Discovery of a novel non-narcotic analgesic derived from the CL-20 explosive: Synthesis, pharmacology, and target identification of thiowurtzine, a potent inhibitor of the opioid receptors and the ion channels

The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here, we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then, we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal, and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling, and molecular dynamics simulations to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action by essentially targeting the mu opioid receptor, the TRPA1 ion channel, and the Cav voltage-gated calcium channel

The significance of circulating progenitor cells with osteogenic activity in the of atherosclerosis development in patients with type 2 diabetes mellitus

BACKGROUND: There is an interaction between cell-mediated pathway of the vessel calcification and atherosclerosis processes. In some studies the relation beeen circulating osteogenic progenitor cells and cardiovascular diseases was shown. Though its role in the development of cerebrovascular diseases (CVD) in Type 2 diabetes mellitus (T2DM) remains unknown. AIM: To study the level of circulating endothelial (CD34 + VEGFR2 +) and osteogenic (CD34 + OCN +) progenitor cells in patients with CVD and T2DM. METHODS: We observed patients with CVD (coronary artery disease and / or chronic limb threatening ischemia) with T2DM and without T2DM. Patients with CVD and T2DM were included in group 1 patients with CVD and without T2D were included in group 2. The level of CD34 + VEGFR2 cells and CD34 + OCN+ cells was determined by flow cytometry.There were no differences in the age, gender, lipid profile, body mass index, creatinine clearance, myocardial revascularization and lower limb revascularization between the 2 groups.The level of CD34 + VEGFR2 cells and CD34 + OCN+ cells was determined by flow cytometry. The number of cells was determined by a percentage of the number of CD34+ cells. RESULTS: We observed 71 patients (38 women, mean age 67 years [62, 74]). Forty six patients were included in group 1 (28 women, mean age 68 years [63;75], 25 patients (10 women, 66 years [55;72]) were included in group 2. We found that in patients with CVD and T2DM demonstrated higher amounts of CD34+OCN+ cells than CD34+VEGFR2+ cells. (29.7% [26.2;36.1] and 11.8% [9.57;17.2], p<0.001). In the 1st group observed higher amounts of CD34+OCN+ cells, than in the 2d group (29.7 [26.2;36.1] и 25.6 [17.3;30.7] соответственно; p=0.035). Positive correlation was established between amount of CD34+OCN+ cells and atherogenic lipid fraction, LDL (r=0.4; р=0.032) and total cholesterol (r=0.27; р=0.05) in patients of group 1.While SYNTAX score tertiles and amount of CD34+OCN+ cells (r = 0.50, p=0.021) were the positive correlation. Between coronary artery calcium score and amount of CD34+OCN+ cells (r = 0.49, p=0.034) was the positive correlation. CONCLUSIONS: Acquired results may indicate the active role of CD34+OCN+ endothelial progenitor cells in atherosclerosis and vascular calcification in patients with T2DM

Diabetes mellitus type 2 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidelines.&nbsp

Diabetes mellitus type 1 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidlines

Standards of specialized diabetes care. Edited by Dedov I.I., Shestakova M.V., Mayorov A.Yu. 10th edition

