[Enoxaparin sodium for pharmacological prevention of postoperative venous thromboembolic complications in urological patients].

INTRODUCTION: Currently, there are paucity of reports on the success of medical prevention of venous thromboembolic complications after urological procedures. AIM: To evaluate the efficiency of enoxaparin sodium for prevention of postoperative venous thromboembolic complications in urological patients. MATERIALS AND METHODS: According to the medical records of 151 men and women aged 22 to 92 years old who were undergone to elective surgical treatment in April 2021, the results of the thrombin generation assay and ultrasound study of the inferior vena cava were retrospectively analyzed. All patients were divided into 6 study groups depending on the degree of risk of postoperative venous thromboembolism (very low, low, moderate, high, very high and extremely high). The data obtained during the thrombin generation assay in patients from different groups were compared with those in healthy volunteers (n=30, control group) and evaluated in dynamics. In addition, intergroup comparison was done. RESULTS: All study participants prior to surgery had a significant increase in peak thrombin and endogenous thrombin potential (ETP) by 5-26% and 13.5-21.5%, respectively. The postoperative findings were as following: 1) one hour after the procedure, a significant (by 9-28.6%) decrease in the normal bleeding time (Lag time); 2) a significant increase in the peak thrombin by 4.8-10.6% 1 hour after surgery and by 11-40.2% at the end of the first postoperative week; 3) reducing the time to peak thrombin (ttPeak) by 13-15%; 4) increase in ETP. According to the ultrasonic data, all study participants had no signs of thrombosis of the inferior vena cava system. CONCLUSION: In urological patients requiring surgical treatment, before and after procedure, there is almost always a shift in the hemostasis towards the predominance of the blood coagulation system. Under such conditions, to prevent the development of postoperative VTE, it is expedient and pathogenetically justified to use enoxaparin sodium in a single dose of 0.4 ml or 4000 anti-Xa IU administered once a day s/c 24 hours before the procedure and till full activation of a patient.

[Evaluation of the results of sodium fumarate, furosemide, and mannitol on the initiation and outcome of renal warm ischemia in an experimental study].

While performing surgical treatment of the localized form of renal cell cancer by means of open or laparoscopic partial nephrectomy, renal warm ischemia is an important issue. Using renal warm ischemia allows to prevent parenchymal bleeding, to optimize conditions for resection of the tumor and to increase significantly the efficiency of hemostasis. However, an important problem is the probability of ischemic hypoxic damage of the remaining part of the kidney tissue during renal warm ischemia and renal functional impairment in the postoperative period. AIM: To compare nephroprotective activity of sodium fumarate, mannitol and furosemide using experimental model of 30- and 60-minute renal warm ischemia in rabbits. MATERIALS AND METHODS: The experiments were carried out on 360 conventional male-rabbits of the "Chinchilla" breed weighed 2,6+/-0,3 kg which were allocated into 10 groups. The control group No1 included intact animals, the control group No2 included the rabbits in which renal artery was not clamped. For the animals from the trial groups (No3-No10) the experimental model of 30- and 60-minute renal warm ischemia was used. In groups No3 and No4 no drugs were provided. Other rabbits undergone renal warm ischemia with a protection by sodium fumarate (groups No5 and No6 - 1,5 ml/kg IV), lasix (groups No7 and No8 - 3,0 mg/kg IV) and mannitol (No9 and No10 - 1,0 g/kg IV). The influence of renal warm ischemia on the renal tissue ultrastructure and the levels of NGAL, Cystatin-C and creatinine in blood and urine were studied. RESULTS: During experimental pharmacologically uncorrected 30-minute renal warm ischemia in animals, edema of the terminal part of microvilli of the proximal tubules epithelium, an increase of lysosome number in the hyaloplasm of epithelial cells, appearance of flaky content of medium electronic density in the lumens of distal tubules and collecting tubules, as well as sharp peak-like increase of NGAL and cystatin-C in blood and urine were observed. Increasing the time of ischemia up to 60 minutes was accompanied by more severe disturbances. In groups where sodium fumarate, lasix and mannitol were used the observed ultrastructural disturbances were expressed to lesser extent, whereas sodium fumarate demonstrated the best nephroprotective activity. After using mannitol the severity of disturbances was less than in the groups where mannitol, lasix or sodium fumarate were not given. Lasix and sodium salt of fumaric acid showed a higher nephroprotective activity. The best results were received in the animals received sodium fumarate. CONCLUSIONS: The studied drugs provided a nephroprotective effect regarding ischemia of rabbit kidney. The effect of sodium fumarate was the most pronounced, followed by furosemide and, to a lesser extent, mannitol. Use of sodium fumarate allows to protect and stimulate the kidney tissue effectively during oxygen deprivation under ischemic state.

