Репозиторий Университета

Thanks to their biocompatibility, biodegradability, injectability and self-setting properties, calcium phosphate cements (CPCs) have been the most economical and effective biomaterials of choice for use as bone void fillers. They have also been extensively used as drug delivery carriers owing to their ability to provide for a steady release of various organic molecules aiding the regeneration of defective bone, including primarily antibiotics and growth factors. This review provides a systematic compilation of studies that reported on the controlled release of drugs from CPCs in the last 25 years. The chemical, compositional and microstructural characteristics of these systems through which the control of the release rates and mechanisms could be achieved have been discussed. In doing so, the effects of (i) the chemistry of the matrix, (ii) porosity, (iii) additives, (iv) drug types, (v) drug concentrations, (vi) drug loading methods and (vii) release media have been distinguished and discussed individually. Kinetic specificities of in vivo release of drugs from CPCs have been reviewed, too. Understanding the kinetic and mechanistic correlations between the CPC properties and the drug release is a prerequisite for the design of bone void fillers with drug release profiles precisely tailored to the application area and the clinical picture. The goal of this review has been to shed light on these fundamental correlations.

Thanks to their biocompatibility, biodegradability, injectability and self-setting properties, calcium phosphate cements (CPCs) have been the most economical and effective biomaterials of choice for use as bone void fillers. They have also been extensively used as drug delivery carriers owing to their ability to provide for a steady release of various organic molecules aiding the regeneration of defective bone, including primarily antibiotics and growth factors. This review provides a systematic compilation of studies that reported on the controlled release of drugs from CPCs in the last 25 years. The chemical, compositional and microstructural characteristics of these systems through which the control of the release rates and mechanisms could be achieved have been discussed. In doing so, the effects of (i) the chemistry of the matrix, (ii) porosity, (iii) additives, (iv) drug types, (v) drug concentrations, (vi) drug loading methods and (vii) release media have been distinguished and discussed individually. Kinetic specificities of in vivo release of drugs from CPCs have been reviewed, too. Understanding the kinetic and mechanistic correlations between the CPC properties and the drug release is a prerequisite for the design of bone void fillers with drug release profiles precisely tailored to the application area and the clinical picture. The goal of this review has been to shed light on these fundamental correlations.

© 2018, Pediatria Ltd. All rights reserved. Clinical guidelines for the selection and use of antibiotics (AB) for common and most important community-acquired infections are aimed at increasing the treatment efficacy and overcoming growth of bacterial pathogens resistance to AB. They are based on the principle of positive ratio of «benefit/risk» of AB and selection of primary and alternative drugs. The article presents Russian and foreign data on pediatricians preferences in the choice of AB for ARI in children, on the level of Streptococcus pneumoniae resistance to penicillins and macrolides and other respiratory bacterial pathogens to macrolides in Russia (including the pediatric population) and abroad, which led to similar changes in grouping of AB in the Eurasian clinical recommendations and WHO recommendations. It demonstrates a significant coincidence of the AB choice for community-acquired pneumonia and acute bacterial rhinosinusitis in children in comparable recommendations with the recognition of amoxicillin as the first choice drug and the general tendency to restrict the use of macrolides. It also points on the need to control the AB use.

© 2018 Publishing House of the Union of Pediatricians. All rights reserved. The rational use of antibacterial drugs in children implies an adequate choice of the necessary medication, its dosing regimen, and the duration of treatment in order to achieve maximum efficacy and minimize toxic effects. The knowledge of pharmacokinetic and pharmacodynamic profiles of the antibacterial drug plays a crucial role for optimizing the dosing regimen. The strategy of individual choice of the dosing regimen, taking into account the principles of pharmacokinetics and pharmacodynamics, can be especially effective in patients with the expectedly changed parameters of pharmacokinetics and in infections caused by bacteria strains with low sensitivity to antibiotics. The review presents a contemporary view of pharmacokinetic and pharmacodynamic profiles of antibacterial drugs most commonly used in pediatrics and their relationship to the clinical efficacy of the administered therapy.

© Group of authors, 2018. Description of the first case of aplastic anemia caused by cefotaxime, a third-generation cephalosporin, with lethal outcome is presented. Clinical record of a patient and post-mortem examination results are given. Possible mechanisms of cytopenias induced by cephalosporin antibiotics are discussed.

© 2018 Media Sphera Publishing Group. All rights reserved. The review analyzes the main etiological and pathogenetic mechanisms of the development of NSAID-enteropathy. Particular attention is paid to the role of intestinal microbiota in the manifestation and progression of NSAID-enteropathy. The special role of probiotics in the prevention and treatment of NSAIDs enteropathy is considered.

