Vol 25, No 4 (2017)

Pharmacology, clinical pharmacology
Study of fabomotizole belonging to p-glycoprotein substrates
Chernykh I.V., Shchulkin A.V., Yakusheva E.N., Gatsanoga M.V., Popova N.v.

P-glycoprotein (Pgp) is a membrane efflux protein transporter with numerous drug-substrates. In addition, a lot of drugs alter the activity of the transporter. It can lead to drug-drug interactions during polypharmacy. Fabomotizole (afobazol) is a Russian anxiolytic drug with neuroprotective activity, applied over a wide range of indications. The drug belongs to a potential substrate of Pgp according to its chemical structure.

Aim. The aim of the study was to assess belonging of fabomotizole to Pgp substrates.

Materials and Methods. The work was performed on 12 male Chinchilla rabbits. The belonging of fabomotizole to Pgp substrates was evaluated by comparing pharmacokinetic parameters of the test-substance after course administration of known transporter inducers and inhibitors – rifampicin and verapamil respectively. Fabomotizole was administered orally as a single dose of 3.8 mg/kg b.w. and blood was taken from the ear vein after 5, 10, 15, 20, 30, 60, 90, 120 and 240 min followed by it's pharmacokinetic analysis by HPLC. Pharmacokinetic parameters of fabomotizole were manually calculated by a model-independent method. The animals were then divided into 2 groups of 6 rabbits each: the 1st group received verapamil at a dose 20 mg/kg b.w. 3 times a day for 14 days, the 2nd – rifampicin in a similar course and dose. After the administration of Pgp modulators the pharmacokinetics of fabomotizole were re-analyzed.

Results. It was found that only the absorption coefficient of fabomotizole in the rifampicin series was significantly reduced by 1.27 times as compared to the parameter of intact animals (90% CI 0.66-0.94, p=0.04322). However, this change was not clinically significant, because 90% CI overlapped the range of 0.80-1.25, noted by FDA. The remaining pharmacokinetic parameters of Pgp marker substrate were not significantly changed in any series. This is evidence that fabomotizole is not a Pgp substrate. The insignificant participation of Pgp in fabomotizole pharmacokinetics testifies that the drug can be administered together with drug-modulators of transporter activity without dose correction.

Conclusion. In vivo experiment on Chinchilla rabbits showed that fabomotizole is not a substrate of P-glycoprotein.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):538-550
Application of enterosorbent on the basis of montmorillonite in acute diarrhea (experimental study)
Tishin A.N., Pokrovskii M.V., Tishina O.М., Sernov L.N., Stepchenko A.A.

Aim. To study the antidiarrheal activity of enterosorbent on the basis of montmorillonite on the model of serotonin-induced diarrhea.

Materials and Methods. The study was conducted on laboratory mice of both sexes, acute diarrhea was induced by intraperitoneal injection of serotonin hydrochloride at the dose of 0.32 mg/kg, enterosorbent was introduced orally in the form of aqueous suspension in a wide range of doses 30 minutes before introduction of serotonin. Within 4 hours, the time of onset of diarrhea, the number of defecations, the fluid content in fecal masses were taken into account. Morphological examination of the small intestine was carried out.

Results. introduction of serotonin led to diarrhea in 100% of animals within 12.8±1.2 minutes, the number of defecations increased 2.5 times as compared to the intact animals and was 19.5±0.5 times in 4 hours, the fecal masses were predominantly semi-liquid and liquid. Use of enterosorbent coded Crim_04 at the maximum dose led to a delay in diarrhea up to 73.6±4.1 minutes, the number of defecations decreased to 9.4±0.1 with a significant solidification of feces. The antidiarrheal effect of enterosorbent was confirmed morphologically.

Conclusions. Enterosorbent on the basis of montmorillonite with laboratory code Crim_04 possesses a dose-dependent antidiarrheal effect in modeling of serotonin-induced diarrhea.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):551-564
Hygiene, ecology, epidemiology, healthcare organization, history of medicine
Forecasting of development of healthcare-associated infectons in puerperas
Agarev A.E., Zdolnik T.D., Kovalenko M.S., Zotov V.V.

Aim. Identification of possible risk factors, assessment of their information value, and compilation of a prognostic table for assessing the risk of healthcare associated infections in puerperas.

Materials and Methods. Experimental and control groups were formed from among the puerperas. The experimental group included 147 women who developed purulent-septic infection within 30 days after delivery. The control group was formed by the mechanical selection of each 50th labor and delivery record for the aforementioned period and included 300 subjects. Possible risk factors were divided into groups: social factors, factors related to the state of woman's health, factors associated with the peculiarities of the pregnancy course, factors associated with the peculiarities of the labor course, factors associated with the postpartum period.

