Gliflozins position update in the treatment algorithms for patients with type 2 diabetes mellitus and chronic kidney disease: new pathogenetic mechanisms and data from subanalyses of the large randomised control trails

The series of the cardiovascular outcome trails have demonstrated the nephroprotective properties of the gliflozins. Canagliflozin in the CREDENCE, which was the first study with a primary focus on the evaluation of the nephroprotective properties of gliflozin, have demonstrated the possibility to slow the progression of the renal disease. The paper summarizes the additional data from the CREDENCE trail: assessment of the efficacy of canagliflozin by initial eGFR; efficacy in individuals with GFR <30 ml/min/1.73 m2 ; long-term effects of canagliflozin on anaemia-related outcomes; effects of canagliflozin on serum potassium; effects on heart failure and cardiovascular mortality. There are discussed the current treatment algorithms for patients with type 2 diabetes and CKD where using of gliflozins is a priority option. Canagliflozin is a drug with a relatively low ratio of SGLT1/SGLT2 selectivity. The effects of the inhibition of SGLT1 transport in the kidney and in the intestine are described and their additional influence on reducing of the postprandial glycemia and additional nephroprotection

Tyrosine hydroxylase of the brain and it’s regulation by glucocorticoids

Early life stress events can produce long-lasting changes in neurochemistry and behaviors related to monoamine systems, with increased risks of cardiovascular, metabolic, neuroendocrine, psychiatric disorders, generalized anxiety and depression in adulthood. Tyrosine hydroxylase (TH), the key enzyme for catecholamine synthesis, also plays an important role in the activity of the noradrenergic system and may be a target for glucocorticoids during the perinatal programming of physiological functions and behavior. Administration of hydrocortisone or dexamethasone to female rats on day 20 of pregnancy and to 3-day-old neonatal pups significantly increased TH mRNA levels (real-time PCR) and enzyme activity as well as protein levels determined by ICH in the locus coeruleus. Moreover, our treatment led to increase in TH mRNA levels in 25- and 70-day-old animals, as well as an increase in enzyme activity in the brainstem and cerebral cortex of adult rats. The long-term changes in TH expression are limited by the perinatal period of development. Administration of hormones on day 8 of life was not accompanied by changes in TH mRNA levels or enzyme activity. Glucocorticoids use several mechanisms to bring about transactivation or transrepression of genes. The main mechanism includes direct binding of the hormone-activated GRs to glucocorticoid responsive elements (GREs) in the promoter region of genes. However, despite optimistic claims made the classical GRE was not found in the TH gene promoter. Protein – protein interactions between hormone-activated GR and other transcription factors, for example, AP-1, provide an additional mechanism for the effects of glucocorticoids on gene expression. An important feature of this mechanism is its dependence on the composition of proteins formed by AP-1. Hormone-activated GRs are able to enhance gene expression when AP-1 consists of the Jun / Jun homodimer, but do not do that when AP-1 appears as the Jun / Fos heterodimer. Furthermore, as has been shown recently, the GRE / AP-1 composite site is the major site of interaction of glucocorticoids with  the TH gene in the pheochromocytoma cell line. Ontogenetic variation in the expression of Fos and Jun family proteins, which affects their ratio, can be one of the reasons for the TH gene regulation by glucocorticoids at near-term fetuses and neonates. However, to date this hypothesis has been supported only by in vitro data, and the existence of this mechanism in in vivo conditions needs to be explored in further studies

Voltage-Dependent Gating in a “Voltage Sensor-Less” Ion Channel

An unusual mechanism of ion channel regulation generates voltage-dependent gating in the absence of a canonical voltage-sensing domain

Canagliflozin: from glycemic control to improvement of cardiovascular and renal prognosis in patients with type 2 diabetes mellitus. Resolution of Advisory Board

Inhibitors of the sodium-glucose cotransporter type 2 (SGLT2i) are a modern class of antihyperglycemic drugs with an insulin-independent mechanism of action. Due to its ability to effectively lower blood glucose levels, improve a number of other cardiometabolic parameters (body weight, blood pressure, uric acid), as well as reduce cardiovascular and renal risks, SGLT2i have become drugs of choice for many of patients with type 2 diabetes mellitus (T2DM). Meanwhile, along with the generally recognized classes-effects of this group of drugs, there are intragroup features, including those associated with their different selectivity in sodium-glucose cotransporters of types 1 and 2 (SGLT1 and SGLT 2). For example, one of the most studied SGLT2i, canagliflozin, in addition to its inhibitory activity against SGLT2, can also moderately block SGLT1 in the intestine and kidneys that could give a maximum efficiency in the control glycemia and others cardiometabolic parameters. In addition, canagliflozin improves not only cardiovascular, but also renal prognosis in patients with T2DM, which is reflected in the corresponding indications in the summary of product characteristics of the drug. This document summarize the established and new data regarding the efficacy and safety of canagliflozin, as well as its place in the treatment of T2DM

