This article provides a review of Lanpressun®, a new formulations of latanoprost micellar nanoemulsion without benzaltonium chloride (BAK). The pharmacokinetics and pharmacodynamics of new formulations are presented. Due to innovative delivery system and absence of detergent preseravative (BAK, poliquaternium and others) Lanpressun® possess better tolerability and safety to ocular surface, that provides patients adherence to longer therapy. The article presents the results of clinical trials demonstrating high hypotensive efficacy of Lanpressun®. Literature analysis of studies on safety and effect on ocular surface shows good tolerability of preservative­free latanoprost nanoemulsion. The authors give the assessment of Lanpressun® future perspectives in treatment of patients with open­angle glaucoma

BACKGROUND: Autoimmune bullous dermatoses are known to be the most severe blistering conditions of skin. HLA-DRB1 and DQB1 alleles might play a crucial role in their onset. In pemphigus HLA class II molecules stimulate the division of T helper cells, which in turn stimulate B cells to produce antibodies to epidermal keratinocytes causing acantholysis. The HLA-DRB1 and DQB1 alleles’ frequencies studied in pemphigus in a vast variety of populations worldwide. However, as of yet, this mechanism was not investigated in Russian population. AIM: To estimate the prevalence of the HLA-DRB1 and DQB1 alleles at a low- and high-resolution levels in patients with various forms of pemphigus. We observed 86 patients with pemphigus vulgaris, 13 ― with pemphigus foliaceus, 6 patients with paraneoplastic pemphigus and 92 healthy volunteers. MATERIALS AND METHODS: HLA typing for DRB1 and DQB1 was performed with 50 nanogram DNA extraction and polymerase chain reaction. RESULTS: At a low-resolution level HLA-DRB1*4 and DRB1*14 alleles were statistically significant more frequent in pemphigus vulgaris and pemphigus foliaceus patients compared to those in control subjects, whereas HLA-DRB1*11, DRB*16, and DRB1*3 alleles were more frequent in healthy volunteers. At a high-resolution level, DRB1*04:02 allele was observed to show its statistically significant higher frequency in all variants of pemphigus, including paraneoplastic pemphigus. However, DRB1*14:05 HLA allele was more frequent in pemphigus vulgaris and pemphigus foliaceus patients, whereas DRB1*11:04 one was found to be 3.7 times more frequent in healthy controls. Additionally, at a low-resolution level for HLA-DQB1 alleles no statistically significant results were observed. However, at a high-resolution level the chances for more frequent indication of DQB1*03:02 allele were 7.09 times higher in pemphigus foliaceus group and 2.49 higher in pemphigus vulgaris patients compared to healthy volunteers. Moreover, DQB1*05:03 was identified more frequently in pemphigus vulgaris and paraneoplastic pemphigus groups of patients, whereas DQB1*03:01 allele was shown to be increased in the group of healthy donors. CONCLUSION: HLA-DRB1*4, DRB1*14, DRB1*04:02, DRB1*14:05, DQB1*03:02 and DQB1*05:03 alleles might be considered as the genetic markers for pemphigus vulgaris susceptibility, while HLA-DRB1*11, DRB*16, DRB1*3, DRB1*11:04 and DQB1*03:01 allelic groups appear to be protective for Russian population.

There are two main isoforms of glucocorticoid receptor (GR) alpha- and beta-isoforms. GR beta isoform is the dominant inhibitor of the GR alpha receptor and plays a significant role in a poor response to systemic glucocorticoids (GCs) under numerous conditions. The A3669G (rs6198) polymorphism (SNP) in the untranslated region of human GR stabilizes the mRNA of the dominant-negative GR beta isoform. However, the mechanisms which generate mRNA encoding the GR beta isoform have been poorly defined, especially in pemphigus patients who do not respond to GCs. The main aim was to study gene SNP of GR in patients with pemphigus vulgaris (PV) and healthy controls. We investigated whether the A3669G SNP of the human GR beta gene is a susceptibility allele for PV and contributes to GC resistance development. The presence of the A3669G SNP was determined by high-resolution melting analysis and then confirmed by direct sequencing. GR A3669G SNP (AG genotype) occurred more frequently in PV patients (n = 72; 25%) compared with healthy controls (n = 92; 3.2%; p<0.001). Allele G was significantly more presented in PV patients (p<0.001). Out of 48 patients with AA genotype of A3669G SNP, only 6 had GC resistance, whereas 11 out of 18 with AG genotype developed GC resistance (p<0.0001). The frequency of a poor response to GC in the group of patients with AG genotype was 4.89 times higher compared to AG negative one (p<0.0001). Our study showed that the A3669G SNP was more present in PV patients. Moreover, GC resistance appeared more frequently in patients with the AG genotype (p<0.0001). Since those patients predominantly with severe pemphigus had GC resistance (p=0.001), we feel that A3669G SNP (AG genotype) contributes to its development. However, more studies are needed to determine whether A3669G SNP of the human GR gene associated with the disease severity and poor response to GCs in these patients.

