[Primary Generalized Glucocorticoid Resistance: a case report].

Primary glucocorticoid resistance (OMIM 615962) is a rare endocrinologic condition caused by resistance of the human glucocorticoid receptor (hGR) to glucocorticoids (GR) and characterised by general or partial insensitivity of target organs to GK. Compensatory activation of hypothalamic-pituitary-andrenal axis results in development of a various pathological conditions caused by overstimulation of adrenal glands. Clinical spectrum may range from asymptomatic cases to severe cases of mineralocorticoid and/or androgen excess. At present time, primary generalized glucocorticoid resistance has been exclusively associated with defects in the NR3C1 gene. Here, we present a case report of an adolescent patient with clinical presentation of glucocorticoid resistance confirmed by detailed endocrinologic evaluation but no confirmed mutations in the NR3C1 gene.

[Personalized patient-oriented approach to the treatment of musculoskeletal pain syndrome using over-the-counter medications. Resolution of the Expert Council (May 28, 2023)]. / Personalizirovannyi patsientoorientirovannyi podkhod k lecheniyu skeletno-myshechnogo bolevogo sindroma s ispol'zovaniem bezretsepturnykh preparatov. Rezolyutsiya ekspertnogo soveta (28 maya 2023 g.).

Diseases of the musculoskeletal system in Russia affect 19.2 million people. Untimely diagnosis and inadequate therapy of pain syndrome negatively affect the daily functioning and quality of life of patients, and create significant socioeconomic problems. The most common variants of musculoskeletal pain (MSP) are osteoarthritis (OA) and low back pain (LBP). OA is seen in 57.6% of individuals over 65 years of age. It should be noted that chronic pain syndrome, rather than anatomical and degenerative changes detected by imaging studies, determines to a greater extent the quality of life of patients with OA and prognosis during the course of the disease. The global burden of disability associated with LBPD increased in all age groups between 1990 and 2019 and was highest in the 50-54 age group.

[Glucosaminylmuramyl dipeptide in treatment of respiratory tract diseases]. / Gliukozaminilmuramildipeptid v terapii infektsionnykh zabolevanii respiratornogo trakta.

INTRODUCTION: Immunomodulators are used as part of a comprehensive therapy of respiratory tract diseases. The systematization of the accumulated data on the use of glucosaminylmuramyldipeptide (GMDP) has great scientific and practical interest. PURPOSE: To study the data on the effectiveness and safety of GMDP in the treatment of infectious diseases of the respiratory tract. MATERIAL AND METHODS: Literature search was carried out in Scientific Electronic Library (elibrary.ru), Google Scholar, ScienceDirect, Cochrane library, Pubmed/MEDLINE and search engines. The level of evidence reliability and methodological quality of researches were assessed. RESULTS: 17 full-text publications were selected based on the results of 13 prospective clinical trials with acceptable methodological quality (including one blind placebo-controlled trial). The effectiveness of GMDP in acute respiratory viral infections, influenza, recurrent respiratory tract infections, rhinosinusitis and chronic tonsillitis was demonstrated. DISCUSSION: An important advantage is that a significant part of the studies was performed with the participation of the child population. Since the use of GMDP in multiple therapy significantly reduces antibiotic consumption (often unjustified). It seems reasonable to estimate the pharmacoeconomic costs of managing adult patients with respiratory tract diseases. Further research can improve understanding of the role of GMDP in the treatment of various medical conditions. CONCLUSION: The use of GMDP in the treatment of respiratory tract diseases makes it possible to faster achieve a clinical effect, reduce the number of relapses, lengthen the relapse-free period, as well as to potentiate the effect of antibacterial therapy (if necessary), reducing the need for antibiotics.

Studying of the Mechanisms of Combined Effect of Dexamethasone, Doxorubicin, and Docetaxel on Breast Cancer Cells.

The sensitivity of MDA-MB231 breast cancer cells to the effects of pharmacological agents was evaluated by their motility and viability. Dexamethasone, doxorubicin, or docetaxel administered separately in their effective concentration suppressed cell motility (in 16 h) and caused cell death (in 48 h). The strength of the effects increased in the following order: dexa methasone

Combined Action of PGRPs-Hsp70 Cytotoxic Complex with Paclitaxel Improves Outcomes of Melanoma Treatment in Mice.

We studied the effect of PGRPs-Hsp70 cytotoxic complex that is analogous to natural complex secreted by cytotoxic lymphocytes and the antitumor drug paclitaxel on the development of M3 melanoma in DBA mice. Significant inhibition of tumor growth was observed in all experimental groups by days 20 and 35 of observation; paclitaxel monotherapy was less effective than administration of PGRPs-Hsp70 cytotoxic complex and its combination with paclitaxel. Pairwise comparison of Kaplan-Meier curves showed that survival was maximum in the group receiving combined therapy with PGRPs-Hsp70 cytotoxic complex and paclitaxel in comparison with groups receiving monotherapy.

