OVARIAN TOXICITY OF FAC CHEMOTHERAPY IN RATS AND POSSIBILITY OF ITS CORRECTION WITH PLATELET-RICH PLASMA.

AIM: To compare the dynamics of changes in the hormonal status of female rats in the setting of the FAC (5-fluorouracil, doxorubicin and cyclophosphamide) chemotherapy and after local administration of platelet-rich plasma (PRP). MATERIALS AND METHODS: The study was carried out on female Wistar rats treated according to the FAC chemotherapy scheme (4 courses with a 3-week interval). The ovariotoxic effect of the FAC chemotherapy was assessed by the levels of anti-Mullerian hormone, estradiol (E2) and follicle-stimulating hormone in the proestrus phase. Three weeks after the last course of chemotherapy, 5 rats were administered with local intra- and periovarian injection of PRP (triply with a 1-week interval). RESULTS: The dynamics of all investigated hormonal markers of the ovarian reserve in experimental animals was characterized by a progressive decrease in anti-Mullerian hormone and E2 levels and an increase in follicle-stimulating hormone level. The dynamics of the studied parameters after the serial administration of PRP demonstrated an improvement in the hormonal status. CONCLUSION: FAC chemotherapy in the experiment causes premature ovarian failure, and local administration of PRP improves the hormonal parameters of the ovarian reserve.

[Myocardial infarction in a patient with a single ventricle of the heart].

A clinical case of myocardial infarction in a patient with single ventricle heart defect is described.

[Influence of demographic characteristics on the clinical course and results of therapy in patients with precapillary pulmonary hypertension].

AIM: To assess the clinical course of the disease and the features of the treatment goals achievement in patients with IPAH and inoperable CTEPH depending on gender and age at the time of diagnosis verification. MATERIALS AND METHODS: The study included 88 patients with IPAH and 38 patients with inoperable CTEPH with a PAWP 12 mm Hg and the duration of PAH-specific therapy treatment more than 12 months. IPAH/CTEPH patients were divided into groups depending on age at the time of diagnosis verification: age 50 years (n=69)/ 50 years (n=57), and gender: 106 women/20 men. RESULTS: Patients with age 50 years at the time of diagnosis verification have significantly more severe functional class (WHO). In IPAH/CTEPH male patients a significant hemodynamic disorder also as significantly higher level of NT-proBNP at the time of diagnosis verification were observed. In men with IPAH/CTEPH and patients aged 50 years more pronounced deterioration of right ventricular systolic function was observed (ECHO). Patients with IPAH younger than 50 years were significantly more likely to achieve the treatment goals by the median 26.5 months of treatment compared to the patients aged 50 years (21% vs 6.45%). Men with IPAH/CTEPH were significantly more likely to have a high risk of death (90%) at baseline compared to the women (61%). CONCLUSION: IPAH/inoperable CTEPH patients with male sex, as well as the age 50 years and older at the time of diagnosis verification, compared with younger ones, are associated with a less favorable course of the disease.

[Features of clinical, functional and hemodynamics profile, medical treatment and prognosis evaluation in patients with inoperable chronic thromboembolic pulmonary hypertension and idiopathic pulmonary arterial hypertension according to the Russian registry].