Results. During the study, the following risk factors were identified: unregistered marriage, prenatal hospitalization to the Department of Pathology of Pregnancy for more than 1 bed-day, first labor, uncoordinated contractions, amniotomy, episiotomy, hysterocervicorrhexis, staying in the ward of separate residence in the postpartum period. Based on the sum of the values of prognostic indices, calculated for each risk factor, three prognostic groups were formed: high, average and low risk. Forecasting of the risk for healthcare associated infection development in a patient is carried out by simple arithmetic addition of prognostic indices.

Conclusion. To prevent healthcare associated infections, it is recommended: to carry out bacteriological examination of an afterbirth and prescribing preventive course of antibiotics to puerperas of the high risk group in the postpartum period; to specify that a woman is at high or average risk, if any, in the discharge documentation to inform the Women's Health Department. The information on belonging of the puerperas to a particular risk group can be used by the hospital epidemiologist when carrying out operational and retrospective analysis.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):565-574
Evaluation of occupational risk for health in multi-factor intensive influence
Kharitonov V.I.

Aim. Practical realization of conceptual model of occupational risk evaluation and methods of analysis of structure and extent of occupational risk.

Materials and Methods. Eva-luation of occupational risk for health completed on an example of labor of hot forging die press operators. In a conceptual model the main information blocks are “Hygienic Evaluation of the Working Conditions and of Workload” (for prior evaluation of occupational risk) and “Evaluation of Health Condition” (for posterior evaluation of occupational risk). The task of the first block was evaluation of exposure doses of such factors as thermal stress of the environment, local and total vibration, noise, and also evaluation of the extent of the workload by parameters of severity and tension of the working process. The health condition was evaluated by four blocks: parameters of the functional condition of an organism, presence of occupational diseases, diseased conditions with temporary disability, and evidence of accelerated ageing by parameters of biological age.

Results and Conclusions. Results are presented on the basis of in-depth analysis of intensive influence of industrial factors in accordance with domestic and ISO standards. Etiogenous analysis of occupational risk for the main stress factors and integral evaluation by the index of occupational diseases were conducted. The index takes into account categories of risk and severity of occupational diseases with respective partial indices for the leading unfavorable industrial factors. This enabled adequate evaluation of damage to health induced by occupational industrial factors of different intensity. Comparison of hygienic and medico-biological parameters of evaluation of occupational risk on the basis of etiogenous analysis showed the probability for quantitative evaluation of multi-factor intensive influences and for development of effective prophylactic measures on their basis.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):575-585
Internal medicine
Clinical case of ixodes tick-borne borreliosis with development a-v blockade and implantation of the pacemaker
Lygina E.V., Miroshkin S.V.

Borreliosis is an infectious transmissible natural-focal disease caused by borrelia of borrelia burgdorferi sensu lato group and transmitted by ixodic ticks. In the article a clinical case of chronic ixodic tick-borne borreliosis is described with the primary damage to the heart, joints and with polyneuropathy of extremities. The described clinical case is interesting on the one hand by demonstration of peculiarities of the heart damage associated with ixodic tick-borne borreliosis which finally lead to transient III degree A-V block with episodes of asystole up to 5.5 s and to implantation of continuous pacemaker. On the other hand, surprising in XXI century is the fact that despite a wide availability of high-tech methods of diagnostics and treatment in any field of medicine, the ixodic tick-borne borreliosis was identified only in 6 years after the moment of manifestations of clinical symptoms.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):586-598
Psychology, clinical psychology, neurology, psychiatry, narcology
Suicide and tuberculosis mortality: a comparative analysis of time series
Razvodovsky Y.E., Zotov P.B.

Until recently tuberculosis mortality and the suicide rates in Russia were among the highest in the world. Tuberculosis and suicide belong to the medico-social problems and these epidemiological parameters are often considered indicators of psychosocial distress. There are theoretical premises and empirical evidence which suggest the positive relationship between suicide and tuberculosis mortality at individual and population levels.

Aim. The aim of the present study was to find out a link between the epidemiological parameters of tuberculosis and the suicide rates in Russia.

Materials and Methods. Trends in tuberculosis incidence/mortality and the suicide rates from 1980 to 2015 were analyzed using a time series analysis in order to asses bivariate relationship between the time series.

Results. The results of analysis indicate the presence of a statistically significant association between tuberculosis mortality and suicide rates for men at lag zero (r=0.71: SE=0.169). The association between tuberculosis mortality and suicide rates for women was also positive, but statistically not significant (r=0.26: SE=0.169).

