Assessment of senior medical care majors’ knowledge in antimicrobial chemotherapy

Introduction: The resistance of microorganisms to antimicrobials has been gradually increasing since 2011 and is now recognized by the World Health Organization as a global biological threat. Causes of antimicrobial resistance must be actively addressed. Healthcare workers’ awareness of rational antimicrobial prescribing practices is of great importance. The increasing relevance of this issue is considered within this study, which started in 2014. Materials and methods: The article represents the results of anonymous prospective surveys within the framework of the KANT multi-centered research project aimed at assessing students’ knowledge of rational antimicrobial prescribing practices also known as “antimicrobial stewardship”. The survey involved 309 Medical Care majors in their fifth- and sixth- years in two Russian regional centers: Belgorod and Voronezh. The answers to four main questions of the survey were analyzed in this work. Results and discussion: According to the survey, 51.5% of the respondents properly identified a pharmacological group of an antimicrobial; 79.3% of the students would change an antibiotic if the desired therapeutic outcome was not achieved within two or three days of treatment; 29.8% of the students believed that an antimicrobial substitution was required even when a positive therapeutic outcome was achieved; and nobody could correctly identify all the proposed pharmacologically irrational combinations of antimicrobials. Conclusions: The survey showed that senior medical students have insufficient knowledge in antimicrobial stewardship. Appropriate use of antibiotics and antimicrobial prescribing practices need to be considered more thoroughly in Pharmacology, Clinical Pharmacology and Medical Care curricula. Likewise, educational activities on antimicrobial stewardship and best prescribing practices are of great importance for students as they will help with improving the knowledge of future doctors.

The results of the study of the carcinogenic properties of glucosaminylmuramyldipeptide GMDP in chronic experiments in mice and rats

Introduction: The drug Licopid® (GMDP, glucosaminylmuramyldipeptide) is intended for complex therapy of conditions accompanied by secondary immunodeficiencies. This drug belongs to the group of microbial immunomodulators of bacterial origin. The transparent mechanism of action of the active substance GMDP allows putting the drug Licopid® into the category of promising immunotherapy drugs that are in demand in the complex therapy of many diseases resistant to traditional treatment. The objective of this study was to investigate the carcinogenicity of GMDP (Licopid®) in chronic animal experiments. Materials and Methods: The study of the carcinogenic effects of GMDP was carried out in mice hybrids F1 CBAxC57BL6 and Wistar rats of both sexes with intragastric administration five days a week (Mon-Tue-Wed-Thu-Fri) for 18 months at doses of 0.186 mg/kg, 1.86 mg/kg and 6.13 mg/kg to mice and for 21 months at doses of 0.086 mg/kg, 0.86 mg/kg and 2.83 mg/kg to rats. Results and Discussion: The results of the clinical observation of the experimental animals in the course of the study demonstrated the absence of differences between mice and rats of the experimental and control groups. Conclusion: Intragastric administration of GMDP to male and female mice for 18 months and rats for 21 months at the studied doses did not lead to tumor formation in the experimental animals.