BACKGROUND: Bullous pemphigoid is known to be an autoimmune, life-threatening blistering skin disorder characterized by subepidermal blister formation. In bullous pemphigoid activation of B-cell immunity depends on the interaction between T-cell receptors and classic HLA II molecules. Similar interrelation has been revealed in a vast variety of studies on severe allergic reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. It was also suggested that Stevens-Johnson syndrome and toxic epidermal necrolysis might be associated both with HLA I and II classes. AIM: To assess the prevalence of HLA-DRB1 and DQB1 alleles at a low and high-resolution levels in patients with bullous pemphigoid and Stevens-Johnson syndrome / toxic epidermal necrolysis. MATERIALS AND METHODS: 29 Bullous pemphigoid, 14 Stevens-Johnson syndrome / toxic epidermal necrolysis patients and 92 health volunteers were included in the study. HLA-DRB1 and DQB1 alleles were assessed by polymerase chain reaction using specific primers. RESULTS: At a low-resolution level, HLA-DRB1*4 (p 0.02) and DRB1*14 (p 0.0015) alleles were statistically significantly revealed in bullous pemphigoid patients compared to health controls. Additionally, at the high-resolution level the predisposing to bullous pemphigoid HLA-DRB1*04:02 allele was also identified (p 0.01). At the low-resolution level of HLA-DQB1 typing we displayed protective and predisposing to bullous pemphigoid alleles HLA-DQB1*1 (p 0.01) and HLA-DQB1*2 (p 0.039) respectively. At the low-resolution level of HLA-DQB1 typing, the chances to obtain DQB1*03:02 allele were 3.71 times higher compared to healthy volunteers (p 0.01). In patients with Stevens-Johnson syndrome / toxic epidermal necrolysis, HLA-DRB1*4 allele was shown to be predisposing (p 0.03). For all other types of HLA alleles (DRB1 and DQB1) at the high-resolution level no any statistically significant results have been observed in these patients. CONCLUSION: We identified HLA-DRB1*4, DRB1*14, DRB1*04:02 alleles predisposing to the development of bullous pemphigoid, with the HLA-DQB1*1 allele being protective for the development of bullous pemphigoid and HLA-DRB1*4 allele predisposing to the development of severe drug reactions of Stevens-Johnson syndrome / toxic epidermal necrolysis. No any protective alleles in Stevens-Johnson syndrome / toxic epidermal necrolysis patients were detected.

BACKGROUND: Pemphigus vulgaris is known to be associated with genetics, immunological and hormonal factors which cause acantholysis resulting in intraepidermal blistering. Moreover, Human class II leukocyte antigen (HLA) alleles are known to be the best-established predisposing factor for its development. Class II HLA alleles vary among racial/ethnic backgrounds. AIM: we investigated an association between HLA class II DRB1 alleles and pemphigus vulgaris among the Russian population. MATERIALS AND METHODS: A total of 70 patients with confirmed diagnosis of pemphigus vulgaris were genotyped for HLA class II alleles. HLA class II frequencies were compared with healthy volunteers (n=92). The statistical significance of differences between patients and controls was evaluated using Fishers exact test. A single blood sample for HLA typing was obtained from all the subjects. The strength of association between HLA alleles and pemphigus vulgaris was estimated by odds ratio (OR) and 95% confidence intervals (CIs) p 0.01 was considered to be statistically significant. P-values were corrected for multiple comparisons according to the BenjaminiHochberg method. RESULTS: We observed that DRB1*4 and DRB1*14 allelic groups were associated with pemphigus vulgaris (41.4% vs 8.7%; OR 2.33 vs 0.34; p=0.000001 and 27.1% vs 6.5%; OR 1.98 vs 0.41; p=0.0004 respectively), while HLA-DRB1*11 and HLA-DRB*15 were negatively associated with pemphigus vulgaris (4.3% vs 21.7%; OR 0.33 vs 1.62; p=0.001 and 5.7% vs 19.6%; OR 0.44 vs 1.5 respectively). CONCLUSIONS: Our findings suggest, that HLA DRB1*4 and DRB1*14 alleles are genetic markers for pemphigus vulgaris susceptibility, whereas DRB1*11 and HLA-DRB*15 groups appear protective in Russian population.

