Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Malygin AS, Demidova MA, Skachilova SYa, Shilova EV

Valproates are commonly used to treat various forms of epilepsy. Problems accompanying their clinical application include drug resistance, adverse effects, acute and chronic toxicity. Safer anticonvulsants with improved efficacy can be obtained through the chemical modification of valproic acid structure. Thiadiazole-linked amide derivatives of valproates hold great promise because 1,3,4-thiadiazole can improve the drug’s bioavailability and reduce its toxicity. The aim of this work was to synthesize a novel amide derivative of valproic acid and 1,3,4-thiadiazole exerting antiepileptic activity. The chemical structure of the synthesized valproate was studied by IR, proton NMR and 13С-NMR-spectroscopy, mass spectroscopy and elemental analysis. The purity and individuality of the compound was confirmed by thin-layer and high-performance liquid chromatography. Its antiepileptic activity was assessed in the test with intraperitoneally injected 250 mg/kg isoniazid and subsequent Probit analysis. The synthesized N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propyl pentane amide (valprazolamide) had the following characteristics. ESI+MS: m/z 256.1 [M + H]+; MRM transitions: m/z 256.1 — m/z 81.0 and m/z 130.1. The valproate exerted antiepileptic activity against isoniazid-induced seizures in mice. In the test with isoniazid, ED50 of intraperitoneally injected VPZ was 126.8 mg/kg (95% CI: 65.5–245.4). Its therapeutic index was 7.3.

Received: 2020-01-17

Published online: 2020-02-10

DOI: 10.24075/brsmu.2020.007

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VIEWS 5129

Nurmukhametova ET, Shlyapnikov ME

Recently specialists take an interest in organ-preserving methods of uterine fibroids treatment, one of which is uterine artery embolization (UAE). One of the method’s negative aspects is the severe postembolization syndrome (PES) development, requiring timely initiation of adequate treatment in order to avoid severe complications that could lead to the organ removal. The study was aimed to search for the prognostic criteria of the severe PES development during the preoperative period. The study included 81 UAE-treated women aged 19–50 with 7–17 week uterine myoma. The patients’ anthropometric measurements were used, as well as the skin microcirculation data obtained by laser Doppler flowmetry together with the occlusion test. Based on prognostic criteria, models with AUC (area under ROC curve) > 0.8 were presented. According to the models, the anthropometric predictors of the severe PES were the following: age under 38.5 (р < 0.05); BMI lower than 25 kg/m2 (р < 0.05), and microcirculation value (M) prior to UAE below 9.55 PU (р = 0.001). Microvascular blood flow during the occlusion test indicate that the higher the oxygen consumption index (I), intravascular resistance (Rc), capillary blood flow reserve capacity in the models, the higher the risk of the severe PES development (р < 0.05). Low alpha angle value obtained by the occlusion test (р = 0.003) as well as the UVLF value (р = 0.004) in the models also indicate the increased risk of severe PES. Multidimensional prognostic modelling admits to expect the severe PES development prior to UAE, which allows the doctor to prepare the woman for specific management and treatment.

Received: 2019-12-31

Published online: 2020-01-30

DOI: 10.24075/brsmu.2020.006

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VIEWS 4676

Frolov MA, Kazakova KA, Dushina GN, Frolov AM, Gonchar PA

A patient presented to our clinic with stage Ia open-angle glaucoma of the right eye and stage IIa surgically corrected open-angle glaucoma of the left eye. The condition of the ocular surface was interpreted as toxic/allergic conjunctivitis provoked by brimonidine 0.15 %. Brimonidine was substituted with non-selective 0.5%; additionally, topical steroids were prescribed. After steroids were discontinued, some of the symptoms came back, including moderate hyperemia and conjunctival edema, which was interpreted as intolerance to a preservative contained in the eye drops. A decision was made to switch from the β-blocker to its preservative-free formulation; regular IOP monitoring was continued. IOP measured during the next visit was above tolerated, so a preservative-free form of the ocular hypotensive combination drug (an analog of prostaglandin 0.005% with non-selective β-blocker 0.5%) was introduced to the regimen, with further IOP monitoring. Because the initial diagnosis was wrong, damage to the ocular surface had been aggravated by inadequate therapy. Preservative-free hypotensive eye drops are beneficial for the corneal surface and have a positive effect on a patient’s adherence to the regimen.