Immunotherapy in the treatment of chronic cystitis

Introduction: The article deals with to the new approaches to the immunotherapy of chronic cystitis. Cystitis appears to be a disease linked to the decreased immunity of the population. Materials and Methods: The study included 200 patients with chronic cystitis, and was performed in three stages. At the first stage, all 200 patients were questioned to determine whether they do or do not have the basic immunopathological syndromes. At the second stage, the patients of 6 clinical groups underwent a routine immunologic examination using tests to evaluate basic populations, lymphocyte subpopulations, immune globulins, circulating immune complexes, average weight molecules, absorbing and metabolic phagocytic ability, pro- and anti-inflammatory cytokines by using flow cytofluorometry methods. The third stage included distribution of the major group of patients with chronic cystitis in the relapse stage into subgroups of 25 patients each who received conventional therapy. Results and Discussion: The study has the following findings: the formation of risk groups depends on immunopathological syndromes and clinical-laboratory markers of disease peculiarities; signal tests of immunologic disorders and their correlative links with metabolic stress parameters were specified and formalized as diagnostic formulas; high clinical-bacteriological and low hemato-immunological efficacy of the conventional therapy patients with chronic cystitis and the capacity of the local and systemic modulators, such as kipferon, superlimf and imunofan, galavit, and their combinations, to normalize the parameters under study during 7-10 days were demonstrated. When combining the correctors, it was possible to achieve new quality independent of the properties of individual agents included in the composition; the reveal targets of various immune therapies were conditioned by the treatment provided, the characteristics of the correctors, the identification period – 7-10 days – 3-4 months. The analysis of the formulas of modulator targets made it possible to identify laboratory findings for their selection. Conclusion: The data obtained during the study support the fact that there was no clinical efficacy of the conventional therapy for patients; this efficacy was maintained through to the administration of the combination of modulators in the acute period. Substantiated differentiated immunotherapy resulted in implementing the proper algorithm of observations, which prevented recurring of chronic cystitis in 3-4 months.

Study of the pharmacological impact of polymeric membranes with antibacterial effect in traumatic lesions of cornea

Introduction: The most common pathology among patients with acute eye infection is conjunctivitis – 78%, keratitis accounts for 14%. The most common infectious agent causing acute infection of the eye is Staphylococcus (55%). The opacity of the cornea in the overall structure of the causes of blindness in the world in 2015 accounted for 3.25% of total blindness and 1.14% in the structure of moderate or severe decline in vision. Materials and methods: The object of the study is antibacterial polymer films based on sodium carboxymethylcellulose, levofloxacin and poludan. In the in vivo experiment was modeled on the adult rabbits, an infected corneal injury in three groups. An infected corneal injury was modeled by removing the corneal epithelium and applying a suspension of microorganisms in the amount of 1 million colonies of Staphylococcus aureus ATCC 25923 to the affected area. In the experiment, 3 groups were studied: the control group (“placebo” treatment – instillation of distilled water 4 times a day), the comparison group (treatment with levofloxacin 0.5% in the form of instillations 4 times a day and poludan twice a day), the experimental group (treatment using antibacterial polymer films with immunomodulating effect once a day). The area of the defect on the cornea was evaluated by staining with a 1% solution of sodium fluorescein. The scoring of the clinical course of the post-traumatic infection of the cornea was performed using the semantic differential method after injury and infection, after 1 hour, 1 day, 3 days, 5 days, 7 days. Results and Discussion: In the study of the rates of resorption of the antibacterial membrane, as well as the release of active substances from the polymer, complete dissolution of the sample was detected within 30 hours. Based on the results of the study of the rate of resorption of the volume of the polymer membrane, a decrease in the index over a period of 24 hours in a physiological solution was found to be 4.5-fold. A weak dependence of the adhesion force on the parameters of the microrelief of the polymer membrane was revealed. The fastest rates of complete restoration of the integrity of the epithelium of the cornea were revealed in the experimental group. In the comparison group, the cornea was completely regenerated on the 7th day. Conclusions: Under the conditions of the in vitro experiment, it was found that the antibacterial polymer membrane gradually dissolves, releasing the active components within 24 hours. When assessing the area of the defect of the cornea after an infected traumatic lesion, it was found that the treatment with polymeric antibacterial membranes with immunomodulating effect resulted in the reduction in the duration of treatment to 5 days.

Pharmacological correction of experimental osteoporosis and fractures related to it by means of rosuvastatin, L-norvaline and their combination