Возможности фармакологического лечения остеоартрита: фокус на симптоматические медленно действующие препараты (SYSADOA) и индивидуальные особенности пациента. Резолюция международного совещания экспертов

The paper presents the results of the Osteoarthritis (OA) Expert Council held on September 8, 2019, which was attended by Russian and foreign specialists. The experts considered pharmacological treatment options for OA. The expert meeting resolution states that the treatment of patients with OA should be based on an individual assessment of the patient and on a modern evidence base of therapy efficacy.Treatment of patients with OA is based on the principles of evidence-based medicine that requires an integrated approach and the need of SYSADOAs prescription. Combined drugs with therapeutic dosages of chondroitin sulfate and glucosamine in the early stages of the disease are available as basic agents. The place of paracetamol in the anesthetic therapy algorithm in OA needs to be clarified. It is also noted that when choosing nonsteroidal anti-inflammatory drugs for OA treatment, it is important to take into account individual patient characteristics and the presence of comorbidities.Представлены результаты Экспертного совета по остеоартриту (ОА), проходившего 8 сентября 2019 г., в котором приняли участие российские и зарубежные специалисты. Рассматривались возможности фармакологического лечения ОА. В резолюции совещания указано, что лечение больных ОА должно быть основано на индивидуальной оценке состояния пациента и современных доказательствах эффективности терапии. Лечение больных ОА на основании принципов доказательной медицины предполагает комплексный подход и назначение SYSADOA. Комбинированные препараты с терапевтическими дозами хондроитина сульфата и глюкозамина уже на ранних стадиях заболевания рассматриваются в качестве базисных средств. Место парацетамола в алгоритме обезболивающей терапии при ОА требует уточнения. Отмечено также, что при выборе нестероидных противовоспалительных препаратов для лечения ОА важно учитывать индивидуальные особенности пациента и наличие коморбидных состояний

ОЦІНКА ГІДРОХІМІЧНИХ ПОКАЗНИКІВ ВОДИ ОЗЕРА СИНЕВИР ТА ЙОГО ПРИТОКІВ

LakeSynevyris the decoration of the Ukrainian Carpathians. It is fed by four tributaries, and one stream originates from the lake. In recent years, the anthropogenic load on LakeSynevyrand its coastal part has increased, primarily due to recreational activities. To evaluation the state of the water of Lake Synevyr, we used hydrochemical parameters, such as total dissolved solids, рН, chloride (Cl-), bicarbonate (HCO3-), sulphate (SO42-), magnesium (Mg2+), calcium (Ca2+), sodium (Na+), nitrate (NO3-), nitrite NO2-, NH4+, content of petroleum products and biochemical oxygen demand (BOD5). Petroleum products were not found in the water ofLakeSynevyr and its tributaries.The hydrochemical parameters of the water of Lake Synevyr change with depth, in particular increasing content of chloride (mg×L-1, 4.9 - 5.5 - 6.1), bicarbonate (mg×L-1, 42.7 - 61.0 - 61.1), sulphate (mg×L-1, 45.7 - 50.9 - 62.5), calcium (mg×L-1, 16.5 - 19.6 - 24.9), sodium (mg×L-1, 28.5 - 31.1 - 39.6) and total dissolved solids (mg×L-1, 132 - 168 - 185), however, decreases рН (7.4 - 6.8 - 6.7) and content of magnesium (mg×L-1, 6.7 - 6.0 - 5.7). The surface waters of Lake Synevyr contain a relatively high content of organic compounds (by indicator BOD5, 4.3±0.2 mgO2×L-1), and in the summer the concentration of inorganic compounds of Nitrogen sharply increases (NO3-, NO2-, NH4+), especially nitrates (31.1 mg(N)×L-1). This is obviously due to the influence of anthropogenic factors, including human recreational activities. The hydrochemical parameters of the tributaries of Lake Synevyr are relatively stable, they contain a small amounts of inorganic compounds of Nitrogen and organic compounds. This confirms the anthropogenic origin of organic compounds and inorganic compounds of Nitrogen (NO3-, NO2-, NH4+) in the water ofLakeSynevyr. Therefore, it is necessary to reduce the anthropogenic influence onLakeSynevyr.The hydrochemical parameters of the stream that originates from Lake Synevyr have a similar chemical composition as the surface water of the lake.Озеро Синевир - окраса Українських Карпат. Воно живиться чотирма притоками, а один потік бере початок з озера. Останніми роками антропогенне навантаження на озеро Синевир та його прибережну частину зросло, насамперед завдяки рекреаційним заходам. Для оцінки стану води озера Синевир ми використовували гідрохімічні параметри, такі як загальна мінералізація, рН, хлориди (Cl-), гідрогенкарбонати (HCO3-), сульфати (SO42-), магній (Mg2+), кальцій (Ca2+), натрій (Na+), нітрати (NO3-), нітрити (NO2-), NH4+, вміст нафтопродуктів та біохімічне споживання кисню (БСК5). Нафтопродукти не були знайдені у воді озера Синевир та його притоках.Гідрохімічні параметри води озера Синевир змінюються з глибиною, зокрема збільшення вмісту хлоридів (мг/дм3, 4,9 - 5,5 - 6,1), гідрогенкарбонатів (мг/дм3, 42,7 - 61,0 - 61,1), сульфатів (мг/дм3, 45,7 - 50,9 - 62,5), кальцію (мг/дм3, 16,5 - 19,6 - 24,9), натрію (мг/дм3, 28,5 - 31,1 - 39,6) та загальна мінералізація (мг/дм3, 132 - 168 - 185), однак знижується рН (7,4 - 6,8 - 6,7) та вміст магнію (мг/дм3, 6,7 - 6,0 - 5,7). Поверхневі води озера Синевир містять відносно високий вміст органічних сполук (за показником БСК5, 4,3+0,2 мгО2/дм3), а влітку концентрація неорганічних сполук Нітрогену різко зростає (NO3-, NO2-, NH4+), особливо нітрати (31,1 мг(N)/дм3). Очевидно, це пов'язано з впливом антропогенних факторів, включаючи рекреаційну діяльність людини. Гідрохімічні параметри приток озера Синевир відносно стабільні, вони містять невелику кількість неорганічних сполук Нітрогену та органічних сполук. Це підтверджує антропогенне походження органічних сполук та неорганічних сполук Нітрогену (NO3-, NO2-, NH4+) у воді озера Синевир. Тому необхідно зменшити антропогенний вплив на озеро Синевир.Гідрохімічні параметри потоки, що бере свій початок з озера Синевир, мають аналогічний хімічний склад, як поверхневі води озера.