The study's aim was to investigate the S100A4-mediated mechanisms of the regulation of tumor cell proliferation and migration in the human triple-positive breast carcinoma cell line MCF-7 (TPBC) and triple-negative breast carcinoma cell line MDA-MB-231 (TNBC). The proliferative activity of TNBC more than doubled during the incubation in the conditioned medium of TPBC. Extracellular S100A4 dose-dependently decreased the proliferative response of TPBC. TPBC negatively impacted the growth of TNBCs during their co-culturing. TPBC significantly decreased the migration activity of the TNBC cells while the S100A4 intracellular level in the TNBC was also decreasing. The decrease in the S100A4 intracellular level occurred due to the protein's monomeric form while the contribution of the dimeric form into the overall S100A4 concentration in TNBC cells increased 1.5-2-fold. The S100A4 pathway in the intercellular communication between TNBC and TPBCs also included the dexamethasone-sensitive mechanisms of S100A4 intra- and extracellular pools regulation.

Liver steatosis is a key pathology in non-alcoholic or metabolic associated fatty liver disease. Though largely ignored for decades it is currently becoming the focus of research in hepatology. It is important to consider its origin and current opportunities in terms of pharmacotherapy. Essential phospholipids (EPLs) rich in phosphatidylcholine (PCH) is a widely used treatment option for fatty liver disease, and there is a solid amount of consistent clinical evidence for the regression of steatosis after treatment with EPLs. As knowledge of PCH (a key component of EPLs) pharmacodynamics and mode of action driving this widely observed clinical effect is currently insufficient, we aimed to explore the potential molecular and metabolic pathways involved in the positive effects of PCH on steatosis regression.

Differences between individual antihistamines are determined by such pharmacokinetic properties as the rate and completeness of absorption, half-life, the participation of hepatic and renal mechanisms of elimination from the body. Pharmacodynamic features of the antihistamine include selectivity and affinity for histamine H1-receptors and the presence of central effects. The mechanisms of the development of unwanted drug interactions with second-generation antihistamines are analyzed in detail. Three levels of interaction have been identified: 1) hepatic enzymes of the P450 system; 2) membrane carriers of organic anions (OATP) transport proteins on the sinusoidal membrane of hepatocytes and the luminal membrane of the epithelium of the proximal nephron tubule; 3) P-glycoprotein (Pgp, ABCB1-protein) of epithelial cells of the small intestine the area of absorption of oral forms of antihistamines, the epithelium of the proximal tubule and the BBB (blood-brain barrier). The emphasis is made on the description of the dependence of the pharmacological profile of antihistamines on its chemical structure. The elasticity of the bilastine molecule, the ability to induce a change in conformation underlies the high complementarity of bilastine to the recognition site of the H1-receptor which is a high affinity. Experimental evaluation confirms this conclusion: the dissociation constant (Dс) of the bilastin-receptor complex is in the nM concentration range. The bilastine molecule, as a representative of antihistamines with zwitterionic properties, carries both a positive and a negative charge at a physiological pH, making it difficult for its penetration into the brain. The peculiarities of the chemical nature of the bilastine molecule are reflected in the specific pharmacological profile of AGP. In vitro studies have shown a high specific affinity of bilastine for H1-receptors with a very low affinity for other histamine receptors (H2, H3, H4), serotonin, bradykinin, muscarinic and adrenergic receptors). According to this indicator, bilastine is 3 times higher than cetirizine and 5 times higher than fexofenadine. Bilastine is practically not metabolized in the body and is excreted mainly unchanged, and also does not have a cardiotoxic effect. Bilastine is well tolerated; as a therapeutic dose it has a less pronounced sedative potential compared to other second-generation antihistamines.

Introduction: Cardiac pacing is indicated for sick sinus syndrome. It is performed with a pacemaker via electrodes implanted in the heart. This technique has several disadvantages. The search for alternative methods of cardiac pacing is underway. One of them is control of heart rhythm through stimulation of the tragus. Objective: To perform the reflex stimulation of the sinoatrial node and to study the influence of the SS-68 substance on it. Materials and methods: Two electrodes were fixed in the reflexogenic zone of rabbits’ auricles, volleys of electrical impulses from an electrical stimulator were applied to the electrodes, and the synchronization range of volley frequency and cardiac contractions was recorded. This range was re-recorded again after injecting the SS-68 substance (2-phenyl-1-(3-pyrrolidine-1-cyclopropyl)-1H-indole hydrochloride) intravenously at a dose of 50 µg/kg. In other experiments on frogs in a high-frequency electromagnetic field, the process of excitation of the area of the medulla oblongata associated with the heart rhythm was visualized. After the application of SS-68 (50 μM) to the surface of this zone, the process of its excitation was recorded. Results and discussion: Stimulation of the auricular reflexogenic zone of rabbits produced a synchronization of volley frequency and heart rate in the range from 173.5 ± 2.0 to 214.0 ± 1.8 per minute. SS-68 extended this range from 168.2 ± 1.9 to 219.4 ± 1.5 per minute. In the frog’s medulla oblongata, an area synchronous to the heart rhythm glowed in the high-frequency electromagnetic field. SS-68 increased the area of glow by 131.0%. Conclusion: The substance SS-68 increases the frequency range of heart rhythm control by activating reflex stimulation of the sinoatrial node. The main point of application of SS-68 is the medulla oblongata. Glow in the high-frequency electromagnetic field reflects the process of neuron excitation. The increase in the glow zone under the influence of SS-68 indicates synchronously excited neurons, which leads to the assimilation of the central heart rhythm generation by the sinoatrial node.

