Non-invasive radionuclide molecular imaging of epidermal growth factor receptor (EGFR) expression can guide patient stratification for EGFR-targeted therapies. The designed ankyrin repeat protein (DARPin) E01, which binds EGFR ectodomain III with sub-nanomolar affinity, is a promising scaffold for single-photon emission computed tomography (SPECT) imaging probes. In the present study, we compared site-specific radioiodination of DARPin E01 using the bifunctional prosthetic group (4-hydroxyphenyl)ethyl maleimide (HPEM) with site-unspecific radioiodination via [123I]I-para-iodobenzoate (PIB). [123I]I-HPEM was conjugated to the C-terminus of DARPin E01 via Glu-Glu-Glu-Cys ([123I]I-E01-E3C-HPEM) or Gly-Gly-Gly-Cys ([123I]I-E01-G3C-HPEM) linkers. Radiolabelling yields were 6 ± 2% and 13 ± 5%, respectively. Size-exclusion purification provided radiochemical purity > 98%. Both HPEM conjugates retained nanomolar EGFR-binding affinity (KD: 3.2 ± 0.6 and 4.8 ± 0.9 nM) and demonstrated EGFR-specific tumour accumulation in A-431 xenografts. Cellular processing was characterised by rapid binding, slow internalisation, and non-residualising behaviour of all variants. Kidney uptake was lower for the site-specifically labelled variants. However, site-specific labelling evidently elevated hepatobiliary excretion and uptake in Na/I-symporter-expressing organs compared to [123I]I-(HE)3-E01-PIB, while linker composition (E3C vs. G3C) did not significantly alter biodistribution. Site-unspecific radioiodination with [123I]I-PIB remains the preferred approach for clinical SPECT imaging of EGFR expression with DARPin E01.

Introduction: This study aimed to investigate a plausible mechanism underlying the potential radiosensitizing activity of lithium L-ascorbate by modelling lithium versus sodium effects in the binding pocket/pore of the sodium-dependent vitamin C transporter SVCT1 in silico. Researchers then conducted in vitro tests to determine if extracellular lithium effectively reduces the accumulation of ascorbate within cells. Methods: SVCT1 protein structures (PDB: 7YTW, 7YTY) were prepared, embedded in lipid membranes, and simulated using GROMACS with CHARMM36 force fields, comparing Na+ and Li+ ion effects on ascorbate transport over 100 ns. Jurkat cells were incubated with ascorbate (100 μM) and Li+ (0.5, 1, 2, and 4 mM) for 24 hours. Intracellular ascorbate levels were measured via stripping voltammetry on a carbon glass electrode. Results: Molecular simulations revealed that Li+ ions delay release from the SVCT1 pocket. It suggested altered ion residence and pore geometry consistent with impaired Na+-coupled ascorbate transport. In vitro experiments showed a significant reduction in intracellular ascorbate concentrations at media Li+ concentrations of 0.5-2 mM. Discussion: We hypothesized that lithium-ion inhibition of SVCT-mediated ascorbate uptake increased extracellular ROS formation. That highlights a potential ion-specific regulatory mechanism in cellular redox homeostasis. Conclusion: These findings support a transport-centered mechanism for lithium-induced radiosensitization, involving inhibition of SVCT1-dependent ascorbate transport. This effect likely promotes extracellular pro-oxidant conditions and oxidative stress, as previously demonstrated.