The Effect of TLR4 Blockade on Some Indicators of Systemic Inflammatory Response to Proteus mirabilis LPS in Rats.

The effects of TLR4 blocker on blood cell morphology, concentrations proinflammatory cytokines, and functional state of the liver and kidneys were studied in outbred male rats (n=60) after intravenous injection of 20 mg/kg LPS isolated from opportunistic Proteus mirabilis strain ATCC 51393. TLR4 blocker TLR4-IN-C34 was injected intravenously in a dose of 1 mg/kg/day over 3 days. Systemic inflammatory reaction induced by LPS was characterized by elevation of serum TNFα, IL-1ß, IL-6, erythrocyte sedimentation rate, leukocytosis, and thrombocytosis. Increased activity of hepatocyte enzymes (ALT, alkaline phosphatase, and lactate dehydrogenase), retention of nitrogen metabolites (urea and creatinine), elevated content of protein oxidation products, and enhanced protein catabolism were also observed. Administration of TLR4 blocker reduced parameters of inflammatory reaction and prevented the development of hypercatabolic syndrome; endotoxicosis and kidney function indicators approached the normal levels.

Effect of Surfagon on Open Field and Elevated Plus Maze Behavior of Gonadectomized and Non-Gonadectomized Male Rats.

We studied the effect of gonadotropin-releasing hormone agonist surfagon (2 µg/kg, once, intraperitoneally) on anxious behavior of adult gonadectomized and non-gonadectomized male rats. It was shown that surfagon significantly increased anxiety of both gonadectomized and non-gonadectomized rats in the open-field test and in elevated plus maze.

[Effects of the of renal warm ischemia time on the recovery of filtration function in the experiment].

AIM: To investigate experimentally ultrastructural and biochemical signs of acute injury to the renal parenchyma after warm renal ischemia of various duration and subsequent reperfusion. MATERIALS AND METHODS: The experiments were performed on 44 healthy conventional female rabbits of the "Chinchilla" breed weighted 2.6-2.7 kg, which were divided into four groups. In the first, control, group included pseudo-operated animals. In the remaining three groups, an experimental model of warm ischemia of renal tissue was created, followed by a 60-minute reperfusion. The renal warm ischemia time was 30, 60 and 90 minutes in the 2nd, 3rd and 4th groups, respectively. Electron microscopy was used to study ultrastructural disturbances of the renal parenchyma. Biochemical signs of acute kidney damage were detected by measuring the following blood serum and/or urine analytes: NGAL, cystatin C, KIM-1, L-FABP, interleukin-18. The glomerular filtration was evaluated by creatinine clearance, which was determined on days 1, 5, 7, 14, 21 and 35 of follow-up. RESULTS: A 30-minute renal warm ischemia followed by a 60-minute reperfusion induced swelling and edema of the brush membrane, vacuolation of the cytoplasm of the endothelial cells of the proximal tubules, and microvilli restructuring. The observed disorders were reversible, and the epithelial cells retained their viability. After 60 minutes of ischemia and 60 minutes of reperfusion, the observed changes in the ultrastructure of the epithelial cells were much more pronounced, some of the epithelial cells were in a state of apoptosis. 90 min of ischemia and 60 min of reperfusion resulted in electron-microscopic signs of the mass cellular death of the tubular epithelium. Concentration in serum and/or biochemical urine markers of acute renal damage increased sharply after ischemic-reperfusion injury. Restoration of indicators was observed only in cases when the renal warm ischemia time did not exceed 60 minutes. The decrease in creatinine clearance occurred in the first 24 hours after the intervention, lasting not less than two weeks after a 30-minute warm ischemia, at least 3 weeks after a 60-minute warm ischemia and continued more than a month after a 90-minute renal artery occlusion. CONCLUSION: Intraoperative warm ischemia and subsequent reperfusion are the actual reasons for the alteration of the ultrastructure of the renal tissue and the impairment of the filtration function. The severity of the disorders depends on the duration of the damaging factors. After a 30-60-minute ischemia, the structural and functional changes in the renal tissue are reversible. The mass death of nephrocytes-effectors is possible only after warm renal ischemia longer than 60 min.

