Evaluation of the genotoxic and antigenotoxic potential of lignin-derivative BP-C2 in the comet assay in vivo.

The genotoxic and antigenotoxic potential of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, was investigated as a radioprotector/radiomitigator for civil applications and as a medical countermeasure for radiation emergencies. Using the alkaline comet assay and methyl methanesulfonate (MMS, 40 mg/kg) as the DNA-damaging agent, these effects of BP-C2 on liver, bone marrow cells and blood leukocytes in rats were studied. The DNA damage was estimated by the DNA content in the comet tail (TDNA, %) 1, 6 and 18 h post exposure to MMS. BP-C2 at doses of 20, 200 and 2000 mg/kg did not exert genotoxic activity in the tested tissues in rats. BP-C2 administered at doses of 20, 100 and 200 mg/kg 1 h before MMS significantly (p < 0.01) mitigated MMS-induced DNA damage, showing a strong genoprotective effect in the liver. In blood leukocytes and bone marrow samples of animals treated with BP-C2, the TDNA % was slightly higher than in the negative control (vehicle) but significantly lower than in the positive control (MMS). Thus, BP-C2 exerted a genoprotective effect against MMS-induced DNA damage to a greater extent towards liver cells, requiring further evaluation of this substance as a genoprotective agent.

[Investigation of ligand-receptor interaction and biodistribution of a drug containing cattle retinal polypeptides in various administration routes]. / Issledovanie ligand-retseptornogo vzaimodeistviya i bioraspredeleniya pri razlichnykh rezhimakh vvedeniya lekarstvennogo sredstva, soderzhashchego polipeptidy setchatki glaz skota.

It is important to understand the features of the interaction of drug components with body receptors and obtain data on its distribution in various administration routes in recommended doses in order for its usage in clinical practice to be safe and effective. PURPOSE: To investigate in vitro the interactions of a drug consisting of water-soluble polypeptide fractions produced on animal retina with a wide range of receptor targets, and to assess its biodistribution in the organs of laboratory animals. MATERIAL AND METHODS: The biodistribution of the radioactively marked drug in different organs and tissues of laboratory mice in various routes of administration was studied at the National Research Centre «Kurchatov Institute¼. Evaluation of the ligand-receptor interaction of the drug was carried out in the laboratory at Eurofins Pharma Discovery Services by the method of competitive radioligand binding. RESULTS: A significant effect of the interaction of the polypeptide drug was revealed with different subtypes of glutamate receptors: AMPA, NMDA, and mGluR1. As a result of an in vivo test, we have obtained biodistribution data of the drug for intravenous, intramuscular and parabulbar administration, and the dynamics of drug accumulation in the tissues of the brain and eyes. CONCLUSION: According to the study results, the peptide drug binds to receptors associated with the loss of retinal ganglion cells. Interaction with these receptors potentially provides the test subject with neuroprotective effect. The content dynamics of the studied drug in the blood of animals depends on the route of administration and the amount of drug administered. At the time point of 0.5 hours for intravenous and intramuscular administration in the dose of 1.7 mg/kg, the studied drug has sufficiently high bioavailability in the tissues of the brain and eye. The data suggest that the main route of excretion of the studied drug is through kidneys.

[Metabolic and hormonal indices in rats with prolonged model of metabolic syndrome induced by high-carbohydrate and high-fat diet].

To develop the approaches for the prevention and treatment of metabolic syndrome (MS), a pathological state widespread in modern population, that involves a complex of metabolic and functional disorders, appropriate animal models of MS are required. One of these models is induced by the consumption of combined high-carbohydrate and high-fat (HC/HF) diet consisting of excess amount of easily digestible carbohydrates and saturated fats. At the same time, the character, temporal dynamics and severity of metabolic abnormalities in MS induced by HC/HF diet are still poorly understood. The aim of work was the characterization of metabolic changes in Wistar rats with MS induced by 10- and 15-week HC/HF diet that includes the consumption of 30% sucrose solution (instead of drinking water) and food rich in saturated fats. Rats that received HC/HF diet for 15 weeks had a number of features characteristic of MS, such as increased body weight and content of abdominal fat, hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, insulin resistance, dyslipidemia, as well as the markers of impaired function of the cardiovascular system (hyperhomocysteinemia, the reduced level of vasodilator nitric oxide, the increased concentration of vasoconstrictor endothelin 1). In rats, which were on the diet for 10 weeks, the metabolic abnormalities were less pronounced, indicating an insufficiency of 10-week duration of HC/HF diet for MS induction. Thus, the model of MS induced by 15-week HC/HF diet has the characteristic features that allow for extrapolation of the obtained data to similar pathologic changes in human, and can be used to study the etiology and pathogenesis of MS and the search of effective ways of MS prevention and treatment.