The objective of the present study was to test the hypothesis that the position of the HYNIC chelator in DARPin G3 variants affects in vivo biodistribution and to select the most effective variant as a 99mTc imaging agent for HER2-expressing tumors. This study evaluated the labelling, affinity, cellular processing, biodistribution, and in vivo targeting specificity of novel N- and C-terminal DARPin G3-HYNIC constructs. In addition, amino acid sequences containing E3C or (G3S)3C at the N- and C-terminus of the protein were used as linkers for HYNIC binding to DARPin G3 to enrich the molecular design of constructs in this study. The results demonstrated that the position of the HYNIC chelating group in DARPin G3 constructs did not affect the binding properties of the target in vitro and in vivo. At the same time, the position of HYNIC was found to strongly influence the biodistribution of labelled DARPin G3 constructs in CD1 mice, showing increased accumulation in the kidneys and decreased levels in the liver, spleen, and lungs when HYNIC was added to the N-terminus of the protein variants. New N- and C-terminal constructs of DARPin G3-HYNIC were generated for HER2 targeting. It is evident that changing the position of the chelator in DARPin G3-HYNIC leads to differences in pharmacokinetic behaviour. The biodistribution of HYNIC variants attached to the N- or C-terminus of DARPin G3 was not significantly altered by different amino acid linkers. Therefore, variants with HYNIC positioned at the N-terminus are more useful for selecting a 99mTc-DARPin G3 imaging tracer. The [99mTc]Tc-HYNIC-C(G3S)3-G3 variant exhibited enhanced biodistribution compared to [99mTc]Tc-HYNIC-CE3-G3, particularly regarding reduced uptake in the liver.

Plant extracts containing polysaccharides, flavonoids, and chelated calcium compounds are effective for the complex therapy of osteomyelitis. In this study, the content of target components in the extracts of seven Saussurea DC species was studied, and their osteogenic and hematopoietic activities in model osteomyelitis were investigated. The content of chelidonic acid by high-performance liquid chromatography, flavonoids by spectrophotometric method, polysaccharides by gravimetric method, and calcium by automatic analyzer in extracts was determined. Biological experiments were carried out on rats using the model of experimental osteomyelitis. The largest amount of calcium (3-4 mmol/l) in S. controversa, S. salicifolia, and S. frolowii, chelidonic acid (122 mg/g) in S. controversa, and flavonoids (63-74 mg/g) and polysaccharides (218-251 mg/g) in S.frolowii and S. parviflora extracts was found. In the model osteomyelitis, the studied extracts stimulated bone marrow hematopoiesis, and the total number of bone marrow cells increased after treatment with S. controversa extract by 50% and with S. parviflora and S. daurica extracts by 28% compared to the control. After treatment with Saussurea extracts, the intensity of inflammation in the bone tissue decreased, and regenerative processes intensified. Moreover, the area of mature bone tissue increased by 72% after treatment with S. controversa and S. parviflora extracts, indicating the successful completion of the bone regeneration process. Plants of the genus Saussurea (S. controversa DC, S. parviflora (Poir.) DC, S. frolovii Ledeb., S. daurica Adams., and S. salicifolia (L.) DC) showed osteogenic and hematopoietic efficacy in the osteomyelitis model of rats. Extracts and biologically active components of these plants can expand the arsenal of sources for the complex therapy of osteomyelitis.

Noninvasive radionuclide imaging of epithelial cell adhesion molecule (EpCAM) expression in lung, ovarian, breast, kidney, and other cancers can stratify patients for EpCAM-targeted therapy. The constructed scaffold proteins, designed ankyrin repeat proteins (DARPins), are highly specific high-affinity probes for radionuclide imaging. A clinical study demonstrated that the anti-EpCAM DARPin [99mTc]Tc-(HE)3-Ec1 showed precise EpCAM imaging at 2, 4, and 6 h after injection in patients with nonsmall cell lung cancer. However, a noticeable accumulation in healthy organs has prompted the development of new Ec1-based agents with improved biodistribution properties. In addition, it would be desirable to substitute a labor-intensive labeling procedure. The purpose of this study was to test the hypothesis that the use of Gly-Gly-Gly-Cys (G3C) or Glu-Glu-Glu-Cys (E3C) peptide chelators placed at the C-terminus of DARPin for labeling with 99mTc (V) could improve the image contrast and biodistribution of Ec1. The radiochemical yield of the new variants exceeded 95%. The labeled proteins specifically bound to human EpCAM-expressing cancer cell lines with affinities of 8-10 nM. The biodistribution of [99mTc]Tc-Ec1-G3C and [99mTc]Tc-Ec1-E3C in mice was compared with the biodistribution of clinically tested [99mTc]Tc-(HE)3-Ec1 in a Nu/j mouse model with SKOV-3 xenografts. The new variants specifically accumulate in human xenografts with EpCAM expression. The accumulation of new variants in healthy organs (liver, salivary glands, spleen, and stomach) was reduced compared to [99mTc]Tc-(HE)3-Ec1. [99mTc]Tc-Ec1-G3C provided the best imaging contrast and is suitable for clinical testing.