AIM: to perform the complex analysis of clinical, functional, hemodynamics profile in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) compared to the idiopathic pulmonary arterial hypertension (IPAH) group at the time of diagnosis verification according to the Russian registry, and to evaluate the features of medical therapy and it's influence on prognosis in these patients. MATERIALS AND METHODS: In the retrospective study 193 patients with IPAH and 130 patients with inoperable CTEPH older than 18 years were included. All included patients were the participants of Russian registry (www.medibase.pro) in 15 Russian expert centers during the period from 01.01.2012 to 31.12.2018 year. The diagnosis was verified according to the algorithm, reflected in the Russian guidelines on diagnosis and treatment of PH and CTEPH (2016 year). The comparison analysis of clinical, functional, hemodynamics parameters in patients with IPAH and inoperable CTEPH was made. RESULTS: The status of 193 patients with IPAH (32 male and 162 female) and 130 patients with inoperable CTEPH - (40 male and 90 female) was analyzed during the study. The CTEPH patients were older compared to the IPAH patients: 52.2 [41.1; 60.6] and 36.5 [26.8; 36.5] years, respectively. The median period since symptom occurrence till CTEPH verification was 1.08 [0.2; 3.1] years, in IPAH patients - 2.01 [0.6; 4.2] years. More than 80% of inoperable CTEPH patients had III and IV functional class (FC) according to the World Health Organization classification at the time of diagnosis verification versus 61% of IPAH patients. According to echocardiography the level of mean pulmonary arterial pressure was comparable in two groups of PH patients. However in inoperable CTEPH patients the right atrial area was larger. The significantly higher value of mean pulmonary arterial pressure and lower value oxygen saturation of arterial blood according to the right heart catheterization were revealed. The 5-year survival in CTEPH patients, receiving initial dual combination therapy in 75% cases (in 40% - combination of riociguat and iloprost ) was 93% versus 86.5% in patients with IPAH. CONCLUSION: It was revealed, that inoperable CTEPH patients were significantly older with severe functional and hemodynamics status at the time of diagnosis verification, although with higher level of 5-year survival compared to the IPAH patients according to the Russian registry.

EXPERIMENTAL STUDY OF PAIN-RELIEVING MECHANISMS OF 4-[4-OXO-(4H)-QUINAZOLIN-3-YL]-BENZOIC ACID (PK-66 COMPOUND).

An in-depth study of the pharmacological properties of 4-[4-oxo-(4h)-quinazolin-3-yl]-benzoic acid as an analgesic agent established that it had a sufficiently high analgesic effect on models of somatic and neuropathic pain syndromes. Study objective was to study the mechanisms of analgesic action of PK-66 compound in rats using the pharmacological analysis. We evaluated the mechanisms of analgesic effect of PK-66 (1 mg/kg, intraperitoneal) compound on the thermal irritation model on Hours 1, 2, 4 and 6 after administration of study compounds. To evaluate the mechanisms of PK-66 compound pain killing, we determined the changes in its efficacy against the effects of pharmacological analyzers - Naloxon, Tramadolum, Clophelinum (Clonidine), Yohimbine, Noraepinephrine, Reserpinum, Chlorpromazine (Aminazin), Levodopa, Diazepam, and Memantine). The anti-nociceptive effect of PK-66 compound was virtually unchanged during all study terms with underlying administration of Naloxon, an opioid receptor antagonist. The results of administration of Reserpinum in rats and the concomitant administration of Noradrenaline, Clophelinum, Yohimbine and quinazoline derivative demonstrated that the adrenergic system, in particular alpha-2 adrenergic receptors, was involved in the mechanisms of PK-66 activity. Changes in the PK-66 compound effect with underlying previous administration of Levodopa and Chlorpromazine suggested that the dopaminergic system was unquestionably involved in the analgesic activity of the compound. Further study of the involvement of inhibitory and exhilarating amino acids, GABA and glutamate, showed that administration of Diazepam potentiated and extended the PK-66 analgesic effect on the thermal nociception models throughout the experiment. At the same time, increased antinociception with underlying Memantine administration preceding PK-66 was observed only in the first hours of the experiment. Therefore, the studies conducted have shown that the adrenergic system, in particular alpha-2 adrenergic receptors, dopaminergic and GABAergic systems, is involved in the mechanisms of analgesic action of 4-[4-oxo-(4h) -quinazolin-3-yl]-benzoic acid (PK-66) without any effect of PK-66 on opioid receptors.

INFLUENCE OF H2S DONOR ON CHANGES IN THE CELL CYCLE AND THE APOPTOSIS PROCESS INDUCED BY DICLOFENAC IN THE RAT GASTRIC MUCOSA.