The role of S100A4 protein in anticancer cytotoxicity: its presence is required on the surface of CD4+CD25+PGRPs+S100A4+ lymphocyte and undesirable on the surface of target cells.

S100A4 is a Ca2+-binding protein that performs an important role in metastasis. It is also known for its antitumor functions. S100A4 is expressed by a specialized subset of CD4+CD25+ lymphocytes and is present on those cell's membranes along with peptidoglycan recognition proteins (PGRPs). There, by interacting with major heat shock protein Hsp70, S100A4 plays an important cytotoxic role. The resulting stably formed complex of PGRPs, S100A4 and Hsp70 is required for the identification and binding between a lymphocyte and a target cell. Here, we investigated the S100A4 functions in CD4+CD25+PGRPs+S100A4+ lymphocyte cytotoxicity against target cells. We demonstrated that those lymphocytes do not form a stable complex with the tumor target cells that themselves have S1004A on their surface. That observation can be explained by our finding that S100A4 precludes the formation of a stable complex between PGRPs, S100A4 (on the lymphocytes' surface), and Hsp70 (on the target cells' surface). The decrease in S100A4 level in CD4+CD25+PGRPs+S100A4+ lymphocytes inhibits their cytotoxic activity, while the addition of S100A4 in the medium restores it. Thus, the resistance of target cells to CD4+CD25+PGRPs+ S100A4+ lymphocyte cytotoxicity depends on their S100A4 expression level and can be countered by S100A4 antibodies.

[Pleiotropic effects of phlebotropic drugs: from pharmacological advantages to adverse drug interaction]. / Pleiotropnye éffekty flebotropnykh preparatov: ot farmakologicheskikh preimushchestv do nezhelatel'nogo lekarstvennogo vzaimodeistviia.

A distinctive property of phlebotropic drugs consists in their intrinsic capability of exerting pronounced pleiotropic (multiple) effects. The authors discuss the fundamental mechanisms of pleiotropy, advantages and disadvantages of various types of targeted therapy (mono- and polytargeted therapy) in treatment of chronic venous diseases. Special attention is paid to analysing the nature of adverse drug interactions, methods of reducing the risk of their development. An electronic service known as the Drug Interactions Checker is proposed as a tool for assessing drug interactions in everyday practice of the angiologist/phlebologist.

[Systemic phlebotrophic agents: from active substance to clinical effect].

The article deals with the modern classification of phlebotrophic agents, followed by generalization and analysis of their mechanisms of action, peculiarities of their entering the systemic circulation, as well as a detailed description of phlebotrophic properties and clinical application of the water-soluble fraction of flavonoids.

The use of nanosized cortisol-polymer complex for analysis of mechanisms of regulation of functional activity of skin fibroblast.

Cortisol in concentrations within the therapeutic range inhibits calcium response of fibroblast to angiotensin II. In physiological concentrations, cortisol potentiates the effects of angiotensin II via modulation of membrane mineralocorticoid receptors. The inhibitory effects of glucocorticoids on cell proliferation and collagen synthesis are manifestations of its genomic effects mediated by intracellular receptors. The use of glucocorticoid preparation based on nanosized polymer structure made it possible to distinguish between the genomic and nongenomic mechanisms of regulation of activity of target-cells.

[Interaction of omnic (tamsulozine) and its generic analogues with alpha-adrenoreceptors].

In current practice of pharmacotherapy of prostatic adenoma alpha1-adrenoblockers are first-line drugs the efficacy and safety of which have been proved in many randomized studies. Because of the appearance of a large amount of generic analogues of tamsulozine on the market we studied the ability of tamsulozine analogues to bind with alpha-adrenoreceptors on rat and human prostate affected by adenoma. Significant differences on the receptor level of interaction were found. Omnik, compared to other generic analogues of tamsulozine, has the highest affinity to alpha1-adrenoreceptors.

Interactions and possible functional characteristics of Tag7-S100A4 protein complex.

Peptidoglycane-recognizing protein Tag7 formed a complex with S100A4 (a representative of S100 protein family), the apparent dissociation constants in the absence and presence of Ca2+ were 2 x l0(-8) M and 10(-9) M, respectively. Analysis of fluorescence spectra of hydrophobic fluorescent probe 2-toluidinyl naphthalene-6-sulfonate in the presence of S100A4 and Tag7 proteins showed that extensive area or several sites are involved into the complex formation between these proteins. The formation of Tag7-S100A4 complex had virtually no effect on the role of S100A4 in the regulation of intracellular Ca2+ metabolism. Removal of not only Tag7, but also S100A4 from neutrophil conditioned medium reduced lysis of E. coli cell, while addition of the Tag7-S100A4 complex to the medium restored antibacterial activity.

