferase – by 28 % (p < 0.05), gamma- glutamyltransferase – by 46 % (p < 0.01), alkaline phosphatase – by 31 % (p < 0.05). Conclusions. We established the absence of hepatotoxic properties of pyrimidine derivatives 3-[2-(1-naphthyl)-2-oxoethyl]-6-bromoquinazoline-4(3H)- oh and 3-(2-tert-butyl-2-oxoethyl)quinazoline-4(3H)-oh. Compound 3-(2-isopropyloxy-2-oxoethyl)quinazoline-4(3H)- oh has a hepatotoxic effect, accompanied by a decrease in protein-synthesizing and detoxifying liver function

Pancreatic β-cell protective effect of novel GABA derivatives in rats with type 2 diabetes

Novel GABA derivatives exhibit significant pancreatic β-cell protective effects that may be mediated by enhanced GLP-1, Klotho protein, and Nrf2 transcription factor, and suppressed NF-κB transcription facto

Screening studies of antimicrobial activity of pyrimidine derivative

Aim of the study was to screen the antimicrobial activity of pyrimidine derivative 3-[2-(1-naphthyl)-2-oxoethyl]-6-bromoquinazoline-4(3H)-oh with laboratory cipher VMA–13–06 in relation to pathogenic and opportunistic flora. Material and methods. Antimicrobial activity of VMA–13–06 was established in vitro against strains of Staphylococcus aureus, Klebsiella pneumonia, Streptococcus pyogenes, Escherichia coli, Acinetobacter baumannii and Citrobacter freundii by the method of serial dilutions, by forming rows with different concentrations of the compound under study. Results. VMA–13–06 was found to exhibit high antibacterial activity against S. aureus, S. pyogenes, E. coli and K. pneumonia at concentrations of 128 and 64 μg/ml comparable to the activity of the comparison drug norfloxacin. At a concentration of 32 μg/ml, the studied derivative is highly active against S. aureus and S. pyogenes and shows average activity against E. coli and K. pneumonia. The compound VMA–13–06 in dilution from 16 to 4 μg/ml is moderately active against the above-mentioned microorganisms. At concentrations from 2 to 0.25 μg/ml, the pyrimidine derivative is inactive against S. aureus, S. pyogenes, E. coli and K. pneumonia, in all dilutions – against C. freundii and A. baumannii. Conclusions. The results of a screening study indicate a pronounced bactericidal effect of VMA–13–06 against S. aureus, S. pyogenes, E. coli и K. pneumonia comparable to the comparison drug norfloxacin

Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3–9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research

Pharmacological correction of the sequelae of acute alcohol-induced myocardial damage with new derivatives of neuroactive amino acids coupled with the blockade of the neuronal NO synthase isoform

Introduction: Acute alcohol intoxication (AAI) induces a number of myocardial disorders, which result in mitochondrial dysfunction in cardiomyocytes, oxidative stress, and decreased cardiac contractility. Nitric oxide produced by the nNOS is one of the major modulators of cardiac activity. New derivatives of GABA (RSPU-260 compound) and glutamate (glufimet) can be potentially regarded as such agents as the interaction between the NO system and the GABA and glutamatergic systems has been proved. Materials and methods: All the studies were performed on female white Wistar rats, aged 10 months, whose weight was 280–320g AAI intoxication was modeled of 32% ethanol (gavage, 4g/kg). Results and discussion: Glufimet and the RSPU-260 compound caused a significant improvement in myocardial contractility, increased oxygen consumption in the V3 state according to Chance, raised the respiratory control ratio and decreased the intensity of LPO intensity. Their effectiveness exceeded that of mildronate, their comparator. nNOS inhibition resulted in a pronounced aggravation of oxidative stress implicated in MDA accumulation in cardiac mitochondria and decreased activity of SOD; myocardial contractility and mitochondrial function indicators did not show a significant difference from the control group. The compounds under study coupled with nNOS inhibition had a cardioprotective effect. Conclusion: Glufimet and the RSPU-260 compound, derivatives of neuroactive amino acids, have a pronounced cardioprotective effect, restrict LPO processes, enhance SOD activity, improve the mitochondrial respiratory function after acute alcohol intoxication when coupled with neuronal NO-synthase inhibition, the expression of which persists after AAI. Graphical abstract