MUSCLE RELAXANTS: ARE THEY NEEDED IN ANKYLOSING SPONDYLITIS?

Guidelines for the treatment of ankylosing spondylitis (AS) lack muscle relaxants. At the same time, the latter are used for combined therapy using nonsteroidal  anti-inflammatory drugs (NSAIDs)  in 53.1% of patients in an outpatient  setting. No clear recommendations make the administration of these agents uncontrolled, on the one hand, and substantially restrict therapeutic  possibilities, on the other.Objective: to investigate the short-term effect and safety of using tolperisone hydrochloride  (THC,  Mydocalm®)  in patients with AS during group therapeutic  exercise (TE).Subjects and methods. The investigation included 40 patients aged over 18 years with a valid diagnosis of AS who had been treated at the Clinic of the V.A. Nasonova Research Institute of Rheumatology and agreed to participate  in the study. All the patients were randomized  in a 1:1 ratio into two groups: 1) 20 patients used NSAIDs in combination with TE; 2) 20 patients received NSAIDs,  TE, and THC 450 mg/day. The groups were matched for age, gender, disease duration,  and functional impairments. Before and after completion  of the investigation, the investigators estimated BASDAI, BASFI, patient-rated numerical pain rating scale (NPRS), patient-rated TE performance  scores (NPRS, where 0 (very effective), 10 (ineffective), THC tolerance monitoring  (consideration of adverse events). Spinal motility was evaluated using BASMI and chest excursion measurement.Results and discussion. During TE, both groups showed a significant increase in the volume of movements (p < 0.03), when measuring chest excursion and carrying out modified Schober's test, a decrease in BASDAI (p < 0.01) and BASFI (p < 0.009), as well as a reduction  in patient-rated overall disease activity assessment (p < 0.02) as compared to the baseline values. At the same time the modified Schober test revealed that the increase in motility was significantly higher in Group 2 than in Group 1 (p < 0.05). During the follow-up, the patient-rated evaluation of TE efficiency remained significantly unchanged  in Group 1 whereas at the end of the study it significantly increased in Group 2 as compared to the baseline values (p < 0.01). There were no significant differences between the groups in the time course of changes in BASDAI and BASFI. When performing the BASMI tests, there was an intensive increment  in the volume of movements after the third TE lesson. The increment  occurred saltatorily in Group 1, but more rapidly and evenly in Group 2. No serious adverse events were recorded in Group 2 during the investigation. Conclusion. Incorporation of THC into the treatment of patients with AS contributes to the enhanced  efficiency of TE. There is a need for further investigations to study the use of muscle relaxants, including THC,  in AS in order to elaborate recommendations on how to administer this class of drugs for this disease