Comparative analysis of secretion of S100A4 metastatic marker by immune and tumor cells.

S100A4 protein is present in low concentrations (2.1-15.7 ng/10(6) cells) in lymphocyte and neutrophil culture medium. Addition of stimulants to the cells did not lead to an appreciable increase in the content of this protein. The initial content of S100A4 is significantly higher (92-447 ng/10(6) cells) in culture media of highly metastatic KSML-100 adenocarcinoma and M3 and B16 melanoma cells. The release of S100A4 by these cells significantly increased after addition of lymphocytes and Tag7/Hsp70 cytotoxic complex. Repeated injection of antibodies to S100A4 to mice with transplanted M3 melanoma inhibited tumor growth.

Molecular mechanisms of vasoconstrictor action of imidazo[1,2-alpha]benzimidazole derivative RU-1117 possessing local anesthetic properties.

We studied the mechanisms of action of imidazobenzimidazole derivative RU-1117 on calcium homeostasis in myocytes isolated from rat thoracic aorta. In therapeutic concentrations, RU-1117 increased the content of free calcium ions due to their mobilization from intracellular depot via the IP3-dependent mechanisms. Antagonists of angiotensin II AT1-receptors irbesartan and, to greater extent, eprosartan abolished the calcium-mobilizing action of RU-1117. Selective antagonist of endothelin ETA-receptors sitaxsentan and alpha1-adrenoceptor agonist prazosin produced no effect on calcium mobilization caused by novel local anesthetic RU-1117.

Nongenomic effect of androgens on Ca(2+) concentration in human lymphocytes.

Testosterone and its high-molecular-weight form (testosterone covalently immobilized on bovine serum albumin) induced a rise of intracellular calcium concentration. The effectiveness of dihydrotestosterone was much lower compared to that of testosterone. Gestagens drospirenone and, to a lesser extent, 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one prevented the testosterone-induced Ca(2+) entry into cells. Antagonist of intracellular androgen receptors cyproterone acetate had no effect on testosterone-induced variations in calcium concentration. Human lymphocytes can be used as an experimental test system for screening and evaluation of the molecular mechanisms of nongenomic membranotropic effect of androgens and new compounds with antiandrogen activity.

Conformation and kinetic characteristics of interactions between local anesthetics and aqueous solutions of hydroxypropylmethylcellulose.

Conformation and kinetic characteristics of the interactions of local anesthetics lidocaine (xycaine), tetracaine (dicaine), bupivacaine, and new RU-1117 compound with proven anesthetic activity with Visiton (1% hydroxypropylmethylcellulose in phosphate buffer) were studied. It was found that complex formation between the local anesthetics and hydroxypropylmethylcellulose is a time-dependent reversible process. The equilibrium is attained within 2.5-8.0 h and depends on the chemical nature of local anesthetic.

Effect of nitroglycerine on content of second messengers in myocytes of rat thoracic aorta.

We evaluated the concentration dependence and time dependence of the effect of nitroglycerine on intracellular content of cAMP, cGMP, and free Ca2+. It was shown that after norepinephrine stimulation, nitroglycerine exhibited calcium-blocking activity in lower concentrations (starting from 10(-7) M). Under conditions of experimental nitrate tolerance the dose-dependent effect of nitroglycerine on intracellular cGMP and Ca2+ was less pronounced. Calcium-blocking activity of nitroglycerine decreased most significantly upon stimulation of myocytes with norepinephrine.

[Genomic and extragenomic mechanisms of antiglucocorticoid action of gestagens on thymocytes].

Effects of a new synthetic progesterone derivative 17a-acetoxy-3b-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (ABMP) and the reference gestagen preparations on the rat thymus were evaluated by the degree of variation of the intracellular levels of calcium and cAMP, 3H-uridine inclusion into RNA, thymocyte viability, and thymus mass. It is shown that gestagens can produce antiglucocorticoid action on thymocytes, this activity being most pronounced in the case of ABMP.

Kinetics of interaction of local anesthetics with human serum albumin.

We studied kinetic parameters of interaction of local anesthetics (lidocaine, tetracaine, bupivacaine, and two novel agents with proved local anesthetic potency RU-353 and RU-1117) with human serum albumin. Complexation of local anesthetics with human serum albumin is a time-dependent and reversible process; equilibrium was attained within 1.5-4.5 h depending on chemical nature of local anesthetics.

Effect of prednisolone on secondary messenger metabolism in the lymphocytes from patients with acantholysis bullosa.

Prednisolone in therapeutic concentrations blocks Ca(2+) channels of lymphocyte plasma membranes and prevents arachidonic acid-induced Ca(2+) entry into the cells. Glucocorticoid virtually did not modulate arachidonic acid-stimulated release of Ca(2+) from intracellular stores. No appreciable effect of the hormone on mitogen-induced changes in the intracellular content of cAMP was detected.