Dear Colleagues!We are glad to present the 10th Edition (revised) of the Standards of Specialized Diabetes Care. These evidence-based guidelines were designed to standardize and facilitate diabetes care in all regions of the Russian Federation.The Standards are updated on the regular basis to incorporate new data and relevant recommendations from national and international clinical societies, including World Health Organization Guidelines (WHO, 2011, 2013), International Diabetes Federation (IDF, 2011, 2012, 2013), European Association for the Study of Diabetes (EASD 2018, 2019), American Diabetes Association (ADA, 2018, 2019, 2021), American Association of Clinical Endocrinologists (AACE, 2020, 2021), International Society for Pediatric and Adolescent Diabetes (ISPAD, 2018) and Russian Association of Endocrinologists (RAE, 2019). Current edition of the “Standards” also integrates results of completed randomized clinical trials (ADVANCE, ACCORD, VADT, UKPDS, SAVOR, TECOS, LEADER, EXAMINE, ELIXA, SUSTAIN, DEVOTE, EMPA-REG OUTCOME, CANVAS, DECLARE, CARMELINA, REWIND, CREDENCE, CAROLINA, DAPA-CKD, DAPA-HF, EMPEROR-Reduced trial, VERIFY, VERTIS CV, PIONEER, etc.), as well as findings from the national studies of diabetes mellitus (DM), conducted in close partnership with a number of Russian hospitals.Latest data indicates that prevalence of DM in the world increased during the last decade more than two-fold, reaching some 537 million patients by the end of 2021. According to the current estimation by the International Diabetes Federation, 643 million patients will be suffering from DM by 2030 and 784 million by 2045.Like many other countries, Russian Federation experiences a sharp rise in the prevalence of DM. According to Russian Federal Diabetes Register, there are at least 4 871 863 patients with DM in this country on 01.01.2021 (3,34% of population) with 92,3% (4 498 826)–Type 2 DM, 5,6% (271 468)–Type 1 DM and 2,1% (101 569)–other types of DM, including 9 729 women with gestational DM. However, these results underestimates real quantity of patients, because they consider only registered cases. Results of Russian epidemiological study (NATION) confirmed that only 54% of Type 2 DM are diagnosed. So real number of patients with DM in Russia is 10 million patients (about 7% of population). This is a great long-term problem, because a lot of patients are not diagnosed, so they don’t receive any treatment and have high risk of vascular complications.Severe consequences of the global pandemic of DM include its vascular complications: nephropathy, retinopathy, coronary, cerebral and peripheral vascular disease. These conditions are responsible for the majority of cases of diabetes-related disability and death.In сurrent edition of the “Standards”:New goals of glycemic control for continuous glucose monitoring (time in range, below range and above range, glucose variability) are given.It also features updated guidelines on stratification of treatment in newly diagnosed Type 2 diabetes.In the recommendations for the personalization of the choice of antidiabetic agents, it is taken into account that in certain clinical situations (the presence of atherosclerotic cardiovascular diseases and their risk factors, chronic heart failure, chronic kidney disease, obesity, the risk of hypoglycemia) certain classes of hypoglycemic agents (or individual drugs) have proven advantages.Indications for the use of antidiabetic agents in chronic kidney disease are expanded.Information about insulin pump therapy is added.Recommendations on vaccination are added.An algorithm for replacing some insulin preparations with others is given.This text represents a consensus by the absolute majority of national experts, achieved through a number of fruitful discussions held at national meetings and forums. These guidelines are intended for endocrinologists, primary care physicians, pediatricians and other medical professionals involved in the treatment of DM.Compared with previous edition of the Standards of Specialized Diabetes Care edited by Dedov I.I., Shestakova M.V., ­Mayorov A.Yu., 10th edition, Moscow, 2021 (signed for printing on 10.09.2021) a number of changes have been made.On behalf of the Working Grou

Microstructure and properties of a nanostructured W-31 wt% Cu composite produced by magnetic pulse compaction of bimetallic nanoparticles

Nanostructured W-31wt.%Cu composite was for the first time produced via magnetic pulse compaction from bimetallic particles obtained using electric explosion of intertwisted copper/tungsten wires in argon and then characterized for microstructures, mechanical strength and tribological behavior at high temperatures. Microstructure of the composite is characterized by recrystallized copper grains with mean grain size of 59 ± 3 nm and unreacted spherical tungsten particles. The composite density was in the range 93–99%. Flexural and compression strengths were 560 ± 10 and 1035 ± 150 MPa, respectively. Tribological high temperature tests showed that this composite develops reduced wear starting from the testing at 250 ◦C. Such an adaptation mechanisms is related to generation of copper tungstate CuWO4 on the worn surfaces

ІМПЛЕМЕНТАЦІЯ ПРОТОКОЛІВ ПРИСКОРЕНОГО ПІСЛЯОПЕРАЦІЙНОГО ВІДНОВЛЕННЯ (ERAS) У ПАЦІЄНТІВ З КОЛОРЕКТАЛЬНИМ РАКОМ ТА СУПУТНІМ МЕТАБОЛІЧНИМ СИНДРОМОМ