At the beginning of the VI Logical Investigation, Husserl interprets expressive acts as bearers of meaning. This interpretation seems to reverse the research perspective established in the previous - as well as subsequent - investigations and which has predetermined the dominant reading of Husserl's phenomenology of sense and meaning in their relation to language. Language, as it is presented in the phenomenology of expression in the First Investigation of the second volume of "Logical Investigations", as well as in a number of other key works (especially "Ideas I"), seems secondary in relation to consciousness, which gives meaning, as well as in relation to meaning itself, which, even when rethought in the spirit of transcendental phenomenology, i. e., deprived of its freedom from consciousness, retains its freedom from language, in other words, from the linguistic point of view, it remains a meaning for which being expressed is no more than an accidental circumstance. This secondary nature (or its semblance) corresponds to the established idea of Husserl's understanding of language as a transparent medium for the transmission of initially extralinguistic data and ideal meanings. On the contrary, where expressive acts prove to be the original bearer of meaning and, consequently, of intentionality itself as a constitutive feature of consciousness, namely acts that, according to Husserl, belong to a meaningfully functioning expression as an essential component, the contours of a completely different phenomenology of language emerge. The article attempts to develop the hermeneutic potential of Husserl's analysis of expressive acts in "Logical Investigations" and to show its significance for Heidegger's phenomenology. Based on this, the author of the paper thematizes how, in a world where everything has already been said and interpreted, is it possible to maintain both the difference and the unity of what has been said and shown (the unity that phenomenology itself claims to be) and does phenomenology give us the opportunity to implement Wittgenstein's strategy of silent showing in language itself, that is, in a fundamentally different, non-Wittgensteinian way.

Chelidonic acid (ChA) is small molecule capable of inducing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and the formation of mineralized bone matrix (MBM) both in vitro and in vivo. However, the molecular mechanisms underlying these effects are unknown. Therefore, in silico modelling of potential molecular targets of ChA was performed. ChA was isolated from Saussurea controversa. The ability of ChA to induce in vitro differentiation MSCs into osteoblasts synthesizing MBM was detected using alizarin red staining. ChA osteogenic activity was studied in mice by in situ test of ectopic osteogenesis, using the subcutaneous implantation of syngeneic bone marrow on the calcium phosphate coated titanium plates. DIGEP-Pred web service was used to simulate in silico the effect of ChA on gene expression, and overrepresentation analysis to search for common ontologies and pathways. ChA linearly increased the number of single (R2 = 0.92, p = 0.039) and the total areas of MBM sites (R2 = 0.96, p = 0.019) in a 21-day MSC culture. Oral administration of ChA led to two to three times improved bone and bone marrow formation in situ. In silico modelling identified 306 genes (including 7 calcium import genes) and 9 signalling pathways potentially involved in ChA osteogenic effect and calcium metabolism in MSCs. In silico analysis revealed a list of key signalling pathways and genes for calcium influx into MSCs and their differentiation into osteoblasts as the first target candidates for studying real gene expression and molecular mechanisms of the ChA osteogenic effects.

Radionuclide-based molecular imaging modalities are active and developing areas of functional and molecular diagnosis. Among the radionuclides used for SPECT imaging in oncology, 99mTc is a leading candidate for radiolabeling. At present, a sufficient number of complexons for 99mTc have been described; however, the development of effective delivery systems for this isotope to the area of interest is a complex research task. The use of tumor-targeting molecules as carriers for radioactive tracers is an effective strategy that has enabled the development of many novel radiopharmaceuticals for cancer imaging. Background: To date, a number of studies have shown tumorotropicity of tetrapyrrole compounds to tumor tissues, in particular derivatives of natural chlorophyll A. Methods: Purification was performed using solid-phase extraction. Assessment of radiochemical yield and purity was performed via radio-ITLC. The in vitro tumor cell accumulation was assessed using SKOV-3 and A-431 cell lines. Dose-dependent biodistribution was evaluated in Nu/J mice bearing epidermoid carcinoma (A-431) xenografts. Results: In this work, we obtained complexes with 99mTc based on water-soluble carboxylate chlorin e6 derivatives in order to evaluate their potential for use as SPECT radiopharmaceuticals. We performed radiolabelling optimization of a series of the novel chlorins and primary preclinical studies, including an assessment of the effect of their lipophilicity and charge on tumor uptake. Conclusions: Modification of the periphery of the chlorin macrocycle with chelating groups allows for complexing a wide range of metals, including 99mTc, which can be used for targeted delivery of the radionuclide to the area of interest.