Introduction: osteoporosis (OP) is a multifactorial disease which is based on a dynamic decrease in bone mass and, as a result, disruption of bone structure, leading to higher chances of skeletal fractures. Endothelial dysfunction is a key cause of impaired blood supply to the bone, resulting in a decreased perfusion, disrupted osteogenesis and, as a consequence, osteoporotic changes. According to modern literature and available research, L-norvaline and rosuvastatin have a powerful endotheliotropic effect. However, there is no information that the osteoprotective properties of these drugs used as a monotherapy and as their combination have ever been studied. Materials and Methods: Simulation of experimental osteoporosis was performed on 120 white female Wistar rats. After eight weeks, the operated rats developed hypoestrogenic osteoporosis. L-norvaline and rosuvastatin, both as a monotherapy and in their combination, were used from week 9 to week 12, inclusive. The extent of changes on the background of osteoporosis was estimated twelve weeks after oophorectomy. Simulation of closed osteoporotic fractures of the femurs and their osteosynthesis were performed on 120 white female Wistar rats. Experimental osteoporosis was modeled on all animals (except the control group). Eight weeks after the removal of the ovaries on the background of developing osteoporosis, fractures of the femur were simulated. The test drugs and their combination were applied from week 1 to week 4, inclusive, after the modeling of osteoporotic fractures and their osteosynthesis. Twelve weeks after the start of the experiment, the results of fracture consolidation were analyzed. Results and Discussion: Rosuvastatin at a dose of 0.86 mg/kg, L-norvaline at a dose of 10 mg/kg, and their combination prevented a decrease in the level of microcirculation in the callus, had an anti-osteoporotic effect, and also contributed to an increased number of healed experimental fractures. The osteoprotective effect of the test drugs is, apparently, due to their endothelial-protective action. Conclusion: The range of the pleiotropic action of drugs with endothelial-protective properties can be extended by adding an osteoprotective element, which, however, requires additional research.

Correction of morphofunctional disorders with asialoerythropoietin and selective inhibitor of arginase II KUD975 in cases of ischemic kidney damage in the experiment

Introduction: Acute kidney injury (AKI), which is based on ischemic-reperfusion damage, is a widespread life-threatening condition and remains a serious public health problem with a high mortality rate among patients. Despite significant advances in various areas of medicine, the prevention and correction of ischemic-reperfusion kidney damage are still far from being at the desired level. Pharmacological preconditioning and the use of endothelioprotectors are promising areas in this field, therefore the purpose of this study was to analyze the nephroprotective properties of asialoerythropoietin and selective inhibitor of arginase II KUD975 in ischemic kidney damage in the experiment. Materials and methods: The study was performed on 260 white adult male Wistar rats, each weighing 180-220 g. Ischemic-reperfusion damage was simulated by applying a clamp on the renal leg for 40 minutes. To determine a degree of correction caused by morphofunctional disorders traditional functional, biochemical and morphological criteria were used. Results and discussion: When administering asialoerythropoietin and selective inhibitor of arginase II KUD975, there is observed an improvement in the glomerular filtration and microcirculation in the kidneys, decrease in the concentration of creatinine and urea, a decrease in fractional excretion of sodium and improvement in the histological pattern at different periods. The most pronounced nephroprotective effects are observed in the combined use of the test pharmacological agents, which are superior to such used in a monotherapy. The use of glibenclamide and L-NAME against the background of the correction of the pathology caused by asialoerythropoietin completely eliminates its positive effects. When glibenclamide and L-NAME are used against the background of correction of the pathology caused by the selective inhibitor of arginase II KUD975, its positive effects are completely eliminated by L-NAME. Glibenclamide does not eliminate positive effects. Conclusions: The results of the experiment prove the presence of pronounced nephroprotective properties of asialoerythropoietin and selective inhibitor of arginase II KUD975 in ischemic kidney damage in the experiment. The most pronounced effects are observed in the combined use of these pharmacological agents. The leading role in causing the positive effects from asialoerythropoietin is played by the activation of K+ATP channels and the activation of eNOS. The leading role in causing the positive effects from the selective inhibitor of arginase II KUD975 is played by the activation of eNOS.

