SOFOSBUVIR: TREATMENT OF CHRONIC HEPATITIS C AND THE MAIN TRENDS IN PATENT PROTECTION

The purpose of the study was to analyze and systematize the literature data on the benefit/risk ratio of sofosbuvir administration in the treatment of patients with chronic hepatitis C and the main trends in its patent protection. Studies were conducted using databases on the Internet: Ukrainian patent office, the European patent office, the US patent office, the Food and drug administration, European Medicines Agency (EMEA), State enterprise “The State Expert Center” of the Ministry of Health of Ukraine. It has used retrospective, logical, systematic and analytical methods. Data from clinical studies abroad and meta-analyses indicate that sofosbuvir is one of the most promising drugs for the treatment of chronic HCV infection. Its indisputable advantages are that this drug can be used with different genotypes of the virus, decompensated liver function, it is well tolerated. Sofosbuvir has an improved safety profile and a low probability of viral resistance. The high cost of sofosbuvir is due to the powerful patent protection. As mechanisms for working with patent barriers, it is recommended to use the flexible mechanisms of the TRIPS Agreement: the grant of compulsory licenses, the implementation of parallel imports, the tightening of the criteria for patentability (prohibition of patenting new forms that do not improve therapeutic efficacy)

Mode-coupling and the pygmy dipole resonance in a relativistic two-phonon model

A two-phonon version of the relativistic quasiparticle time blocking approximation (RQTBA-2) represents a new class of many-body models for nuclear structure calculations based on the covariant energy density functional. As a fully consistent extension of the relativistic quasiparticle random phase approximation (RQRPA), the two-phonon RQTBA implies a fragmentation of nuclear states over two-quasiparticle and two-phonon configurations. This leads, in particular, to a splitting-out of the lowest 1$^-$ state as a member of the two-phonon $[2^+\otimes3^-]$ quintuplet from the RQRPA pygmy dipole mode, thus establishing a physical mixing between these three modes. The inclusion of the two-phonon configurations in the model space allows to describe the positions and the reduced transition probabilities of the lowest 1$^-$ states in isotopes $^{116,120}$Sn as well as the low-energy fraction of the dipole strength without any adjustment procedures. The model is also applied to the low-lying dipole strength in neutron-rich $^{68,70,72}$Ni isotopes. Recent experimental data for $^{68}$Ni are reproduced fairly well

Perspectives of growth of economic security by clustering of small innovation enterprises

The authors analyze the notion, sense, criteria, and indicators of evaluation of economic security and perform the evaluation of economic security of modern economic systems with the help of the offered methodology, which leads to the conclusion that one of the most successful countries are characterized by low level of economic security; therefore, there is a necessity for the search for perspectives of the increase of economic security. As a tool for increasing economic security, clustering is offered. The authors performed the structural analysis of formation of modern clusters and allowed allocating the problems of clustering which can be solved by clustering of small innovational enterprises. It is necessary that small innovational enterprises participate in the development of the program; their joint projects should at least concern, or, even better, solve their common problems (which will increase the competitiveness of cluster, as small innovational enterprises are connected by chains of value added with the same large companies); small innovational enterprises should participate – within the limits of their competencies – in the formation of the program of cluster development; there should be no artificial disunion between clusters of large enterprises and clusters of small innovational enterprises (which requires creation of common list of clusters). As a result of the research, the authors come to the conclusion that cluster is a form of increasing competitiveness within one country and in the global market, which stipulates the growth of national economic security. The highest efficiency of cluster is achieved by clustering small innovational enterprises, which stipulates the optimal level of competition in a cluster and leads to creation of innovations – which is a moving force of development of modern economy and the basis for economic security.peer-reviewe

Problems and perspectives of formation of agricultural clusters for increasing food security of developing countries

The authors of the article develop the proprietary methodology of integral approach to formation of the projects and programs of socio-economic development, which allows differentiating the sub-system of previously viewed indicators as to the level of users’ demands. The sense of cluster approach to increasing the competitiveness of agro-industrial complex is analyzed, and the problems and perspectives for formation of agricultural clusters for the growth of food security of developing countries are determined. As a result of the research, the authors came to the conclusion that agricultural clusters are a perspective course of increasing food security of developing countries, as they improve competitiveness of domestic agricultural producers and increase food independence and food self-sufficiency of economic systems. However, implementation of internal cluster cooperation requires reconsidering the existing notions of management, related to the level of methods and control, protection of intellectual property, education, and integration. The created system of relations should allow economic agents to keep balance between self-organizing and manageable behavior, combining innovational diversity and freedom of actions with the necessary level of integration. Intercompany cooperation in this regard should be similar to cooperation of ecosystem elements.peer-reviewe