The kinetic dependencies of the surface pressure, the dilational dynamic surface elasticity and ellipsometric angles of cupin-1.2 and vicilin solutions in 8M urea were measured at different concentrations. The analysis of these kinetics dependencies and the obtained master curves allowed us to determine a few adsorption steps in the investigated systems and showed that the master curves are individual characteristics of the protein for a given solvent. At the same time, the shape of these curves can be different for adsorbed and spread layers of plant proteins indicating different structures of these layers. The dependencies of the dynamic surface elasticity on surface pressure are non-monotonic, unlike the corresponding results for most of the solutions of the investigated plant proteins. The extremums of these dependencies can be connected to the formation of the distal region of the surface layer in agreement with the theory for the surface viscoelasticity of polymer solutions.

Small molecules are biologically active organic compounds with molecular weight below 1 kDa. Their small size enables efficient transport across cell membranes and modulation of intracellular signaling, making them promising for drug development. Chelidonic acid (ChA) is a small molecule (184 Da) with a wide range of biological effects, but its transport mechanisms and molecular targets remain unknown. The aim of this study is to identify a possibility of ChA uptake by human cells and to search for transporter proteins that may be involved in the intracellular trafficking of ChA using a combination of in silico and in vitro approaches. Co-culturing of human MCF-7 cells with ChA was conducted in vitro for 4 h and residual (not absorbed by cells) ChA concentration in solution was measured using HPLC. Candidate transporters were screened from databases. Molecular docking was performed with Autodock Vina, and molecular dynamics simulations were run for 50 ns using GROMACS to assess protein–ligand interactions. Statistical analysis used the R language with Newey–West estimator and Welch’s t-test. HOLE and VMD were used for 3D-reconstruction and visualization of transport channels. MCF-7 cancer cells uptake ChA through one or several of the common cell transport proteins. Initial screening identified six transmembrane proteins, with further analysis pinpointing three candidates (GLUT3, SVCT1, URAT1) demonstrating structural and functional compatibility for ChA transport. The study contributes to the understanding of the pharmacokinetics and pharmacodynamics of ChA and provides the basis for the rational design of pharmaceutical substances based on it.

The use of radiopharmaceuticals for diagnostics in oncology allows for the detection of the disease at an early stage. Among diagnostic radionuclides, 99mTc is a promising isotope that has been used to create several drugs for clinical use. One of the most effective 99mTc chelators is 6-hydrazinylnicotinic acid (HYNIC), which, when combined with various vector molecules, can be used for targeted delivery of radionuclides to tumor tissues. At the same time, it is known that tetrapyrrole macrocycles are capable of selective accumulation in tumors, and thus can be used to target radiopharmaceuticals with 99mTc. In this work, the conjugate of natural chlorin and HYNIC was obtained, and preliminary preclinical studies were carried out on its radiocomplex with 99mTc.