© ISUCT Publishing. Macrolide antibiotics represent a valuable class of broad-spectrum, high active natural compounds with polyketide structure. A well-known FOF1 ATP-synthase inhibitor,[1] namely oligomycin A (1), is a 26-membered α,β-unsaturatedpolyketide lactone with conjugated diene, fused to spiroketal moiety. Oligomycin A possesses strong antifungal, antiactinomycotic and cytotoxic activity, but lacks antibacterial activity. According to recent investigations, the development of anti-cancer drugs based on oligomycin A is quite perspective due to its high cytotoxic activity toward tumor cells, ability to inhibit a multidrug resistance protein p-gp and to prevent an activation of oncogenic K-Ras by inhibition of its localization at the plasma membrane.[2-4] However, high toxicity for mammalian cells and low water solubility are significant limitations of oligomycin A, making it unacceptable for clinical application. Chemical modification is a promising way to improve pharmacological properties of natural compounds. Recently we have found that site-selective modifications of oligomycin A afforded semi-synthetic derivatives with high antiproliferative activity against tumor cell lines[5-7] or selective antifungal activity against Candida spp.[8] and, at the same time, with lower toxicity toward mammalian cells. Also, semi-synthetic oligomycin A derivatives are useful tools for molecular genetic studies of additional targets for this family of antibiotics.[9,10] Previously Ramirez F. et al. have described the reaction of oligomycins with sodium borohydride resulting in mixture of diastereomeric 7-dihydro-and 7,11-tetrahydro derivatives without further separation and characterization of individual products.[11] Also, there is no data on biological activity of these reduced oligomycins against fungal/actinomycetes strains and tumor cell lines in article mentioned above. Thus, in this paper we report regio-and stereoselective methods for borohydride reduction of oligomycin A, structure determination of obtained derivatives and investigation of theirs antiproliferative, antifungal and antiactinomycotic properties. The feasibility of regio-and stereoselective reduction of C7-carbonyl group in a core structure of oligomycin A was proposed due to the presence of haptophilic hydroxyl groups[12] at C5 and C9 positions and sterical hindrance of C-11 carbonyl group. Actually, treatment of oligomycin A with bulky sodium triacetoxyborohydride in acetic acid according to the method[13] led to (7S)-dihydrooligomycin A (2) in a good yield. The second carbonyl group (C-11) reduced in more harsh conditions: only the extended treatment of (7S)-dihydrooligomycin A with sodium borohydride in ethanol give (7S,11R)-7,11-tetrahydrooligomycin A (3) as major product. Reaction proceeds with acceptable stere-oselectivity and gives tetrahydro derivative 3, but in low yield (35 %), which associated with low stability of oligomycins in basic conditions.[14] Structure of compounds 2 and 3 was confirmed by high resolution mass spectrometry (HRMS ESI) and NMR spectroscopy. Absolute configurations at C7 and C11 positions of obtained derivatives were unambiguously confirmed by observed interactions between neighboring protons in corresponding1H-1H ROESY spectra. Testing of antimicrobial properties of oligomycins 2 and 3 against Candida spp., filamentous fungi and S. fradiae (strain, extremely sensitive to oligomycins) that of the parent antibiotic in comparison with starting oligomycin A revealed that reduction of carbonyl groups led to decreasing of activity (except strain M. canis). Also, reduced derivatives 2, 3 were less potent against human colon carcinoma cell line HCT116 and its doxorubicin-resistant subline HCT116(-/-), while activity against leukemia cell line K562 and doxorubicin-resistant subline K562/4 retained at the same level as for 1. It might be pointed that biological properties of (7S)-dihydrooligomycin A and (7S,11R)-7,11-tetrahydrooligomycin A are quite similar, consequently C7-carbonyl group has a greater influence on biological activity of oligomycin A than C-11 carbonyl group.

© 2018. A strain B-13176 that manifested the antibacterial and fungicidal activities has been isolated by screening of sporiferous bacteria and identified as Bacillus pumilus on the basis of the analysis of variable regions of 16S RNA sequences. Cultural and morphological characteristics of the strain were studied, the dynamics of the synthesis of fungicidal and antibacterial metabolites and their location in culture were determined, and their resistance to physicochemical factors was investigated. It was shown that the strain possesses a pronounced activity against the fungi of Aspergillus niger and the methycillinresistant bacteria of Staphylococcus aureus strain (MRSA). The culture liquid of the strain was fractioned using centrifugation, ultrafiltration, extraction and HPLC. Mass-spectrometry was used to show that the Bacillus pumilus B-13176 strain produces active thermostable protease-resistant metabolites of the peptide origin that are located in the CL pellet (the fungicidal component) and in the CL supernatant (the antibacterial component).