[Adenosine A2A receptor as a drug target for treatment of sepsis].

Sepsis is a generalized infection accompanied by response of the body that manifests in a clinical and laboratory syndrome, namely, in the systemic inflammatory response syndrome (SIRS) from the organism to the infection. Although sepsis is a widespread and life-threatening disease, the assortment of drugs for its treatment is mostly limited by antibiotics. Therefore, the search for new cellular targets for drug therapy of sepsis is an urgent task of modern medicine and pharmacology. One of the most promising targets is the adenosine A(2A) receptor (A(2A)AR). The activation of this receptor, which is mediated by extracellular adenosine, manifests in almost all types of immune cells (lymphocytes, monocytes, macrophages, and dendritic cells) and results in reducing the severity of inflammation and reperfusion injury in various tissues. The activation of adenosine A(2A) receptor inhibits the proliferation of T cells and production of proinflammatory cytokines, which contributes to the activation of the synthesis of anti-inflammatory cytokines, thereby suppressing the systemic response. For this reason, various selective A(2A)AR agonists and antagonists may be considered to be drug candidates for sepsis pharmacotherapy. Nevertheless, they remain only efficient ligands and objects of pre-clinical and clinical trials. This review examines the molecular mechanisms of inflammatory response in sepsis and the structure and functions of A(2A)AR and its role in the pathogenesis of sepsis, as well as examples of using agonists and antagonists of this receptor for the treatment of SIRS and sepsis.

INFLUENCE OF INFLUENZA A VIRUS AND BACTERIAL LIPOPOLYSACCHARIDE ON PROLIFERATION AND GENE EXPRESSION OF CYTOKINES AND OTHER CELLULAR FACTORS IN CELLS OF ESTABLISHED ENDOTHELIAL CELL LINE ECV-304.

Change of state of endothelial cells occurs under the action of viral infection and bacterial lipopolysaccharide (LPS) that leads to cell dysfunction. Therefore, the aim of the current study was to investigate the effect of LPS from Escherichia coli and influenza A virus on proliferative activity of human endothelial cells (ECV-304) and gene expression of several cytokines and cellular factors: TNFá, TGFâ, IFN-ã, MMP-9, NF-êB, Rho A, eNOS and iNOS. It was found that ECV-304 cells once infected with very low infectious doses of influenza virus acquire the ability to long-term active proliferation (over 8 passages). Addition of LPS E. coli reduced the virus-stimulated cell proliferation. It was shown that influenza virus and LPS can affect on gene expression of cytokine and other cellular factors. When endothelial cells had been infected with influenza A virus in the presence of LPS, there was a significant increase in the expression of several genes and replacement of some genes expression on the expression of other genes. Expression of MMP-9 gene was inhibited in the case of separate exposure to the virus and LPS, but it was significantly increased during the first day under the adding of the virus and LPS together, as well as the activity of the IFN-ã gene; gene of TNFá was active for only 1­3 days whereas genes expression of other factors (TGFâ, eNOS, iNOS, NF-êB and Rho A) increased significantly at the 5th day as in the case of adding only LPS. Thus, the change of physiological state of endothelial cells occurs in the presence of influenza A virus and LPS and it can be caused during different time periods (as well as by varying degrees of virus infection of cells) by different cellular factors and possibly with involvement of different signaling pathways.

