Pharmacogenetics of efficiency and tolerance of the peroral antidiabetic drug metformin

Elektroniskā versija nesatur pielikumusMetformīns ir pirmās izvēles medikaments jaundiagnosticētu 2.tipa cukura diabēta (T2DM) pacientu ārstēšanā. Mēs identificējām asociāciju starp metformīna blakusparādībām un 2 ģenētiskiem variantiem (rs628031 and rs36056065) Organisko Katjonu transportierī 1 (OCT1/SLC22A1). Polimorfismiem rs3119309, rs2481030 un rs7757336, lokalizētiem Organisko Katjonu transportieru 2 un 3 (OCT2/SLC22A2 un OCT3/SLC22A3) starpgēnu reģionā, tika noteikta būtiska asociācija ar metformīna īstermiņa terapijas efektivitāti. Divi no šiem variantiem tika analizēti replikācijas pētījumā ar 126 T2DM pacientiem no Slovākijas un farmakokinētikas pētījumā ar 15 veseliem brīvprātīgajiem. Visbeidzot, 33 ģenētiskas variācijas tika izpētītas ATM, STK11 un T2DM kandidātgēnos, bet tikai dažas no tām bija nomināli asociētas ar metformīna īstermiņa terapijas efektivitāti. Atslēgas vārdi: OCTs, metformīns, farmakoģenētika, blakusparādības, efektivitāte.Metformin is the first-line medication used in treatment of newly-diagnosticed Type 2 diabetes mellitus (T2DM). We show an association between metformin side-effects and two genetic variants (rs628031 and rs36056065) in Organic Cation Transporter 1 (OCT1/SLC22A1). Polymorphisms rs3119309, rs2481030 un rs7757336 in intergenic region between Organic Cation Transporter 2 and 3 (OCT2/SLC22A2 and OCT3/ SLC22A3) were found to be associated with short-term efficiency of metformin therapy. Two of these variants were analysed in replication study in 126 T2DM patients from Slovakia and in pharmacokinetic study with 15 healthy participants. At last, 33 genetic variants in ATM, STK11 and list of T2DM susceptibility genes were investigated, but only few showed a nominal association with short-term efficiency of metformin monotherapy. Keywords: OCTs, metformin, pharmacogenetics, side-effects, efficiency

The Risks in Cement Particle Boards Production

Промышленность строительных материалов непосредственно участвует в создании инфраструктуры современного мира, но ухудшает состояние окружающей среды, истощая ресурсы и выделяя большое количество вредных веществ в атмосферу. В статье рассмотрены основные риски, возникающие при производстве цементно-стружечных плит.The building materials industry is directly involved in the development of the modern world infrastructure, but it deteriorates the environment by depleting resources and releasing the large amount of harmful substances into the atmosphere. The article discusses the main risks that arise in the cement particleboards production

«Современная молодежь в современной библиотеке»: второй Международный конгресс

On the International Congress “The Youth of Today in the Modern Library” which was held in Moscow on 11–13 October,2011 on the base of the Russian State Library for Young Adults.О Международном конгресса «Современная молодежь в современной библиотеке», который прошел в Москве 11–13 октября 2011 г. на базе Российской государственной библиотеки для молодежи (РГБМ)

Metformin Transport Rates Between Plasma and Red Blood Cells in Humans

Background Metformin has been used for the treatment of type 2 diabetes for over 60 years; however, its mechanism of pharmacological action is not fully clear. Different hypotheses exist regarding metformin distribution and redistribution mechanisms between plasma and erythrocytes/red blood cells (RBCs). Objective We aimed to test the hypothesis that the metformin distribution between plasma and RBC occurs via concentration difference-driven passive transport and estimated transport rate coefficient values based on metformin concentration time series in plasma and RBCs from in vivo studies. Methods An ordinary differential equation (ODE) system with two compartments was used to describe diffusion-based passive transport between plasma and RBCs. Metformin concentration time series in plasma and RBCs of 35 individuals were used for metformin transport parametrization. Plasma concentration has been approximated by biexponential decline. Results A single passive transport coefficient, k = 0.044 +/- 0.014 (h(-1)), can be applied, describing the uptake and release transport rate versus the linear equation v = k x (M-pl - M-RBC), where M-pl is the metformin concentration in plasma and M-RBC is the metformin concentration in RBCs. Conclusions Our research suggests that passive transport can explain metformin distribution dynamics between plasma and RBCs because transport speed is proportional to the metformin concentration difference and independent of the transport direction. Concentration difference-driven passive transport can explain the mechanism of faster metformin distribution to RBCs the first few hours after administration, and faster release and domination of the redistribution transport rate after metformin concentration in plasma becomes smaller than in RBCs.Peer reviewe

Binding Specificity of Sea Anemone Toxins to Nav 1.1-1.6 Sodium Channels UNEXPECTED CONTRIBUTIONS FROM DIFFERENCES IN THE IV/S3-S4 OUTER LOOP