On Th229 and time-dependent fundamental constants

The electromagnetic transition between the almost degenerate 5/2+ and 3/2+ states in Th229 is deemed to be very sensitive to potential changes in the fine structure constant alpha. State of the art Hartree-Fock and Hartree-Fock-Bogoliubov calculations are performed to compute the difference in Coulomb energies of the two states which determines the amplification of variations in alpha into variations of the transition frequency. The kinetic energies are also calculated which reflect a possible variation in the nucleon or quark masses. A generalized Hellmann-Feynman theorem is proved including the use of density-matrix functionals. As the two states differ mainly in the orbit occupied by the last unpaired neutron the Coulomb energy difference results from a change in the nuclear polarization of the proton distribution. This effect turns out to be rather small and to depend on the nuclear model, the amplification varies between about -4 x 10^4 and +4 x 10^4. Therefore much more effort must be put into the improvement of the nuclear models before one can draw conclusions from a measured drift in the transition frequency on a temporal drift of fundamental constants. All calculations published so far do not reach the necessary fidelity. PACS 06.20.Jr,21.60.Jz,27.90.+bComment: 13 pages with 3 figure

Multimodal optical measurement for study of lower limb tissue viability in patients with diabetes mellitus

According to the International Diabetes Federation, the challenge of early stage diagnosis and treatment effectiveness monitoring in diabetes is currently one of the highest priorities in modern healthcare. The potential of combined measurements of skin fluorescence and blood perfusion by the laser Doppler flowmetry method in diagnostics of low limb diabetes complications was evaluated. Using Monte Carlo probabilistic modeling, the diagnostic volume and depth of the diagnosis were evaluated. The experimental study involved 76 patients with type 2 diabetes mellitus. These patients were divided into two groups depending on the degree of complications. The control group consisted of 48 healthy volunteers. The local thermal stimulation was selected as a stimulus on the blood microcirculation system. The experimental studies have shown that diabetic patients have elevated values of normalized fluorescence amplitudes, as well as a lower perfusion response to local heating. In the group of people with diabetes with trophic ulcers, these parameters also significantly differ from the control and diabetes only groups. Thus, the intensity of skin fluorescence and level of tissue blood perfusion can act as markers for various degrees of complications from the beginning of diabetes to the formation of trophic ulcers

The role of Leu260Phe polymorphism of the receptor gene to GLP-1 incretin in the pathogenesis of diabetes type 2 diabetes with obesity

BACKGROUND: Glucagon-like peptide-1 (GLP-1) stimulates the proliferation of β-cells, enhances their resistance to apoptosis and increases glucose-dependent insulin secretion. AIMS: Study of the relationship of Leu260Phe polymorphism (rs1042044) of the GLP-1R gene with postprandial hormone production (C-peptide, insulin, ghrelin, GLP-1) in obese patients with type 2 diabetes. MATERIALS AND METHODS: A total of 174 patients, 82 patients with obesity with type 2 diabetes (BMI=40.4±14.3 kg/m2)and 92 conditionally healthy donors (BMI=22.6±2.7 kg/m2) were studied. The material for the study was venous blood taken on an empty stomach and 60 minutes after the test breakfast. Genotyping was performed by PCR using the sets for determining polymorphism (rs1042044) of the GLP-1R gene (Sintol) and the amplificator (CFX96 BioRad, USA). Plasma hormone levels were evaluated by flow fluorimetry (Bio-PlexProteinAssaySystem, Bio-Rad, USA) using commercial test systems (Bio-PlexProHumanDiabetes 10-Plex Assay, Bio-Rad, USA). Statistical analysis and graphs were obtained at R Statistical Software. RESULTS: A violation of postprandial production of GLP-1 and ghrelin after a test breakfast in obese patients with type 2 diabetes was found. A postprandial increase in C-peptide levels of 3.25[1.83;4.16] ng/ml and insulin 3048 [1978;4972] ng/ml in carriers of the CC genotype compared with carriers of the CA genotype in the group of patients with obesity with type 2 diabetes type In carriers of the CA genotype, there was a decrease in the C-peptide level of 2.21 [1.8;2.49] ng/ml and insulin 1462 [1146; 2304] ng/ml with a constant concentration of GLP-1. The postprandial level of ghrelin in carriers of the CA genotype of the Leu260Phe polymorphism increased to 118[96.1;157] ng/ml compared to carriers of the AA 98 genotype [86; 109] ng/ml. CONCLUSION: The presence of the CC genotype of the Leu260Phe polymorphism of the GLP-1 receptor gene is associated with an increase in postprandial plasma levels of C-peptide and insulin in obese patients with type 2 diabetes, and the CA genotype with a decrease in these indicators and an increase in ghrelin content