We observed 31 children received fenspirid (Erespal) including 15 bronchial asthma children (the study group) and 16 children with chronic non-specific inflammatory bronchopulmonary diseases (the comparative group). The bronchial asthmatic children showed increased H 1 -receptors sensitivity for histamine accompanied by exceeded intracellular calcium ion concentration as a response to the histamine stimulation. They also showed an increase of ɑ 1 -adrenoreceptors number. Meantime the intracellular calcium ion concentration arise less than it was in the children with chronic non-specific inflammatory bronchopulmonary diseases under the noradrenaline stimulation. Against the background of treatment with fenspirid (Erespal) the H 1 -histamine receptors sensitivity as well as calcium ions response to histamine and noradrenalin stimulations decreased in the bronchial asthma children and the similar events appeared in less degree after the histamine stimulation in children with chronic inflammatory bronchopulmonary diseases. Simultaneously clinical bronchial obstruction signs solved and lung function improved.

Gliclazide is a second generation sulphonylurea oral hypoglycaemic agent used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM).It improves defective insulin secretion and may reverse insulin resistance observed in patients with NIDDM.These actions are reflected in a reduction in blood glucose levels which is maintained during both short and long term administration, and is comparable with that achieved by other sulphonylurea agents.Gradually accumulating evidence suggests that gliclazide may be useful in patients with diabetic retinopathy, due to its haemobiological actions, and that addition of gliclazide to insulin therapy enables insulin dosage to be reduced.Thus, gliclazide is an effective agent for the treatment of the metabolic defects associated with NIDDM and may have the added advantage of potentially slowing the progression of diabetic retinopathy.These actions, together with its good general tolerability and low incidence of hypoglycaemia have allowed gliclazide to be well placed within the array of oral hypoglycaemic agents available for the control of NIDDM.

The article describes the basic rules for the selection of a systemic antifungal drug from the fluconazole-based preparations available on the Russian pharmaceutical market. Questions of interchangeability of generic and original drugs, research of equivalence (pharmaceutical, pharmacokinetic), possible methodological difficulties of its estimation are discussed. Data on comparative analysis of original and generic fluconazole drugs are presented. The algorithm of rational choice of a drug on an example of fluconazole is formulated, property of a drug to suppress selectively activity of fungi of genus Candida, not showing hepatotoxic drugs, and also questions of correlation between reference and generic drugs on the basis of fluconazole is considered. The Federal Law “On Amendments to the Federal Law “On Circulation of Medicines“ No. 429-FZ (adopted on December 22, 2014 and entered into force on July 1, 2015) regarding the establishment of the procedure for determining the interchangeability of drugs, states: “Information on the interchangeability of drugs shall be included in the State Register of Medicines from January 1, 2018“. The law discloses the notion of interchangeable drugs, which “means a drug with proven therapeutic equivalence or bioequivalence regarding reference drugs, having equivalent qualitative formula and quantitative composition of active substances, formula and method of administration“. However, some definitions used so far in the law have been changed. Thus, instead of the term “original medicine“ the term “reference drug“ is used from July 1, 2015, which is defined as a medicine first registered in the Russian Federation, the quality, efficacy and safety of which has been proved based on the results of preclinical and clinical studies, and which is used to assess the bioequivalence or therapeutic equivalence, quality, efficacy and safety of generic or bioanalogue medicine. However, this article still uses the terms “original“ and “generic“ drugs, which are familiar to our medical community.

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.

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<doxorubicin≤docetaxel. The combined effects of the drugs were multidirectional: the total effect of dexamethasone and doxorubicin combination was inferior to their separate effect, while the effect of dexamethasone and docetaxel surpassed their individual effects. The combination of dexamethasone, doxorubicin, and docetaxel allowed negating the negative reciprocal interactions between dexamethasone and doxorubicin. The studying of the mechanisms underlying the observed phenomena attested to a potential role of S100A4 in the regulation of MDA-MB231 cells to the studied drugs.

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 following three groups of factors must be taken into consideration for selecting an optimum pH value of a topical drug: pharmaceutical, pharmacological and compatibility factors. To ensure a stable pH value, the drug vehicle comprises different buffer systems: single component and two-component ones. The optimum conditions for selecting and maintaining the vehicle pH were examined by the example of glucocorticosteroid-based topical drugs.