The purpose of this work was to study the effect of concomitant administration of sodium hydrosulfide and diclofenac sodium on the parameters cell cycle of the gastric mucosa cells by DNA flow cytometry. The experiments were performed on 24 white rats of Wistar straints. The parameters of the cell cycle of cells of the gastric mucosa of rats were determined by the method of flow-through DNA-cytometry. of mucosal cells of the stomach of rats was determined by DNA flow cytometry. It was established that NaHS monotherapy in the conditional therapeutic dose of 1.5 mg/kg ip (1/20 LD50) did not influence on DNA fragmentation and the parameters of the gastric mucosal cell cycle in the experimental rats. The sign of this was the lack of statistically significant differences in the parameters studied in comparison with the intact group. The data obtained suggested of the safety of H2S when used at the conditional therapeutic dose. The combined administration of NaHS and diclofenac sodium neutralized the negative effects of a non-steroidal anti-inflammatory agent on cell cycle indicators. An indication of the anti-apoptotic effect of NaHS was statistically significant reduction in number of cell events in the SUB-G0G1 interval by 1.68 times. The growth of BP, phase S and G2 + M indicators was also recorded. Therefore, the concomitant administration of diclofenac sodium and donor hydrogen sulfide reduced the number of cells with fragmented DNA and normalized regenerative properties of the mucous membrane of the stomach.

The economic burden of chronic thromboembolic pulmonary hypertension in Russian Federation.

AIM: The aim of current study was to estimate the economic burden of the chronic thromboembolic pulmonary hypertension (CTEPH) in Russia based on patient registry. MATERIALS AND METHODS: Cost of illness study was based on data derived from CTEPH patient registry that was developed at the Division of hypertension of FSBI "National Medical Research Center of Cardiology". Demographic and clinical patient characteristics were analyzed with descriptive statistic methods. Cost of illness study was performed from the state perspective and with bottom-up approach. Bootstrapping was used for calculation of average costs per patient/year. Within the study direct costs (medical costs: outpatient, inpatient, emergency, PAH-specific therapy, concomitant therapy; non-medical costs: pension due to disability status, payments for patients on sick-leave) and indirect costs (loss in GDP) were estimated. RESULTS: Overall, 113 CTEPH patients (67 women and 46 men) from 33 Russian regions were included, mean age of patients with CTEPH was 54.6±13.95 years. Most of the patients (55%) were in able-bodied age. It was found that about half of patients with diagnosed CTEPH had a disability. Average duration of disease at the time of analysis was 6.88±11.41 years. Period from the first occurrence of symptoms to the confirmation of diagnosis of CTEPH was 2.58±5.21 years on average. More than 70% of patients had III and IV FC (WHO) at the time of diagnosis. Mean number of outpatient visits was 1.97±1.65 per patient/year, and inpatient visits were reported for 59% of patients. About 54% of patients used PAH-specific therapy, moreover 46% patients had interruptions of PAH-specific therapy (58.4±66.3 days). The total costs of CTEPH per patient/year were calculated as 805,901 RUB. The overall burden of CTEPH in Russia for total CTEPH population (470 patients) was 379 million RUB per year. CONCLUSION: CTEPH is the rare disease that is characterized with later diagnosis due to absence of disease-specific symptoms. Therefore economic burden of the CTEPH is significantly low in comparison to widespread cardiovascular diseases. Development of network of expert PH-centers and increase of the access for PAH-specific therapy will help to increase the quality of health care for patients with CTEPH.

Modern view on the place of riociguat in the treatment of pulmonary hypertension.

Current research is aimed at studying the fundamental therapeutic targets and discovering new drugs acting on previously set targets. Until recently, the only therapeutic strategy to influence the molecular pathway of nitric oxide (NO) - soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) was the use of phosphodiesterase type 5 inhibitors (PDE-5 inhibitors), such as sildenafil. In September 2014, the first member of sGC stimulators riociguat was licensed in Russia. In the paper, the results of 5 multicenter studies (CHEST-1 and PATENT-1, CHEST-2 and PATENT-2, RESPITE), which reflect the effectiveness and safety of mono - and combination therapy with riociguat in patients suffer from some forms of pulmonary arterial hypertension, and patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTPH), as well as the possibility of optimizing therapy in patients with PAH using iPDE-5 -> riociguat switching was reviewed. It also provides information on the recently launched international registries EXPERT CTEPH; new REPLACE study was announced.