Multi-aspect approach to the optimization of pharmacotherapy of patients with arterial hypertension of high and very high risk

Introduction: Personalization of pharmacotherapy of cardiovascular diseases is one of the urgent problems of cardiology. Material and methods: The study includes 120 patients with grades 2-3 arterial hypertension with the criteria of high and very high risk of developing cardiovascular complications. The patients were randomized into three groups with differentstarting regimens of pharmacotherapy – fixed and free combinations of ACE inhibitors and dihydropyridine CCB. Evaluation of the efficacy, safety and individualization of a therapy was carried out by using pharmacokinetic, pharmacoeconomic, sonographic, and laboratory methods. Results and discussion: Antihypertensive treatment with the inclusion of Amlodipine and Lisinopril or Ramipril in patients with arterial hypertension, having a slow and very slow oxidative metabolism phenotype, is characterized by the development of a more pronounced hypotensive effect in this group of patients (p<0.05-0.001) (Δ% SBP from 12.7 to 24.6 and from 19.6 to 27.9, respectively; Δ% DBP from 10.6 to 19.1 and from 15.9 to 23.6, respectively) in comparison to the group of patients with a fast phenotype (Δ% SBP from 6.42 to 9.34; Δ% DBP from 1.04 to 5.66), which allows administering a personalized pharmacotherapy. For patients with arterial hypertension of high and very high risk, the use of a fixed combination of Amlodipine and Lisinopril as a basic variant of the two-four-component therapy compared with treatment options based on free combinations of the studied drugs provided a significantly more pronounced decrease in systolic blood pressure (24.9%, 17.8 %, 19.0%, respectively, p<0.01), a greater degree of regression of left ventricular myocardial hypertrophy (8.70%, 5.67%, 5.84%, respectively, p<0.05), significant (p<0.05-0.001) improvement in a number of parameters of the patients’ quality of life, and was characterized by the greatest economic efficiency according to various criteria of hypotensive action. Conclusion: The results obtained in the study demonstrate the advantages of a fixed combination over free combinations of antihypertensive drugs and demonstrate the possibility of a pharmacokinetic approach to individualization of pharmacotherapy.

Evaluation of pharmacological correction of L-name-induced endothelial dysfunction, platelet aggregation and venous tone with diosmin Detralex 1000 mg

Introduction.Chronic venous diseases are one of the urgent problems of modern medicine. Recent studies have shown high significance of endothelial dysfunction (ED) and oxidative stress in their pathogenesis. For the correction of the occurring changes, drugs of the flavonoid group, particularly diosmin and hesperidin, are currently used. Numerous studies have confirmed a vast range of biological effects of diosmin; however, there are only sporadic data on its endothelium protective effects.Materials and methods.The study was performed in 70 white mature male rats of Wistar line, weighing 180-220 g. ED simulation was performed using non-selective blocker of NO-synthase N-nitro-L-arginine methyl ester (L-NAME). Functional vascular tests and biochemical markers were used to determine a degree of correction of functional disorders. An anti-inflammatory effect of Detralex 1000 mg was estimated in 10 mature albino rabbits weighing 2800 - 3200 g by using o-xylene. The study of the venotonic property of the drug was carried out in the experiment in an isolated segment of the rats’ portal vein with Ca2+solutions at a concentration of 0.08-1.75 mcM. The histologic specimens were prepared in accordance with the generally accepted methods.Results and discussion.The administration of the test drug did not lead to a statistically significant decrease in blood pressure in the conditions of L-NAME-induced ED. However, there was a dose-dependent statistically significant decrease in the coefficient of ED (CED), which indicates a positive endothelium protective effect. Course administration of Detralex 1000 mg leads to a significant dose-dependent correction of platelet aggregation disorders, which is manifested in the extended aggregation time. The results of studying an anti-inflammatory activity of the drug showed a decrease in the size of spots caused by the application of o-xylene, and the extention of the time interval before their onset. Studying a Ca2+-mediated smooth muscle response showed that the vein contractile force reaches its maximum at a higher dosage of the drug with a lower concentration of Ca2+. In the morphological study of the stomach wall, small and large intestine of the intact rats and rats receiving a course of Detralex 1000 mg, there were no inflammatory changes in the mucosa of the comparison group.Conclusions.The study found that Detralex 1000 mg significantly reduces the ED coefficient and slows platelet aggregation against the background of L-NAME-induced ED; the efficacy is dose-dependent. Detralex 1000 mg dose-dependently reduces vascular permeability disorders caused by the application of o-xylene. The test drug has a Ca2+-mediated mechanism of increasing the contractile activity of the venous wall. It was found that the course administration of the drug per os has no local irritative effect.