[Ebola hemorrhagic fever: Properties of the pathogen and development of vaccines and chemotherapeutic agents].

Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. While being of a relatively low genetic capacity, the virus can be ranked as a standard for pathogenicity with the ability to evade the host immune response in uttermost perfection. The EHF virus has similarities with retroviruses, but belongs to (-)RNA viruses of a nonretroviral origin. Genetic elements of the virus, NIRV, were detected in animal and human genomes. EHF virus glycoprotein (GP) is a class I fusion protein and shows more similarities than distinctions in tertiary structure with SIV and HIV gp41 proteins and even influenza virus hemagglutinin. EHF is an unusual infectious disease, and studying the molecular basis of its pathogenesis may contribute to new findings in therapy of severe conditions leading to a fatal outcome.

Hypolipidemic and hypoglycemic effect of peptide Lys-Glu-Trp-NH(2) in rats with associated metabolic disorders.

The effect of peptide Lys-Glu-Trp-NH2 in doses of 0.2, 20, and 2000 µg/kg on lipid and carbohydrate metabolism was studied in Wistar rats with experimental hyperlipidemia and diabetes mellitus. This tripeptide in a dose of 2000 µg/kg produced a hypolipidemic effect on atherogenic lipoproteins, decreased the intensity of LPO, improved the state of the antioxidant system, and normalized the content of HDL. Treatment with this tripeptide had a hypolipidemic effect and reduced the severity of specifi c morphofunctional changes in the pancreatic and hepatic tissue.

[Experimental justification of approaches to pharmacological correction of delayed disorders caused by acute ethylene glycol poisoning].

The development of delayed disorders caused by acute ethylene glycol poisoning has been studied in experiments on male rats. These disorders include chronic renal failure and secondary combined immunodeficiency status of the "circulus vitiosus" type. Urgent pharmacological correction was shown to be necessary shortly after the poisoning. The experimental therapy (administration of immunomodulators with various mechanisms of action in addition to conventional antidote treatment with ethanol) resulted in the restoration of nonspecific resistance and both cellular and humoral immunity. Reduction of the urinary system damage after the administration of immunomodulators was observed. The results demonstrated the importance of multiagent immunotherapy for the correction of delayed effects of acute ethylene glycol poisoning.

[Gastroprotective activity of modified glutamyl-tryptophan dipeptide analogs and melatonin].

The gastroprotective action of synthetic dipeptides glutamyl-tryptophane (EW), iso-valeroyl-glutamyl-tryptophane (ivEW) and nicotinoyl-glutamyl-tryptophane (nEW) in comparison to melatonin was studied in experiments on male with the model indometacine and starvation stress-induced stomach ulcers. It was shown, that EW and melatonin exhibit antiulcer activity upon preventive intragastric administration on the model of starvation stress stomach ulcers. At the same time, ivEW, nEW, EW and melatonin exhibit antiulcer activity during the treatment of model indometacine-induced stomach ulcers. The maximum gastroprotective action was observed for ivEW on the model of indomethacin-induced stomach ulcer. The therapeutic efficiency of substances studied is based on their cytoprotective, antioxidant and immunomodulating action.

[Effect of prostatilen AC suppositories on course of experimental prostatitis].

The article presents the results of evaluation of efficacy of new drug prostatilen AC (rectal suppositories), containing regulatory peptides of the bovine prostate and zinc arginate-glycinate complex, in the treatment of prostatitis. The experiment was conducted on 40 Sprague-Dawley rats weighing 180-200 g. Chronic prostatitis was modeled by injection of 10% Dimexidum in combination with water, mixed with turpentine, a volumetric ratio of 4:1. It is shown that prostatilen AC has pronounced organotropic antiinflammatory effect, which manifests in reducing the weight of the prostate, reducing the protein level in the urine, activity of acid phosphatase, and levels of ceruloplasmin and C-reactive protein. In addition, this drug normalizes the act of urination and increases the diurnal diuresis, has antioxidant properties and increases the blood level of the male sex hormone testosterone.