Vitamin D binding protein polymorphysm in patients with acute coronary syndrome in kaliningrad region

BACKGROUND: Vitamin D binding protein is a main vitamin D carrier in serum. It also has an impact on macrophagial function. Role of vitamin D and macrophages in the pathogenesis of atherosclerosis is scientifically proven but there is lack of data on vitamin D binding protein in this regard. AIMS: To evaluate the vitamin D binding protein polymorphism in patients with acute coronary syndrome without diabetes mellitus, autoimmune diseases and malignant tumors. Determine correlation, if there is, between vitamin D binding protein allele and features of acute coronary syndrome among this patient group. MATERIALS AND METHODS: It is a cross-sectional observational study. Study subjects are patients with acute coronary syndrome. Exclusion criteria are the presence of diabetes mellitus, autoimmune diseases and malignant tumors. In all participants were evaluated: predisposing factors for heart diseases, CBC, biochemical blood test, troponin, coronarography, echocardiography. The study lasted for 5 months from November 2017 until March 2018. Primary end point – assessment of vitamin D binding protein polymorphysm in this group of patients with acute coronary syndrome by means of vitamin D binding protein gene sequencing. 50 patients were enrolled into this study who were urgently admitted to hospital and diagnosed with acute coronary syndrome. Among them – 36 males and 14 females. Mean age was 60 (55;66) years. All participants were sequenced for single nucleotide polymorphysm in VDBP p.T436K (rs4588) and P.432E (rs7041). RESULTS: Gene polymorphysms of interest were found in 43 patients among 50 enrolled. Haplotype Gc1s/2 (rs7041G-rs4588A) was found in 7 (14%) patients, Gc2 (rs7041T-rs4588A) — in 9 (18%) patients, Gc1s (rs7041G-rs4588C) – in 20 (40%) patients, Gc1f (rs7041T-rs4588C) in 14 (28%). Coronarography showed that coronary artery occlusions obstructing more than 50% of vessel lumen was found in 16 patients; obstruction greater than 90% was seen in 8 patients; total occlusion – in 4 patients. CONCLUSIONS: In patient group with acute coronary syndrome prevalence of vitamin D binding protein gene polymorphysm was high – in 86% of participants. The features of Gc2 haplotype were higher frequency of recurrent myocardial infarction and total coronary artery occlusion, as well as tendency to decreased serum vitamin D3 (25(OH)D) levels

Human Mesenchymal Stem Cells as a Carrier for a Cell-Mediated Drug Delivery

A number of preclinical and clinical studies have demonstrated the efficiency of mesenchymal stromal cells to serve as an excellent base for a cell-mediated drug delivery system. Cell-based targeted drug delivery has received much attention as a system to facilitate the uptake a nd transfer of active substances to specific organs and tissues with high efficiency. Human mesenchymal stem cells (MSCs) are attracting increased interest as a promising tool for cell-based therapy due to their high proliferative capacity, multi-potency, and anti-inflammatory and immunomodulatory properties. In particular, these cells are potentially suitable for use as encapsulated drug transporters to sites of inflammation. Here, we studied the in vitro effects of incorporating synthetic polymer microcapsules at various microcapsule-to-cell ratios on the morphology, ultrastructure, cytokine profile, and migration ability of human adipose-derived MSCs at various time points post-phagocytosis. The data show that under appropriate conditions, human MSCs can be efficiently loaded with synthesized microcapsules without damaging the cell’s structural integrity with unexpressed cytokine secretion, retained motility, and ability to migrate through 8 ?m pores. Thus, the strategy of using human MSCs as a delivery vehicle for transferring microcapsules, containing bioactive material, across the tissue–blood or tumor–blood barriers to facilitate the treatment of stroke, cancer, or inflammatory diseases may open a new therapeutic perspective