EXPERIMENTAL ASSESSMENT OF THE SPECIFIC EFFICIENCY OF NEW METABOLIC DRUG RUNIKHOL ON MODELS OF NON-ALCOHOLIC FATTY LIVER DISEASE.

We present results of preclinical evaluation of the specific efficiency of new metabolic corrector runikhol on models of non-alcoholic fatty liver disease in laboratory rats (228 albino males of gray Wistar rats weighing 220 - 240 g). The drug based on succinic acid positively influences the key types of metabolism impaired under conditions of development of the metabolic syndrome. Results of research testify to high efficiency and good prospects of using runikhol in the treatment of metabolic syndrome accompanied by organ disorders.

[INFLUENCE OF ANGIOPROTECTOR DRUGS ON THE EFFICACY OF CYTOSTATIC THERAPY (EXPERIMENTAL STUDY)].

The influence of angioprotector and endothelium-protector drugs pentoxifylline and unifuzol as components of supportive therapy on the efficacy of combined cytostatic treatment has been experimentally studied. It is established that pentoxifylline and unifuzol do not affect the antitumor and antimetastatic activity of doxorubicin and cyclophosphan with respect to Pliss lymphosarcoma and Walker 256 carcinosarcoma, and in some cases even potentiate the effect of cytostatic therapy.

[Pathophysiological and clinical aspects of using L-arginine in cardiology and angiology]. / Patofiziologicheskie i klinicheskie aspekty primeneniia L-arginina v kardiologii i angiologii.

Presented herein is a review of scientific publications dedicated to studying the pharmacodynamics of L-arginine and possibilities of its clinical application. Interest to L-arginine is associated, first of all, with its role as a precursor in endogenous synthesis of nitric oxide (NO), playing an important role in regulation of the functional state of the vascular wall. According to numerous studies, oral and parenteral administration of L-arginine restores endothelial production of NO in such diseases as atherosclerosis, hypertension, type 2 diabetes mellitus, obliterating diseases of arteries of lower extremities. The NO-mediated effect of L-arginine manifests itself in increasing the capability of vessels to dilatation, decreasing blood platelet aggregation, and inhibiting proliferation of smooth muscle cells of vessels. The effect is most pronounced in patients presenting with hypercholesterolaemia and initially decreased reactivity of the blood channel. The mostly pronounced NO-mediated effect of L-arginine is observed in parenteral route of its administration. Prolonged administration of L-arginine slows down progression of atherosclerosis.

Sodium-L-arginine succinate - a new vasodilating medicine for the treatment and prophylaxis of doxorubicin-induced cardiotoxicity.

The purpose: to ascertain possible cardioprotective effect of Sodium-L-arginine Succinate in case of myocardial lesions caused by Doxorubicin in rats. Methods. The effectiveness of the drug was assessed by morphometric and biochemical changes reflecting peroxidation intensity and structural and functional changes in myocardium. Results. Sodium-L-arginine Succinate used for the treatment and prophylaxis of antracyclic cardiomyopathy was demonstrated to decrease Doxorubicin effects lessening cardiomyocytal destruction and the left ventricular dysfunction with myocardial hypertrophy.

P388 leukemia in CDF1 mice as the test system for studies of tumor-associated neoangiogenesis and hypercoagulation.

Blood levels of vascular endothelial growth factor, the main marker of angiogenesis activity, and coagulation hemostasis were studied in CDF1 mice with transplanted P-388 lymphocytic leukemia. Blood levels of vascular endothelial growth factor increased by 168% in mice with tumors. The animals developed the hypercoagulation syndrome manifesting in shorter activated partial thromboplastin time and prothrombin time and development of hyperfibrinogenemia.

[Metabolic therapy of nephrolithiasis in two different rat models of kidney disease].