Introduction. Implementation of enhanced recovery after surgery protocol (ERAS) is becoming more and more widespread due to their effectiveness and safety. At the same time, there is a rather limited number of studies focusing on the opportunities of ERAS in the context of its association with metabolic syndrome in patients with colorectal cancer. This study represents the results of our early experience implementing elements of the ERAS program in the perioperative management of patients with colorectal cancer associated with metabolic syndrome. The aim. To conduct a comparative analysis and evaluate the results of surgical treatment using the enhanced recovery after surgery protocol in patients with colorectal cancer and accompanying metabolic syndrome. Materials and methods. This study included 106 patients with colorectal cancer and accompanying metabolic syndrome, divided into two groups: the first group with the use of elements of the ERAS protocol in colorectal surgery from 2018 – 56 patients, and the second group in which the principles of ERAS were not used (50 patients). Results. In the first group, with a statistically significant difference, a less severe pain syndrome was observed according to VAS (p<0.001), as well as a lower necessity for prescribing opioid analgesics in the postoperative period. Activation of patients, restoration of enteral nutrition and peristalsis occurred earlier in first group (p<0.001). Mean hospital stay in the first group was 5.7±1.5 days, and in second group – 7.7±1.7 days (p<0.001). In the 2nd group, the percentage of complications such as: postoperative wound seroma, abdominal organ eventration, and anastomotic leaks in the 30-day postoperative period were higher than in the group with ERAS elements included. Conclusion. The implementation of elements from the Enhanced Recovery After Surgery (ERAS) protocol for the treatment of patients with colorectal cancer and concomitant metabolic syndrome is effective and safe. It is associated with a decreased duration of hospitalization, less postoperative pain, earlier return to enteral nutrition, quicker patient mobilization, and restoration of peristalsis. Additionally, it reduces the frequency of postoperative complications and readmission rates.Вступ: Імплементація протоколів прискореного післяопераційного відновлення (ERAS) набуває дедалі більшого поширення завдяки їх ефективності та безпечності використання. При цьому існує досить обмежена кількість праць, що акцентують увагу на темі можливостей застосування ERAS в контексті асоціації метаболічного синдрому у пацієнтів з колоректальним раком. В цьому дослідженні представлено результати нашого раннього досвіду впровадження елементів програми ERAS у периопераційному веденні пацієнтів з колоректальним раком асоційованого з метаболічним синдромом. Мета: Провести порівняльний аналіз та оцінити результати хірургічного лікування з використанням протоколів прискореного післяопераційного відновлення у пацієнтів з колоректальним раком та супутнім метаболічним синдромом. Матеріали та методи: В дослідження увійшло 106 пацієнтів з колоректальним раком та супутнім метаболічним синдромом, розділених на дві групи: 1 група із застосуванням елементів протоколу ERAS в колоректальній хірургії від 2018 року – 56 пацієнтів, та 2 група у веденні яких принципи ERAS не використовувались (50 пацієнтів). Результати: В 1 групі зі статистично достовірною різницею спостерігався менш виражений больовий синдром за ВАШ (р<0,001), та менша потреба у призначенні опіоїдних анальгетиків у післяопераційному періоді. Активізація пацієнтів, відновлення ентерального харчування та відновлення перистальтики відбувалася раніше в 1 групі (р<0,001). Середня тривалість перебування пацієнтів в стаціонарі у 1 групі становила 5,7±1,5 днів, а в 2 групі – 7,7±1,7 днів (р<0,001). У 2 групі дослідження в 30-денний термін післяопераційного періоду відсоток ускладнень у вигляді сероми післяопераційної рани, евентерації та неспроможності кишкових анастомозів був вищим, ніж у групі із застосуванням елементів ERAS. Висновки: Впровадження в хірургічну практику елементів протоколу прискореного післяопераційного відновлення (ERAS) у програму лікування пацієнтів з колоректальним раком та супутнім метаболічним синдромом є ефективним і безпечним, та асоційовано зі зниженням тривалості госпіталізації, меншим больовим синдромом в післяопераційному періоді, раннім відновленням ентерального харчування, ранньою активізацією пацієнтів та відновленням перистальтики, а також зменшенням частоти післяопераційних ускладнень та повторних хірургічних втручань

Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology, and Target Identification of Thiowurtzine, a Potent Inhibitor of the Opioid Receptors and the Ion Channels

[Image: see text] The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here, we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then, we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal, and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling, and molecular dynamics simulations to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action by essentially targeting the mu opioid receptor, the TRPA1 ion channel, and the Ca(v) voltage-gated calcium channel