Received: 2019-12-26

Published online: 2020-01-27

DOI: 10.24075/brsmu.2020.005

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VIEWS 4647

Tsimbalist NS, Suftin BA, Kriuchkova AV, Chupyatova EA, Babichenko II

Buerger's disease is a rather rare pathology characterized by nonatherogenic vascular lesion associated with the inflammation in the intima of the vessel and the thrombus formation. Most often the pathological process affects small and medium caliber arteries. Vascular occlusion can lead to tissue ischemia and the trophic ulcers, and cause the extremity amputation. The disorder pathogenesis has not been fully explored. Literature data indicate that the disease development may be associated with autoimmune processes. The paper presents the results of immunohistochemical study of the material obtained after amputation of the lower extremity in a patient diagnosed with Buerger's disease. The patient had a 15-year tobacco smoking experience. In the inflammatory cell infiltrates around the affected vessels, lymphocytes with CD4, CD8 antigens and IgG immunoglobulin deposits were found, which could be considered as the evidence of the autoimmune mechanisms’ involvment. Immunohistochemical reactions with markers of NK cells CD56 and the central component of the C3d complement system were negative. The results of the study suggest that the key role is played by helper and suppressor T lymphocytes, as well as by humoral antibodies of the IgG class.

Received: 2019-12-09

Published online: 2020-01-24

DOI: 10.24075/brsmu.2020.004

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VIEWS 4549

Bochkova AG, Domozhirova AS, Aksenovа IA

In Russia, for more than 10 years, within the framework of national projects, the activities have been carried out aimed at restructuring of the primary and specialized (including high-tech) medical care, as well as strengthening of primary health care directed at early detection of malignant neoplasms. The study was aimed to evaluate the effectiveness of the patient examination rooms for women in improvement of the adjusted cumulative survival of patients with gynecologic malignancies detected actively in 2005–2015 in the Chelyabinsk Region. Using the Population Based Cancer Registry (PBCR) of the Chelyabinsk Region database, the adjusted cumulative survival calculation for patients with cervical cancer (389), uterine corpus cancer (373) and ovarian cancer (161) detected actively in the patient examination rooms of the Chelyabinsk Region (treatment group), as well as for cervical cancer (395), uterine corpus cancer (380) and ovarian cancer (163) detected in patients who sought medical assistance (control group), was performed for the first time. The staging of cervical cancer detected in the examination rooms in 2010–2017 was characterized by the high proportion of I/II stage tumors compared with the rest of patients’ population of the Chelyabinsk Region (an average of 50.8 and 46.1% respectively). For uterine corpus cancer the average proportion was 85.5 and 82.0% respectively, and for ovarian cancers it was 42.0 and 37.4% respectively. Analysis of the PBCR of the Chelyabinsk Region for a 10-year period revealed the 5-year adjusted cumulative survival improvement in the actively detected cervical cancer patients compared to the control group (62.3 and 55.8%) respectively (p = 0.11). In patients with uterine corpus cancer, it was 82.0% for the main group and 70.4% for the control group (p = 0.001). In ovarian cancer patients, no significant differences in the 5-year adjusted cumulative survival were observed (47.5% in the main group, 43.2% in the control group) (p = 0.49). Thus, the patient examination rooms are the effective model of the cancer secondary prevention available in the Chelyabinsk Region.