Conclusions. The results of this study suggest positive aggregate-level relationship between tuberculosis mortality and suicide rates in men. This study indirectly supports the hypothesis that tuberculosis mortality can be considered an indicator of psychosocial distress.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):599-611
Obstetrics and gynecology
Vascularization of chorion villi in the first trimester of gestation with physiological course and in recurrent miscarriage with underlying chronic endometritis
Peretiatko L.P., Fateeva N.V., Kuznetsov R.A., Malyshkina A.I.

Aim. To study stages of vasculo- and angiogenesis in uncomplicated course of the first trimester of gestation and to identify disorders in vascularization of the villous chorion in recurrent miscarriages and chronic endometritis.

Materials and Methods. The main group – villous chorion of 5-12 weeks of gestation obtained from female patients with recurrent miscarriage and chronic endometritis (n=35); comparison group – villous chorion obtained from clinically healthy females in official abortions (n=30). On the basis of the results of morphological examination the analysis of stages of vascularization of villous chorion was carried out.

Results. In recurrent miscarriage associated with chronic inflammation of the endometrium, structural changes of the villous chorion were detected manifested by retardation of differentiation of villi starting from the 5th week of gestation, by delay of vasculogenesis at the stage of formation of hemangioblastic cords typical of the 6-7th week with its inhibition in the subsequent periods. In villi of the 8-12th weeks of gestation no further differentiation of vessels was seen, hence, branched angiogenesis did not form.

Conclusion. Disorders in differentiation of villi, in vasculo- and angiogenesis in the stroma of chorion villi with the underlying chronic inflammation of the endometrium that produced negative effect on further development and successful completion of gestation, were proved.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):612-620
Features of the histological structure of trophoblast and chorionic villi with recurrent pregnancy loss in women with thrombophilias
Mirov A.I., Kharkevich O.N., Golofast O.E., Glukhovets I.B.

The frequency of recurrent pregnancy loss does not tend to decrease. This pathology continues to be one of the important problems of modern medicine. It is known that thrombophilia can play a significant role in the etiology of spontaneous reproductive losses. However, the pathogenesis of recurrent spontaneous loss of pregnancy in the presence of maternal thrombophilia is not fully understood.

Aim. To identify the features of the histological structure of trophoblasts and chorionic villi in the first trimester of pregnancy in women with thrombophilia and recurrent pregnancy loss, with careful exclusion of other possible causes of fetal loss syndrome.

Material and Methods. Histological examination of 49 chorion tissue samples from 24 patients with thrombophilia and recurrent pregnancy loss in the first trimester (study group) was performed. The controls were samples of chorion tissue taken during artificial abortion in 33 healthy women who had a history of 2 or more spontaneous labor without significant complications. Thrombophilia diagnosis and hemostasis system state evaluation was performed for all patients on the basis of analysis of 30 parameters according to standard methods. All studies were conducted at the Regional clinical hospital № 8 in Ryazan as well as the scientific and clinical center of hematology, oncology and immunology of the Ryazan State Medical University named after academician I.P. Pavlov of Health Ministry of the Russian Federation. Statistical processing of the obtained results was carried out with the help of computer program package Statistica (version 10).

Results. Significant differences in the histological structure of trophoblast and chorionic villi in the studied women were revealed, in comparison with those in the control group. It is proved that the presence of thrombophilia negatively affects the process of embryogenesis and contributes to a significant reduction in the area of the chorionic villus vessels in the first trimester of pregnancy.

Conclusion. It is proved that the presence of thrombophilia has a negative effect on the process of embryogenesis and significantly reduces the vascular area of chorionic villi that can probably play a significant role in the pathogenesis of recurrent pregnancy loss.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):621-641
Biochemistry, physiology, biophysics, pathological physiology
Development of phenotypical individualization of the person social activity criteria and indicators
Shatyr Y.A., Ulesikova I.V., Mulik I.G., Bulatetsky S.V., Mulik A.B.

Social activity being one of the main elements of organization of human vital activity, is characterized by systemic principle of formation and individuality of manifestations. Recognizing importance of the role of factors of social nature in development of social activity of an individual, one should agree that individual specialness of behavior largely depends on phenotypically determined psychophysiological and psychological features of an individual.

Aim. The aim of research was to develop criteria and parameters of phenotypic individualization of social activity of a person.

Materials and Methods. Into the study 146 individuals, males and females of 18-23 years of age were included. As the main criteria of psychophysiological and socio-psychological typologization of expressiveness and direction of social activity of an individual 2 groups of respective traits were used: impulsivity - initiativity - passivity, and prosociality - social neutrality - asociality.