© 2018 Stavropol State Medical University. All rights reserved. The review presents data on the relationship of intestinal dysbiosis with irritable bowel syndrome (IBS) and the possibility of modulation of the intestinal microbiota (MB) in IBS therapy. It is shown that imbalance of MB caused by the influence of diet, antibiotics or other exogenous factors leads to gastrointestinal disorders, in particular, to the development of IBS. The data are presented that the modulation of MB with the help of prebiotics, antibiotics, probiotics and fecal microbiota transplantation has a positive therapeutic effect in patients with IBS.

© ISUCT Publishing. The macrolide antibiotic oligomycin A (1), produced by actinomycetes Streptomyces,[1] is a well-known inhibitor of FO F1 ATP-synthase, which is regarded as a molecular target for new drugs in the treatment of tumors and infections. Oligomycin A (1) exhibits antifungal and cytotoxic activities, but Gram-negative and Gram-positive bacteria are resistant to 1 except actinobacteria.[2] In micromolar concentrations, oligomycin binds to FO c-subunit, blocks proton translocation and disrupts bioenergetic metabolism.[3] However, a clinical application of oligomycin A is limited by high cytotoxicity for mammalian cells. The searches of new derivatives of oligomycin A with more selective pharmacological activity and low toxicity for normal cells are of great interest. New semi-synthetic oligomycins also would be valuable for SAR studies and depicting the mechanism of FO F1 ATP-synthase inhibition. The complicity of oligomycin structure and its lability in basic conditions[4] significantly impede modifications and an applicability of this antibiotic. However, previously we have managed this challenge and developed some modifications of the side chain and chemical transformations of the lactone moiety of 1.[4-9] In this paper, throughout our research we describe synthesis and biological investigation of novel oligomycin A derivatives, namely 16,33-O,O-diformyl-16,17-dihydro-16(S),17(R)-dihydroxyoligomycin A (3) and 33-O-formyloligomycin A (4). First, we have studied Prilezhaev epoxidation of double bonds in core structure of oligomycin A. It was found that treatment 1 with m-CPBA at -17oC in dichloromethane led to 16,17-epoxyoligomycin (2). Unfortunately, all attempts for isolation of product 2 were failed due to its instability on silica gel, and, consequently, we were unable to determine the structure of 2 by direct physicochemical and spectral methods. The presence of epoxide at C16-C19 positions was confirmed by tandem mass spectrometry, but its exact localization was still elusive. We assumed that it might be at C16-C17 positions, because C18-C19 double bond is hindered by ethyl side chain at C20. In order to obtain a stable oligomycin A derivative we performed an epoxide ring-opening reaction by the treatment of the crude epoxyoligomycin 2 with formic acid. This acid-catalyzed opening of the epoxide accompanied with acylation of 33-OH group and led to16,33-O,O-diformyl-16,17-dihydro-16(S),17(R)-dihydroxyoligomycin A (3). The structure of 3 was confirmed by NMR spectroscopy and high resolution mass spectrometry. Configurations at C16 and C17 positions were determined by detecting correlations in1H-1H ROESY spectrum. Obtained results allowed to confirm an assumption about localization of the epoxide ring and establish the structure of 2 as (R,R)-16,17-epoxyoligomycin A, since inversion of configuration has taken place at the attacked carbon atom.[23] It is known that O-acyl derivatives of pharmacologically active agents are widely used as prodrugs.[24] Acylation of 2-hydroxypropyl side chain in 2 prompts us to examine the reaction of oligomycin A (1) with formic acid. Thus, stirring the solution of 1 in HCOOH (98 %) for 2 h at room temperature afforded 33-O-formyloligomycin A (4) in a good yield. The structure of 4 was confirmed by NMR-spectroscopy and high resolution mass spectrometry. Also, biological data of new derivatives were evaluated. The modification of C16-C17 positions of the macrocycle as well as acylation of C33 hydroxyl group led to the decreasing of activity against S. fradiae, Candida spp. and filamentous fungi. Obtained results were in agreement with docking studies. A simulation of an interaction of 1, 3 and 4 with the FO subunit of the ATP-synthase (PDB: 4f4s) revealed that these modifications led to a significant change in the solvation energy and an increase in the conformational capacity of the ligands during the binding with the target. This resulted in decrease of the binding affinity for derivatives 2, 3. However, 33-O-formyloligomycin A (4) showed similar antiproliferative activity against tumor cell lines (HCT-116 colon carcinoma, К562 myeloid leukemia cell lines and MDR K562/4 subline) as for 1, but less cytotoxic for non-malignant human cells.