Background: Radiosensitivity of tumour cells is a serious problem in the treatment of oncological diseases, which, along with the dama- ging effect of irradiation on healthy tissues, significantly limit the possibilities of radiation therapy; therefore, an important task of modern oncopharmacology is the search and study of new radiosensitizing compounds. The main objective of this study was to investigate the radiosensitising effect of lithium ascorbate in vitro and in vivo under neutron radiation exposure. Material and methods: Evaluation of biological effect in vitro was performed on cell culture of tumour line HCT-116 (human colorectal cancer). To develop a model of tumour growth in vivo, SPF-nude immunodeficient mice (line Nu/j) were used. In vivo xenografts were formed by subcutaneous injection of cell suspension of HCT-116 cell line at a concentration of 2 million cells per 100 µl. The drug was administered to animals before irradiation by intraperitoneal injection in physiological solution at the rate of 2.4 mM/kg of animal weight. Neutron irradiation of cells was performed on cyclotron P-7M, by neutron flux with average energy of 7.5 MeV in the range of absorbed doses of 0.5‒1.5 Gy. Local irradiation of mice tumours was performed once at a dose of 1.5 Gy on a cyclotron with the same flux parameters. Cell viability was assessed by MTT test. Tumour growth parameters were assessed by measuring the sizes of xenografts and calculating the average volume, tumour doubling time and animal life span. Results: Enhancement of cytotoxic effect with combined application of radiation exposure and lithium ascorbate in vitro and in vivo was shown. A dose-dependent decrease in cancer cell viability was found when lithium ascorbate was used at a concentration of 0.1‒0.3 mM in combination with neutron irradiation. It was shown that the average tumour volume decreased by more than 50 % in comparison with the control, the xenografts growth rate slowed down to 72 %, and the median life expectancy of experimental animals increased by 86 % when lithium ascorbate and neutron irradiation were combined. Mechanisms of radiosensitising effect by induction of oxidative stress were proposed. Conclusion: The use of lithium ascorbate results in a more pronounced therapeutic effect of neutron radiation exposure in cellular and animal models of tumour growth.

Substances of silver nanoparticles dialyzed through a 13 kDa membrane, synthesized in a medium of humic ligands modified with hydroquinone and 2-hydroxynaphthoquinone from PowHumus brown coal, specifically enhance the M2 properties of peritoneal macrophages due to inhibition of NO synthase and significant activation of arginase, thus enhancing anti-inflammatory properties of cells. In small, but effective concentrations, they do not have cytotoxic properties and do not contain pyrogenic impurities. The studied humates are able to influence the mechanisms of immune response formation and are an effective means for correcting inflammation and regeneration.

Over the past two decades, targeted therapy has actively developed and, demonstrating impressive clinical results, has gained an increasingly important role in the treatment of cancer. This was facilitated to a large extent by an in-depth understanding of the mechanisms of cancer development, and mainly, the discovery of molecular targets. Despite the fact that targeted therapy can radically change the results of treatment and the prognosis of the disease course in some cancer cases, its effectiveness is sometimes replaced by drug resistance, in others. The authors of the lecture analyzed and systematized therapeutic approaches to addressing a number of important molecular targets that are key for implementing a specific stage in human tumor pathogenesis. These include maintaining chronic proliferative signaling, promoting evasion of cell growth suppressors, inducing angiogenesis, forming immune surveillance, and activating invasion and metastasis. The lecture presented targeted therapy drugs used in the Russian Federation, including antibody-based drugs and small molecule tyrosine kinase inhibitors. It also analyzed mechanisms of molecular interaction between these drugs and their targets, as well as possible factors for developing resistance and ways to overcome these resistance mechanisms.

Проведено сравнительное изучение состава фенольных соединений в растительном сырье копеечника альпийского (Hedysarum alpinum L.), интродуцированного на экосистемной дендрологической территории Сибирского ботанического сада ТГУ, и его каллусной культуры с использованием методов ВЭЖХ-УФ и ВЭЖХ-МС. Установлено, что в полученной на питательной МС-среде с добавлением 1.0 мг/л 2,4-Д и 0.1 мг/л 6-БАП и последующим культивированием на среде с α-НУК (2.0 мг/л) + 6-БАП (0.5 мг/л) каллусной культуре копеечника происходит активация фенилпропаноидного пути с образованием флавоноидов, изофлавонов, ксантонов и др. В результате сравнительного анализа установлено, что в извлечениях каллусной культуры содержание суммы флавоноидов (в пересчете на кверцетин) и формононетина ниже на 35 и 11% соответственно, а содержание мангиферина превышает более чем на 50% в сравнении с извлечением из интродуцированного растения.