Effect of benzoyl taurine dipotassium salt on coagulation, hemostasis and vascular activity in the microvasculature of the brain in violation of cerebral circulation

Cerebral circulation disorders (CCD) are one of the most common causes of mortality and disability in the population. Improving the microcirculation of brain tissue is one of the main directions in the treatment and prevention of CCD.Aim of the study was to evaluate the effect of a new derivative of hydroxybenzoic (salicylic) acid on neurological deficit, hemostasis and functional state of arterial pial vessels in the study of prostacyclin-synthetic activity and evaluation of NOmediated endothelial dysfunction in rats under experimental CCD conditions. Material and methods. The experiment was carried out on 50 Wistar rats, which were simulated for CCD by occlusion of common carotid arteries. Within 7 days after the operation, the animals received treatment according to the group: saline, C-60 (N-(3-hydroxybenzoyl)taurine dipotassium salt) and acetylsalicylic acid. After treatment, the activity of the prostacyclin-synthetic system was assessed by the reaction of pial vessels to indomethacin, endothelial dysfunction was estimated by tests with acetylcholine and L-NAME. The parameters of plasma and platelet hemostasis were also studied, and behavioral tests (open field, adhesion test, rotarod, Morris water maze, passive avoidance task) were used to assess neurological deficits in animals. Results. When studying the level of neurological deficit in animals with brain ischemia after a course of administration of the test compound, it was noted that in the treated groups, compared with the control group, there was a significant increase in motor and exploratory activity, improvement in sensory-motor function and coordination of movements (p < 0.05). Also, in the group treated with the salicylic acid derivative, normalization of the parameters of platelet and plasma hemostasis, improvement of the functional state of the vascular endothelium was observed. According to the results of assessing the prostacyclin-synthesizing activity of the endothelium of the cerebral vessels, it follows that the test compound inhibits cyclooxygenase at a level comparable with effect of acetylsalicylic acid. Conclusions. A new derivative of salicylic acid, the dipotassium salt of N-(3-hydroxybenzoyl)taurine, reduces the severity of neurological deficit, improves hemostasis parameters and the functional state of cerebral vessels in rats with brain ischemia in the experiment

Этические аспекты доклинических исследований

Animal experiments are fundamental for the biomedical science. The development of new drugs is always associated with a large number of preclinical experiments in animals. Experimental data make it possible to predict the drug efficacy and safety in humans. There are more than 100 million laboratory animals that are used by researchers every year worldwide. This fact raises a number of concerns regarding the legality and ethical appropriateness of using such a large number of animals. This article discusses the problem of using an unreasonably large number of experimental animals during preclinical drug studies, as well as potential ways of streamlining existing methods used for determining the acute and subacute toxicity of drugs in order to minimize the time of the study and the number of animals used. In addition, we review the problem of systematizing experimental data and potential ways of their standardization in line with the European legislation regulating ethically approved use of animals in experiments.Эксперименты на животных фундаментальны для биомедицинских наук, поэтому разработка новых лекарственных препаратов всегда связана с проведением достаточно большого объема доклинических исследований на животных. Полученные данные позволяют прогнозировать эффективность и безопасность лекарственных средств для человека. Однако, в мире ежегодно в исследовательских, образовательных и производственных целях используется более 100 миллионов подопытных животных. Данный факт представляет широкий интерес с точки зрения правомерности и этичности использования такого большого количества животных объектов. В данной статье рассматривается актуальность проблемы необоснованно завышенного количества экспериментальных животных при проведении доклинических исследований лекарственных препаратов, а также возможные методы модернизации имеющихся методик определения острой и подострой токсичности лекарственных веществ с целью минимизации времени исследования, а также количества задействованных в нем живых особей. Также рассматривается проблема систематизации полученных экспериментальных данных и возможные пути ее стандартизации в соответствии с европейскими законодательными актами, регулирующими этически оправданное использование животных в эксперименте