108 albino male rats were used in two experimental rat models reproducing urolithiasis for the assessment of metabolic drug medicine Remaxol nephroprotective effect upon the development of this disease. "Ethyleneglycol" model consisted of adding 1% ethylene glycol solution in drinking water for 37 days and "fructose-induced" one--of adding 10% fructose solution in drinking water for the same period. Therapy included a 10-day course of daily i.v. injections of Remaxol (14 ml/kg). Both experimental models were successful in producing urolithiasis with considerable disturbances in the structure and functioning of kidneys up to revealing microconcrement formation. The "ethyleneglycol" model proved to cause maximum changes while the "Fructose-induced" model--only moderate ones. Metabolic correction of these changes was successful in nephroprotection effectively normalizing kidney functions and the total protein concentration, eliminating hyperglycemia and reducing creatinine and urea blood plasma concentration in both rat experimental models.

[Age dynamics of angiogenesis markers in transgenic HER-2/neu (FBV/N) mammary adenocarcinoma-prone mice].

Age-dependent angiogenesis intensity changes have been studied in transgenic HER-2/neu (FBV/N) mice characteristic of breast tumors' high incidence with hyperexpression of HER-2/neu. Concentration of vascular endothelial growth factor, insulin-dependent growth factor 1, nitrogen monoxide, tissue plasminogen activator and type 1 plasminogen activator inhibitor were assessed by means of immune-enzyme assay. The results testify to angiogenesis processes activation side by side with aging and growth of the tumors. Maximum manifestation of these disturbances (growth factors' blood concentrations increase and endotheliocytes' functional activity inhibition) has been revealed in 6-month-old mice during neoplasma maximum intensive and aggressive growth period.

[Pathogenic variants of brain injuries and pharmalogic cerebroprotection performed on the model of brain condition during cardiovascular bypass surgery].

Developed and approved a pathogenic grounded experimental model of brain condition during cardiovascular bypass surgery. Undertaken in Wistar rats research allowed to evaluate in detail effectiveness and safety of protracted cerebroprotective treatment. Advantages of this model are researches in laboratory animals with the aim to research condition of nerve tissue, not intensive procedures and consequently high reproducibility and possibility of complex evaluation of changes at every stage of research. Results of neurons, neuroglia and activation of neurotrophic mechanisms prove that simulation of brain condition during cardiovascular bypass surgery is accompanied with acute and delayed brain injuries. Use of Cytoflavin under pharmalogic cerebroprotection had prolonged multimodal and neuroprotactive effect, leading to improvement of neurotrophic protection from the first days.

[Brain functional state and cytoprotective potential in model of acute cerebral hypoxia (experimental research)].

The functional state of the brain and the potential of pharmacologic cytoprotection after an acute cerebral hypoxia were studied. The experiment involved 186 adult male rats. The rats in experimental groups underwent acute thromboembolism of the right carotid artery. The functional state of the brain and the efficacy and safety of the Cytoflavin complex cytoprotective drug treatment had been analyzed over the 10 days following the thromboembolism. A neurological examination was accomplished daily, the serum levels of NSE, GFAP, S100beta and brain cytolysate levels of NSE were measured on the 1st, 3rd, 10th day. The NSE brain cytolysate level went up on the 1st day and the NSE serum level was up on the 3rd day following the thromboembolism, which may have indicated an acute delayed alteration of neurons and an increase of the blood-brain barrier permeability on the 3rd day after the thromboemboIism. Neuroglial biomarkers went up on the 1st (GFAP), 3rd and 10th (S100beta) day, which indicated an acute delayed alteration and/or activation of glial cells. Therefore, the applied experimental model promotes acute delayed alteration of neurons and neuroglia with a possible activation of the latter. The Cytoflavin proved to have a cytoprotective effect on neurons and to diminish the alteration and/or activation of glial cells over the observed period after the acute thromboembolism of the carotid artery.

[Characteristics of the regulation of neurotrophic mechanisms in ischemic stroke].

AIM: To explore the endogenous and pharmacological activation of neurotrophic mechanisms in a model of brain ischemic lesion in rats. MATERIAL AND METHODS: The study was performed on 170 male albino rats (195-205 g). The model of ischemic stroke was accomplished by the electrocoagulation of the proximal segment of the left middle cerebral artery and simultaneous permanent ligation of the left common carotid artery. RESULTS AND CONCLUSION: The evaluation of NSE, NO, VEGF, NGF levels in the brain cytoplasmic lysate and plasma showed the delayed activation of neurotrophic mechanisms in astrocytes accompanied by a decrease in delayed alteration of neurons. The use of cytoflavin in the treatment of stroke was accompanied by the earlier and more intense activation of neurotrophic mechanisms in astrocytes, delayed activation of neurotrophic mechanisms in endothelial cells, which promoted neuroprotection in acute ischemic stroke.