[Remaxol in pharmacological correction of long-term disorders caused by acute ethylene glycol poisoning].

The effect of remaxol therapy as a part of the complex acute treatment of ethylene glycol poisoning has been experimentally studied on rats. Special attention was paid to the development of acidosis and hypoxia and a decrease in the functional activity of the urinary and immune systems. It was shown that remaxol is capable of restoring the functional activity of organs and systems susceptible to the toxic effect of ethylene glycol. It is suggested that the therapeutic efficiency of remaxol is based on the normalization of metabolic processes in the cell.

[Antinicrobial, antiexudative and immunotropic properties of chlorhexidine bigluconate in combination with zinc oxide, succinic and ascorbic acids].

Optimal combination of chlorhexidine bigluconate with ascorbic acid, succinic acid, and zinc oxide was found as a result of comparative trials. The composition shows antioxidative effects and is capable of initiating antibody producing and phagocytosis. This combination can be used as an active substance of orodispersible tablets for the treatment respiratory tract infections.

[Oxidative stress and combined antioxidant energy correction in the treatment of periodontitis].

Experimental-clinical study with inclusion of 50 Wistar rats with modeled parodontitis and 71 patients with chronic generalized parodontitis of different severity degree was conducted. Significance of oxidation stress in disease development and running was established in the course of the study. Disbalance of free-radical processes (FRP) in case of periodontal diseases affects oxygen stage of the oxidation stress in bigger degree and continues for a long time. In the course of experiment positive influence of cytoflavine preparation as energy-correction and antioxidant was confirmed as well as its combination with calcium-D3. In the course of comprehensive clinical study the efficacy of cytoflavine use was verified by the example of FRP correction that was accompanied by clinical picture and treatment results improvement.

Evaluation of the diuretic effect of crude ethanol and saponin-rich extracts of Herniaria glabra L. in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Herniaria glabra L. popularly known in Morocco as "Herras lehjer" which means "Stonebreaker" in English is a plant that has been used in traditional medicine to treat edema, water retention, urinary diseases and renal problems including kidney stones. AIM OF THE STUDY: The present study aims to investigate the diuretic activity of the crude ethanol extract (CEE) and the saponin-rich extract (SRE) of the Herniaria glabra L. METHODS: CEE and SRE were prepared using maceration. SRE was obtained after using the selective liquid-liquid extraction method with organic solvents. Control (normal saline, 10 ml/kg), reference drug (furosemide 10 mg/kg) and three different doses (10 mg/kg, 50 mg/kg, 200 mg/kg) of the CEE and SRE were administered orally to male Wistar rats. The diuretic activity of the extracts was determined by measuring urine volume, urinary electrolyte and urine pH. The urine output measured at 5 h and 24 h, electrolyte concentration and pH were measured at 24 h duration. Data were analyzed by one way ANOVA followed by Dunnett's t-test. RESULTS: The findings indicated that the CEE significantly increased diuresis at 50 mg/kg and 200 mg/kg. Moreover, the SRE showed significant diuretic effect at all doses. CEE at a dose of 200 mg/kg increases the volume of urine by 81%, while SRE at a dose of 200 mg/kg increases the volume of urine by 114%. SRE demonstrated at 200 mg/kg the highest diuretic properties comparable to the reference drug. Na+, K+ and Cl- urinary excretion was also significantly increased at 50 mg/kg and 200 mg/kg of CEE and at all doses of SRE. HPLC analysis revealed the presence of the saponin aglycones, the main ones are medicagenic acid and oleanolic acid, their content in CEE 3.1 ± 0.4%, 2.4 ± 0.3% respectively and in SRE 7.9 ± 0.2%, 5.9 ± 0.3% respectively. Triterpenoid saponins could be responsible for the diuretic activity of Herniaria glabra. CONCLUSION: This study could make it useful to develop a pharmaceutical product based on purified saponin-rich extract of Herniaria glabra L. as a diuretic agent.