Introduction. Cellular systems for targeted delivery of drug and biological molecules (drug delivery systems, DDSs) are currently considered as a promising solution to the problems of nano- and micro-sized drug carriers.Text. The review briefly examines fundamental and applied issues in the development of cellular DDSs, the morphofunctional diversity of which theoretically makes it possible to solve the problems of pharmacotherapy of various diseases. Sources are presented summarizing clinical protocols for the use of cellular DDSs, which are, however, limited to antitumor and anti-inflammatory therapy. The advantages, as well as particular and general disadvantages of using certain cells (blood cells, immunocytes, stem cells) as promising platforms for translation into clinical practice of delivery vehicles for various drugs (antibiotics, cytostatics, monoclonal antibodies, enzymes, etc.) loaded into nano- and micro-sized DDSs.Conclusion. Despite the obvious and impressive successes of fundamental and applied research in this area, a difficult path lies ahead in optimizing the processes of targeted delivery and controlled release of drug and biological molecules using cellular DDSs.

Introduction. Representatives of the Ericaceae family are quite common in Russia and are promising for the creation of new medicines of plant origin. At the same time, only 4 of them are official. The study of biologically active substances and pharmacological activity of Andromeda polifolia L., Chamaеdaphne calyculata (L.) Moench, Ledum palustre L., Empetrum nigrum L. with rich resource reserves is promising.Aim. Comparative study of the composition of total flavonoid fractions from A. polifolia, C. calyculata, L. palustre, E. nigrum and study of their effect on the NO-stimulating activity of peritoneal macrophagesMaterials and methods. The crushed aboveground part (leafy shoots) was previously depigmented with chloroform, treated with 70 % aqueous acetone, then acetone was removed. Flavonoids were extracted with ethyl acetate from the aqueous phase. The identification of flavonoids was carried out by HPLC (UltiMate 3000 chromatograph) according to the coincidence of retention times and spectral characteristics, the calculation of the content was carried out by simple normalization. The effect of the samples on nitric oxide production was studied on macrophages of C57BL/6 mice. Endotoxin control in the samples was carried out using a LAL test and cell incubation in the presence of polymyxin B.Results and discussion. The composition of flavonoid fractions from A. polifolia, C. calyculata, L. palustre and E. nigrum has been studied. 8 phenolic compounds were found in C. calyculata shoots, including isoquercitrin, herbacetin, naringenin and naringin – for the first time for this species. 5 compounds were detected in A. polifolia shoots, including isoquercitrin and herbacetin, for the first time for this species. 5 and 4 compounds were identified in L. palustre and E. nigrum shoots, respectively, while quercetin glycosides are predominant in all samples: isoquercitrin, hyperoside and rutin. The fraction of C. calyculata flavonoids at doses of 1, 5, 10 mcg/ml inhibits the production of nitric oxide by macrophages by 30 %, and E. nigrum flavonoids at doses of 100 and 200 mcg/ml, on the contrary, enhance the production of nitrites by macrophages by 33 and 37 %, respectively.Conclusion. A comparative study of the composition of total flavonoid fractions from A. polifolia, C. calyculata, L. palustre, and E. nigrum, which are capable of activating both M1 and M2 polarization of peritoneal macrophages in mice, has been conducted, which requires further in-depth study. The flavonoids C. calyculata and E. nigrum are promising for further study.

The aim of this work was to study the immunomodulatory effects of lithium salt gamma-lactone of 2,3-dehydro-Lgulonic acid (LiAc) on healthy blood leukocytes and leukemia cells in vitro . Materials and methods. Peripheral blood lymphocytes and neutrophils obtained from healthy donors, as well as THP-1 cells (human monocytic leukemia) were used as test systems. To assess the proliferative activity, lymphocyte blast transformation was used. The antiproliferative effect was studied by the 3H-thymidine incorporation assay. Cytotoxic effects were studied using the Alamar Blue test. The effect on the phagocytic activity was studied using the method for assessing the neutrophil function during bacterial phagocytosis. Results. LiAc exerted a dose-dependent effect on target cells, including antiproliferative and cytotoxic effects on leukemia cells and a stimulating effect on neutrophils in phagocytosis. Conclusion. LiAc can be considered as a promising drug with immunomodulatory effects, including a suppressive effect on the proliferative activity of leukemia cells and a stimulating effect on immune mechanisms mediated by neutrophils and macrophages.