Effects of Dimephosphone on skin survival in conditions of reduced blood circulation

Introduction: The search for and creation of drugs with dermatoprotective and metabotropic activity is one of the priorities of modern diabetology. Synthetic organophosphorus compounds with no anticholinesterase activity, to which Dimephosphone belongs to, deserve great attention in this respect. Materials and Methods: Experiments included 355 white non-linear male mice (18-34 g) and 799 male rats (150–305 g). The dermatoprotective activity (DPA) of Dimephosphone regarding the survival of a skin graft was studied against the background of normoglycemia, as well as against the background of experimental diabetes complicated by hypercholesterolemia. The study of microhemodynamics in the skin was performed using laser Doppler flowmetry. The effects on metabolic processes and the antioxidant system were studied by determining the levels of glucose, urea, creatinine, total bilirubin, total cholesterol, triglycerides, total protein, albumin, globulin, catalase, malondialdehyde, superoxide dismutase, glutathione reductase, glutathione and glutathione peroxidase. Results: Dimephosphone has a pronounced DPA in conditions of reduced blood circulation against the background of normoglycemia and experimental (alloxan) diabetes complicated by exogenous hypercholesterolemia. By DPA, in most cases against the background of normoglycemia Dimephosphone exceeds Actovegine, is comparable to or inferior to Trental and Mexidol, and is more significant in terms of the therapeutic width than all the drugs taken for comparison. Discussion: According to the obtained data , DPA of Dimephosphone may be due to its ability to exhibit significant vasodilating, antihypoxic, antioxidant, antiaggregant, membrane-stabilizing, anti-acidotic, antimicrobial and other properties and also to exert a normalizing effect on carbohydrate, protein, lipid and energy metabolism Conclusion: Dimephosphone can be recommended for further preclinical and clinical studies in the form of various dosage forms, as well as in a combination therapy for metabolic disorders.

On local anesthetic action of some dimethylacetamide compounds

The study aim was to explore local anesthetic properties of some tertiary and quaternary derivatives of dimethylacetamide. Materials and methods. The study was performed on white laboratory mice and rats of both sexes, male Agouti guinea pigs, and isolated sciatic nerves of lake frog. In the focus of the study there were two quaternary and eight tertiary compounds of dimethylacetamide with substituted anion with some amino and carbonic acids residue. A local anesthetic property was predicted by computational analysis. Acute toxicity of the most promising substances was studied in mice through subcutaneous route. Local anesthetic activity of tertiary compounds LKhT-3-00, LKhT-4-00 and quaternary LKhT-12-02 was studied on models of terminal, infiltration and conduction anesthesia. The influence of substances on mixed nerve conduction was investigated on lake frog’s isolated sciatic nerves. Results and discussion. The greatest probability of the local anesthetic activity during computational analysis was estimated for the tertiary derivatives of dimethylacetamide LKhT-3-00 and LKhT-4-00 and for the quaternary compound LKhT-12-02. According to their toxicological profile, the compounds belong to moderately toxic substances (class 3). On the model of terminal and infiltration anesthesia, substances LKhT-3-00 and LKhT-4-00 at concentrations of 0.5-1% rapidly cause deep and prolonged anesthesia. On the models of conduction anesthesia, the quaternary derivative of dimethylacetamide LKhT-12-02 has the greatest analgesic effect. The duration of the effect of the substance is over 3 hours. All the investigated compounds block sciatic nerve conduction. The longest effect is registered for LKhT-12-02. Conclusions. Dimethylacetamide derivatives at concentrations of 0.5-1.0% exhibit a local anesthetic activity, and are effective for terminal, conduction and infiltration anesthesia. Their effect is due to blockade of nerve conduction.