[Detoxicating properties of remaxol with respect to multiple organ failure during severe ethanol poisoning].

Experiments on male rats showed that severe alcohol poisoning results in a multiple organ failure followed by functional impairment of heart, liver and kidney. Intensive infusion therapy with remaxol was found to significantly restore the functional activity and morphological structure of the target organs of ethanol intoxication. The results suggest that remaxol possesses antihypoxic, detoxicating, and hepatic and renal protective properties with respect to severe ethanol intoxication.

[Preclinical study of Reamberin and Remaxol safety].

Preclinical safety of reamberin, a preparation of succinic acid intended for the treatment of patients with shock conditions of different etiology, and remaxol a drug intended for the treatment of patients with liver dysfunction caused by acute intoxication was performed. Both medicines belong to the 5th class of practically non-toxic drugs. Their administration to experimental animals for 30 days did not cause toxic effects on the functional and morphological state of main systems and organs. Both medicines do not affect specific (humoral and cellular) and non-specific immune response and do not cause sensibilization, mutagenic, embryotoxic and teratogenic effects, and also do no alter parameters of reproductive functions of rats.

[Methodological approaches to the experimental investigation of dermotropic drugs].

Methodological approaches to preclinical evaluation of the efficiency of potential dermotropic preparations are proposed on the basis of original investigations and an analysis of published data. At the first stage of the preclinical investigation of preparations for external application, it is necessary to estimate their acute toxicity, allergenic activity, and local irritation effect in addition to studying the specific activity.

Long-Term Maintenance of the Functional Changes Induced by Influenza A Virus and/or LPS in Human Endothelial ECV-304 Cell Sublines.

Influenza A virus and secondary bacterial infection may have remote effects in the form of cardiovascular complications or fibrosis in different organs. However, the mechanisms governing the development of complications remain poorly studied. The present work reports the comparative assessment of the functional changes which take place in human ECV-304 endothelial cell sublines obtained previously by the long-term culturing of cells after exposure to varying infectious doses (IDs) of influenza A virus, and/or bacterial lipopolysaccharide (LPS). It has been demonstrated that, in the course of long-term culturing (six passages) after exposure to pathogenic agents (influenza virus and/or LPS), endothelial cells maintain changes in their migratory activity, permeability, and expression of mRNA for cytokines TNFα and TGFß (along with the changes in their proliferation activity, which has been demonstrated earlier). The pattern of changes depended on the type of the agent (agents) to which the cells were exposed. The differences in migratory activity (which was at its maximum 4 h after wounding) between the cell sublines at the sixth passage correlated with the differences in their proliferation activity at the first passage (proliferation data were obtained previously). In particular, an increase in migration and proliferation was observed in the sublines exposed to low virus doses (ECV-1ID), as well as exposed to LPS (ECV-LPS), while the suppression of migration and proliferation was observed in the subline exposed to high virus doses (ECV-1000ID). In the ECV-1ID, ECV-LPS, and most notably in ECV-1ID + LPS sublines, we detected an increase in the expression of mRNA for cytokines TNFα and TGFß, which, however, didn't lead to the induction of apoptosis. We have also demonstrated an increase in cell permeability in the analyzed sublines, which was indicated by a decrease in the expression of the mRNAs for the genes encoding occludin and ZO-1, the tight junctions proteins . This paper also reports an evaluation of the effects of the antiviral preparations rimantadine and alpisarin on the functional state of cell sublines. As a result, it has been demonstrated that these drugs may be able to prevent the development of the pathological changes caused by influenza A virus and/or LPS in endothelial cells. The results obtained in the present work may be of use when studying the mechanisms of development of the influenza A virus and secondary bacterial infection complications.