Congenital genitourinary anomalies and sexual function.

Congenital urologic abnormalities in males may contribute to sexual dysfunction seen in young men. It is the purpose of this paper to review some of the more common congenital urologic anomalies and their impact on sexual and reproductive function.

Influence of preapheresis clinical factors on the efficiency of CD34+ cell collection by large-volume apheresis.

We evaluated 120 leukapheresis procedures (93 patients), in order to detect clinical factors that influence the efficiency of CD34+ collection using Cobe Spectra trade mark cell separators. Hematocrit was >27% and platelet count >30 000/microl in >95% of patients. Platelet transfusions were given if the postprocedure count was &<20 000/microl. Multiple regression analysis was used to analyze putative factors, and a predictive equation defined by stepwise regression modeling. The mean efficiency was 0.59 (s.d. 0.27). Sex (M>F; P=0.01), the volume processed (inversely; P=0.01) and CD34+ cell count (inversely; P=0.04) were associated with efficiency, whereas hematocrit, platelet or leukocyte count, catheter type and patient weight were not. The effect size for predictive factors was small (R(2)=0.21). Adverse events were limited to hypocalcemia. We conclude that female sex, volume processed and CD34+ cell count adversely influence the efficiency of CD34+ cell leukapheresis. However, the impact of volume and CD34+ cell count is small, and likely to be offset by the influence of these same factors on overall yield. Leukapheresis appears to be safe and efficient for autologous blood and marrow transplantation patients with hematocrit >27% and platelet count >30 000/microl.

[Situation of brucellosis in the regions of Stavropol Territory affected by the flood of 2002]. / Obstanovka po brutsellezu v raionakh Stavropol'skogo Kraia, postradavshikh ot navodeniia v 2002 g..

The emergency situation caused by inundations and high floods on the rivers in the affected regions exerts no direct influence on brucellosis morbidity among humans. Still the urgent evacuation of agricultural animals in connection with the natural calamity, their displacement and regrouping give grounds to prognosticate the deterioration of the epizootic situation in this infection in a number of regions of the territory where no sufficient veterinary surveillance has been ensured.

[The epidemiological characteristics of brucellosis in the region of the northern Caucasus]. / Epidemiologicheskie osobennosti brutselleza v regione Severnogo Kavkaza.

At present, the Northern Caucus Region is the most unfavourable brucellosis area of the Russian Federation where 43.5% of the total Russian incidence of this infection was recorded in 1993. Over the past years (1988-1993) there was a highly unsteady-state improvement of the epidemiological situation, however, the rates of human morbidity with this infection greatly lag behind those in Russia. The active foci of small cattle brucellosis as the leading source of human contamination with brucellosis are of major epidemiological importance. There is a trend to the activation of the epidemiological factors associated with the operation of individual-sector stock farms (such as farmers', peasants', rental and cooperative ones for processing agricultural products), which corresponds to the changes emerged in the economic mode of production in agricultural areas.

[The effect of the in-vitro interaction of antibacterial preparations on Brucella melitensis]. / Effekt vzaimodeistviia in vitro antibakterial'nykh preparatov v otnoshenii Brucella melitensis.

The character of drug interaction in 18 various combinations of sisomicin, amikacin, gentamicin, cefotaxime, doxycycline, trimethoprim and nitroxaline was studied by the chess board method with respect to 25 strains of Brucella melitensis. The synergistic effect with respect to the majority of the cultures was observed with the use of the combinations of gentamicin, amikacin or sisomicin with doxycycline. The combinations of the aminoglycosides with cefotaxime and sisomicin or gentamicin with rifampicin had a summation effect on the majority of the cultures. With the use of the combinations of cefotaxime with nitroxaline or trimethoprim and rifampicin with nitroxaline the effect on the majority of the cultures was indifferent. The effect was mainly antagonistic with the use of the combinations of amikacin with rifampicin, gentamicin with trimethoprim and cefotaxime with doxycycline. The effect of the combinations of gentamicin with nitroxaline and cefotaxime with rifampicin was different with respect to different strains of B. melitensis. It was indifferent, antagonistic or summation depending on the strain.