Sea anemones are an important source of various biologically active peptides, and it is known that ATX-II from Anemonia sulcata slows sodium current inactivation. Using six different sodium channel genes (from Nav1.1 to Nav1.6), we investigated the differential selectivity of the toxins AFT-II (purified from Anthopleura fuscoviridis) and Bc-III (purified from Bunodosoma caissarum) and compared their effects with those recorded in the presence of ATX-II. Interestingly, ATX-II and AFT-II differ by only one amino acid (L36A) and Bc-III has 70% similarity. The three toxins induced a low voltage-activated persistent component primarily in the Nav1.3 and Nav1.6 channels. An analysis showed that the 18 dose-response curves only partially fit the hypothesized binding of Lys-37 (sea anemone toxin Anthopleurin B) to the Asp (or Glu) residue of the extracellular IV/S3-S4 loop in cardiac (or nervous) Na+ channels, thus suggesting the substantial contribution of some nearby amino acids that are different in the various channels. As these channels are atypically expressed in mammalian tissues, the data not only suggest that the toxicity is highly dependent on the channel type but also that these toxins and their various physiological effects should be considered prototype models for the design of new and specific pharmacological tools

Novel susceptibility loci identified in a genome-wide association study of type 2 diabetes complications in population of Latvia

Funding Information: The study was supported by European Regional Development Fund (ERDF) On Implementation of Activity 1.1.1.2 “Post-doctoral Research Aid” of the Specific Aid Objective 1.1.1 “To increase the research and innovative capacity of scientific institutions of Latvia and the ability to attract external financing, investing in human resources and infrastructure” of the Operational Programme “Growth and Employment”. Project No 1.1.1.2/VIAA/2/18/287 “Identification of clinical subgroups of Type 2 diabetes mellitus and application of pharmacogenetics in the development of personalized antidiabetic therapy”. The funding body was not involved in the design of the study, collection, analysis or interpretation of data, or writing the manuscript. Publisher Copyright: © 2021, The Author(s).Background: Type 2 diabetes complications cause a serious emotional and economical burden to patients and healthcare systems globally. Management of both acute and chronic complications of diabetes, which dramatically impair the quality of patients' life, is still an unsolved issue in diabetes care, suggesting a need for early identification of individuals with high risk for developing diabetes complications. Methods: We performed a genome-wide association study in 601 type 2 diabetes patients after stratifying them according to the presence or absence of four types of diabetes complications: diabetic neuropathy, diabetic nephropathy, macrovascular complications, and ophthalmic complications. Results: The analysis revealed ten novel associations showing genome-wide significance, including rs1132787 (GYPA, OR = 2.71; 95% CI = 2.02–3.64) and diabetic neuropathy, rs2477088 (PDE4DIP, OR = 2.50; 95% CI = 1.87–3.34), rs4852954 (NAT8, OR = 2.27; 95% CI = 2.71–3.01), rs6032 (F5, OR = 2.12; 95% CI = 1.63–2.77), rs6935464 (RPS6KA2, OR = 2.25; 95% CI = 6.69–3.01) and macrovascular complications, rs3095447 (CCDC146, OR = 2.18; 95% CI = 1.66–2.87) and ophthalmic complications. By applying the targeted approach of previously reported susceptibility loci we managed to replicate three associations: MAPK14 (rs3761980, rs80028505) and diabetic neuropathy, APOL1 (rs136161) and diabetic nephropathy. Conclusions: Together these results provide further evidence for the implication of genetic factors in the development of type 2 diabetes complications and highlight several potential key loci, able to modify the risk of developing these conditions. Moreover, the candidate variant approach proves a strong and consistent effect for multiple variants across different populations.publishersversionPeer reviewe

Quelques Aspects du Role du Programme Tempus dans l'Internationalisation de l'Enseignement Supérior.

L’expérience de l’Institut Universitaire de Technologie (I. U. T.) de Béthune (Université d’Artois) dans le programme Tempus-Phare provient de son activité depuis le 1er septembre 1991 dans 17 projets différents générant un budget global d’environ 5 millions d’ECU

Helio-Distillate Basin-Type

In that work, spelled out the principles of the action of the distiller basin type. Existing solar desalination plants were analyzer, their advantages and disadvantages. In work were considered three types of solar desalination and one helio distiller. The principle of operation of the proposed helio distiller. In concluding, it is said that the proposed helio distiller will find wide application in countries with a deficit of fresh water.В данной работе изложены принципы действия дистиллятора бассейнового типа. Были проанализированы существующие солнечные опреснители, их плюсы и минусы. В работе были рассмотрены три вида солнечных опреснителей и один гелиодистиллятор. Изложен принцип действия предлагаемого гелиодистиллятора. В заключении говорится о том, что предложенный гелиодистиллятор найдет широкое применение в станах с дефицитом пресной воды