Results. The conducted experimental study permitted to correlate the device-detectable levels of the general nonspecific reactivity of an organism with the extent of expressiveness of social activity in human behavior. Here, a high level of general nonspecific reactivity was associated with inclination to impulsive behavior, a low level was associated with passive behavior, and the medium level of the general nonspecific reactivity of an organism was associated with inclination to initiative behavior. A method of qualitative differentiation and quantitative assessment of the individual prosociality-asociality balance in human behavior has been developed and tested. In order to technologize the process of complex evaluation of the expression and orientation of social behavior, a matrix of social activity of an individual has been developed that integrally characterizes the psychophysiological and psychological potential of an individual.

Conclusion. The results of the study made it possible to specify the criteria and parameters of the phenotypical individualization of the social activity of an individual. The proposed method for assessment of the social activity of an individual provides a complex consideration of the physiological and psychological factors of the "sociality" of behavior, the possibility of qualitative typologization and quantitative determination of the individual prosociality-asociality balance, as well as algorithmization of the testing process.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):521-537
Surgical correction of functional disorders in performing sphincterosafing operations for rectal cancer (literature review)
Kulikov E.P., Kaminsky Y.D., Klevcova S.V.

For many decades the main goal of oncologists was to increase life expectancy of patients with malignant tumors, without paying due attention to quality of life. Currently, the goals of patients’ treatment with rectal cancer are to cure, to minimize the risk of local recurrence, preserve the normal course of intestine, to optimize it's function and to ensure quality of life. For a long time, the standard surgical treatment of patients with low rectal cancer was abdominoperineal extirpation, but recently sphincterosafing operations have seen a widespread introduction in surgical practice. However, functional results after these types of operations don't always meet the expectations of surgeons and patients. In the postoperative period, patients often develop a syndrome of low anterior resection, characterized by frequent bowel movements, repeated, prolonged and incomplete evacuation of bowel and the imperative urge to defecate. The manifestation of this syndrome can significantly impair the quality of patient's life and reduce to nothing the efforts of the surgeon to preserve the sphincter of the rectum. For surgical correction of low anterior resection syndrome, various types of colonic reservoir anastomoses have been proposed. The purpose of formation of colonic reservoirs is to increase the cumulative function of intestine. However, the existing methods have several disadvantages related to technical complications and the risk of developing evacuation dysfunction, which is the reason for search the new ways of optimization of anastomoses when performing sphincterotomy operations for cancer of the rectum.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):642-654
The use of plasmapheresis and intravenous laser blood irradiation in treatment of patients with newly diagnosed tuberculosis at the late stages of hiv infection (references review)
Polyakov A.A., Kornilova Z.H., Demikhova O.V.

This article presents an overview of the current domestic and foreign literature on the problems of treatment of newly diagnosed tuberculosis in patients with late stages of HIV infection. The urgency of the problem, peculiarities of the clinical course and treatment of tuberculosis, the principles of antiretroviral therapy in the combination of tuberculosis and HIV infection are considered. It has been established that long-term chronic (или “long term” или “chronic”) tuberculosis intoxication, as well as aggressive antituberculosis therapy, lead to disruption of metabolic processes, hypercatabolism, intoxication, and development of hypercoagulable syndrome. At the same time, data is provided on the toxic effects of antiretroviral therapy. Treatment of adverse reactions begins with detoxification and antihistamine therapy followed by the addition of vitamin therapy, antioxidants, antihypoxants, hepatoprotectors, anabolic agents, and enterosorbents. Various methods of pathogenetic therapy are of great interest, including extracorporal hemocorrection (plasmapheresis) and intravenous laser irradiation of blood (ILIB). Plasmapheresis (PA) allows the effective and short time normalization of homeostasis indices as well as reduction or elimination of intoxication effects, toxic and allergic reactions, hence increasing the effectiveness of basic therapy. Course of PA in patients with common forms of tuberculosis (3-5 procedures, with an interval of 2-3 days, removal of 20-25% of the volume of circulating plasma and replacement with crystalloid solutions in combination with hydroxyethyl starches) allows the elimination of symptoms of intoxication, increases tolerance of the organism to chemotherapy, and suppresses undesirable side effects. The method of quantum therapy (ILIB) is based on the effect of quantum energy on blood directly in the vascular bed. As the result photo biological influence of ILIB, all body systems are activated to correct the existing disorders. This is manifested to a great extent in tissues suffering from oxygen deficiency, since it is in these areas the metabolism increases and the processes of tissue reparation are activated. ILID helps for activation of white blood cell function, phagocytosis, synthesis of antibodies, interferon, and in general, improves the immune status.

I.P. Pavlov Russian Medical Biological Herald. 2017;25(4):655-668

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