[Sensitivity of Brucella melitensis to various antibiotics, drug preparations and their combinations]. / Chuvstvitel'nost' Brucella melitensis k nekotorym antibiotikam, khimiopreparatam i ikh sochetaniiam.

In vitro activity of 13 antibiotics and drug preparations as well as some of their combinations was studied with respect to Brucella melitensis. It was shown that the strains of B. melitensis were sensitive to sisomicin, amikacin, gentamicin, cefotaxime, rifaprim +, nitroxoline and trimethoprim. Variations in the doxycycline sensitivity depending on the strain were observed. The strains of B. melitensis were resistant to cephalexin, phosphomycin, chinoxydine, dioxydine and oxolinic acid. Combinations of sisomicin and trimethoprim at a ratio of 1:10 and sisomicin and nitroxoline at a ratio of 1:2 had a summation effect.

[Bacteriocinogenicity of brucellae isolated in foci in the Caucasus and their evaluation from taxonomic viewpoints]. / Bakteriotsinogennost' brutsell, vydelennykh v ochagakh Kavkaza, ee otsenka s taksonomicheskikh pozitsii.

The aim of the study was to elucidate the possibility of using bacteriocinogenicity of Brucella as taxonomic feature, to determine their phylogenetic relation to other microorganisms by their bacteriocinogenic properties and to investigate the physicochemical properties of brucellacin and conditions for its stable detection. The Brucella cultures were isolated in the Caucasus. Investigation of their capacity for production of bacteriocin according to the procedure described by M.A. Konstantinova and A.D. Garmazova (1979) revealed that 62.1 per cent of the 216 cultures tested produced brucellacin. Isolation of bacteriocin with the methods developed was shown possible in all of the tested strains of B. melitensis, B. abortus, B. suis and in most of the strains of B. ovis. The methods also provided an increase in the synthesis and activity of brucellacin. The analysis of the characteristic features of bacteriocinogenicity and the properties of bacteriocin allowed recommending the use of additional taxonomic features for identification and differentiation of Brucella. Sensitivity of the indicator strains of Brucella to bacteriocins of other species (F. tularensis, Campylobacter fetus intestinalis B-8833, Y. enterocolitica, Vibrio cholerae and E. coli Fredericq) was noted which was additional evidence of the phylogenic relation between the above organisms. Investigation of the physicochemical properties of brucellacin confirmed the suggestion of the protein nature of the active principle of brucellacin and its similarity in different Brucella species.

[Taxonomic position and ecology of the causative agent of brucellosis isolated from murine rodents in regions of the northern foothills of the Greater Caucasus. II. The ecological and pathogenetic characteristics of Brucella strains isolated from murine rodents]. / Taksonomicheskoe polozhenie i ékologiia vozbuditelia brutselleza, vydeliaemogo ot myshevidnykh gryzunov v raionakh severnykh predgorii Bol'shogo Kavkaza. Soobshchenie II. Ekologicheskie i patogeneticheskie osobennosti shtammov brutsell, vydeliaemykh ot myshevidnykh gryzunov.

To establish the possibility of the circulation of brucellae among the population of myomorphous rodents, the mass survey of these rodents was carried out in the mountainous and foothill regions of the Caucasus. In the area of the northern foothills of the Caucasian Mountains 23 Brucella cultures were isolated from 2715 rodents under examination; these cultures proved to be similar to B. suis 1330 in respect to their pathogenicity and the character of pathomorphological changes induced in guinea pigs. Experiments on white mice demonstrated the possibility of brucellar contamination through sexual route and through feces.