Aim. To study the effect of compositions with nanosilver and humic substances on restoration of sensitivity of methicillin-resistant Staphylococcus aureus to lincomycin. Materials and methods. Compositions of humic substances with silver nanoparticles were synthesized from commercial sodium humate Powhumus and silver nitrate in the presence of NaOH (1 M) to modulate alkaline pH. To synthesize one of the two compositions, sodium humate was modified with hydroquinone. To describe the characteristics of the resulting compositions, surface plasmon resonance spectra of silver nanoparticles and their images obtained by transmission electron microscopy were recorded. Sensitivity of a clinical strain of methicillinresistant Staphylococcus aureus was determined by measuring the minimum inhibitory concentration (MIC) with the addition of lincomycin and tetracycline to the compositions. Results. 100% conversion of ionic silver into metallic silver with a characteristic nanoparticle size of 6 nm was shown. The effects of tetracycline and lincomycin on the studied strain of Staphylococcus aureus were compared, and high sensitivity to tetracycline (MIC < 10 μg / ml) and resistance to lincomycin (MIC > 200 μg / ml) were shown. Studying the effect of the composition containing sodium humates with nanosilver with the introduction of lincomycin into it showed that this approach can significantly reduce MIC of lincomycin to 0.1 μg/ml in the presence of compositions with hydroquinone-modified sodium humate at a concentration of 40 μg / ml and compositions with unmodified sodium humate at a concentration of 60 μg / ml. Conclusion. The study demonstrated that the use of compositions with humic substances and nanosilver completely restores sensitivity of methicillin-resistant Staphylococcus aureus to lincomycin.

Introduction. The widespread use of heparin preparations for the treatment and prevention of venous thromboembolic complications is known. One of the low molecular weight heparin drugs successfully used in clinical practice is calcium nadroparin. The modern approach to assessing the quality of medicines involves the use of standards, in comparison with which the quality control of the drug is carried out – standard samples (SS). The most important specific parameter in assessing the authenticity of low molecular weight heparins is the characteristic of the fractional composition.Aim. The aim of the work was to develop, attestation and determine the stability during the shelf life of a secondary standard sample to determine the authenticity of calcium nadroparin as part of improving the quality control system of the enterprise with the prospect of creating a domestic pharmacopoeia standard sample.Materials and methods. The object of development and attestation was the standard sample of the enterprise – low molecular weight heparin, obtained on the basis of the Technology implementation center of Siberian state medical university. The certified standard sample was obtained by purification of calcium nadroparin by solid-phase extraction. The completeness of the purification was confirmed by comparing the chromatograms of the purified samples with the chromatograms of the international standard sample. The characteristics of the molecular weight distribution were determined chromatographically. The stability of the certified SSE (the standard sample of the enterprise) was studied under two storage conditions – at a temperature below 8 °C in a dry state for 16 months and in solution at –40 °C for 6 months by evaluating trends in molecular weight distribution.Results and discussion. For each batch of the certified standard sample, the molecular weight and molecular weight characteristics are calculated in 2 parallel definitions, and a representative chromatogram is presented. The values of the relative standard deviation of the molecular weight of the samples and the content of the controlled fractions did not exceed 2.5 %. A detailed analysis of the molecular weight distribution showed the "classical" dependence of RSD (relative standard deviation) from the average value with a significant increase up to 30 % for small fraction values (less than 0.5 %). It was found that during 16 months at a storage temperature below 8 ºC, the molecular weight and molecular weight characteristics of standard samples of low molecular weight heparin did not significantly change. However, in the SSE solution at a storage temperature of minus 40 °C for 6 months, they degraded by more than 10 %.Conclusion. According to the results of the study, a protocol has been developed for obtaining a standard sample of low-molecular-weight heparin for the standardization of the calcium nadroparin substance according to the indicator "molecular weight distribution". The established shelf life of the sample is at least 16 months at temperatures below 8 °C. The stability of solutions of the standard sample at a storage temperature of –40 °C for 3 months is shown.