Received: 2019-12-23

Published online: 2020-01-23

DOI: 10.24075/brsmu.2020.003

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VIEWS 4214

Alekseev VV, Kade AKh

The immune system is subject to all sorts of influences. Pain is one of them, accompanying an organism’s existence. It is essential to be aware of and account for age-related characteristics of the innate immunity in order to adequately assess their dynamics in ontogenesis. The literature is scarce on the changes to the killing activity of neutrophils occurring in newborns in response to acute pain. The aim of this study was to detect potential changes to the phagocytic activity of neutrophils in response to an algogenic stimulus in newborn rats. The experiments were carried out in 3-5-day-old rats. Two groups were formed: the control group and the main group, in which acute pain was modelled. Blood samples were collected 2, 30–60 and 120–180 minutes after exposure to the algogenic stimulus. The microbicidal activity of neutrophils was measured using a spectrophotometric modification of the spontaneous/stimulated nitroblue tetrazolium (NBT) reduction test. The results were compared using the Mann-Whitney U test. In the first hour following pain modeling, the stimulated NBT reduction test demonstrated an increase in the measured parameters from 71.5 to 87.4 a.u. (р < 0.001); the spontaneous NBT reduction test showed an increase from 50.7 to 58.6 a.u. (p < 0.01) 30 to 60 min after exposure. The most pronounced change of the microbicidal activity coefficient was observed 2 min after pain modeling, increasing from 1.40 to 1.72 a.u (р < 0.001). By the end of the experiment, the measured parameters approximated their initial values. During the analysis, we accounted for the fact that the neutrophil response to the algogenic stimulus was unfolding in the setting of microbial colonization occurring in newborns.

Received: 2019-12-17

Published online: 2020-01-20

DOI: 10.24075/brsmu.2020.002

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VIEWS 4720

Andreevskaya SN, Smirnova TG, Larionova EE, Andrievskaya IYu, Chernousova LN, Ergeshov A

The lack of simple, rapid diagnostic tests for isoniazid-resistant rifampicin-susceptible tuberculosis infection (Hr-TB) can result in low treatment efficacy and further amplification of drug resistance. Based on the clinical data, this study sought to estimate the prevalence of Hr-TB in the general population and characterize the phenotypic susceptibility and genetic determinants of isoniazid resistance in M. tuberculosis strains. Molecular-genetic and culture-based drug susceptibility tests were performed on M. tuberculosis isolates and M. tuberculosis DNA obtained from the patients with pulmonary TB undergoing treatment at the Central Tuberculosis Research Institute between 2011 and 2018. The tests revealed that Hr-TB accounted for 12% of all TB cases in the studied sample. Hr-TB strains were either resistant to isoniazid only (45%) or had multiple resistance to 2–6 anti-TB agents. Resistance to isoniazid was caused by mutations in the katG gene. Based on the literature analysis and our own observations, we emphasize the importance of developing simple molecular drug susceptibility tests capable of detecting simultaneous resistance to rifampicin and isoniazid and the necessity of their translation into clinical practice.

Received: 2019-12-11

Published online: 2020-01-12

DOI: 10.24075/brsmu.2020.001

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VIEWS 5779

Rogozhina AA, Minushkina LO, Alessenko AV, Gutner UA, Shupik MA, Kurochkin IN, Maloshitskaya OA, Sokolov SA, Zateyshchikov DA

Development of modern methods for metabolome assessment, such as gas chromatography–mass spectrometry, allows one to expand the knowledge about the features of lipid metabolism in various clinical conditions. The study was aimed to investigate lipidome features in patients with different probability of family hypercholesterolemia (FH). The study involved 35 patients: 15 men (42.9%) and 20 women (57.1%) with dislipidemia or early cardiovascular diseases which manifested below 55 in men and 60 in women (average age of patients was 49.8 ± 9.96). The family dislipidemia probability was evaluated using the Dutch Lipid Clinic Network Score. In 10 patients the probability of FH was low (score 1–2), 22 patients had possible FH (score 3–5). Three patients had probable or definite FH (score 6 in 2 patients, score 9 in one patient). Determination of molecular species of sphingomyelins, ceramides and sphingoid bases (sphingosine, sphinganine) as well as galactosylceramide was carried out using gas chromatography–mass spectrometry. In patients with definite/probable FH the sphingosine level was significantly higher compared with patients having low probability of FH (144.36 ± 107.863 and 50.14 ± 62.409 ng/ml; р = 0.01). In patients with FH, an increase in the proportion of long chain sphingomyelin SM 18 : 1/22 : 0 as well as a significant increase in the level of long chain ceramides with С 20 : 1 and С 22 : 1 was determined. Positive correlation of low-density lipoproteins and sphingosine level (r = 0.344; p = 0.047) together with negative correlation of high-density lipoproteins (HDL), sphinganine (r = –0.52; p = 0.002), and galactosylceramide level (r = –0.56; p = 0.001) were detected. Thus, in patients with high probability of FH the lipidome changes were observed, which could be considered the cardiovascular risk markers.

Received: 2019-11-30

Published online: 2019-12-27

DOI: 10.24075/brsmu.2019.090

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VIEWS 4887