Coronavirus Infection 2019 (COVID-19) and Autoimmunity.

The pandemic of coronavirus disease 2019, etiologically associated with the SARS-CoV-2 virus, has drawn the attention of the medical community to new clinical and fundamental problems in the immunopathology of human diseases. During a detailed analysis of the clinical manifestations and immunopathological disorders in COVID-19, it became apparent that SARS-CoV-2 infection is accompanied by the development of a wide range of extrapulmonary clinical and laboratory disorders, some of which are characteristic of immunoinflammatory rheumatic diseases and other human autoimmune and autoinflammatory diseases. All this taken together served as a theoretical justification for the repositioning of anti-inflammatory drugs in COVID-19, previously specifically designed for the treatment of immunoinflammatory rheumatic diseases. The prospects for studying the autoimmune mechanisms of COVID-19 and the possibility of anti-inflammatory therapy are discussed.

Interleukin-1 blockade with RPH-104 in patients with acute ST-elevation myocardial infarction: study design and rationale.

BACKGROUND: Myocardial injury of ST-segment elevation myocardial infarction (STEMI) initiates an intense inflammatory response that contributes to further damage and is a predictor of increased risk of death or heart failure (HF). Interleukin-1 (IL-1) is a key mediator of local and systemic inflammatory response to myocardial damage. We postulate that the use of the drug RPH-104, which selectively binds and inactivates both α and ß isoforms of IL-1 will lead to a decrease in the severity of the inflammatory response which will be reflected by decrease in the concentration of hsCRP, as well as the rate of fatal outcomes, frequency of new cases of HF, changes in levels of brain natriuretic peptide (BNP) and changes in structural and functional echocardiographic parameters. METHODS: This is a double blind, randomized, placebo-controlled study in which 102 patients with STEMI will receive a single administration of RPH-104 80 mg, RPH-104 160 mg or placebo (1:1:1). The primary endpoint will be hsCRP area under curve (AUC) from day 1 until day 14. Secondary endpoints will include hsCRP AUC from day 1 until day 28, rate of fatal outcomes, hospitalizations due to HF and other cardiac and non-cardiac reasons during 12-month follow-up period, frequency of new cases of HF, changes in levels of brain natriuretic peptide (BNP, NT-pro-BNP), changes in structural and functional echocardiographic parameters during 12-month follow-up period compared to baseline. The study started in October 2020 and is anticipated to end in 2Q 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04463251. Registered on July 9, 2020.

The role of Interleukin 6 inhibitors in therapy of severe COVID-19.

Cytokine storm syndrome (CSS) is a severe complication of inflammatory immune diseases or treatment of malignancies; it may also appear during the progression of COVID-19. CSS is caused by dysregulation of the synthesis of cytokines, including pro-inflammatory, regulatory, and anti-inflammatory cytokines and chemokines, leading to pathologic activation of innate and adaptive (Th1 and Th17 mediated) immunity. Interleukin-6 (IL-6) plays an important role in the pathogenesis of CSS. The significant role of IL-6 in pathogenesis of COVID-19 was confirmed in a range of studies, which showed that the plasma concentration of IL-6 was increased in patients with severe COVID-19. Currently, IL-6 inhibitor therapeutics are not yet approved for the treatment of COVID-19; however, these medicines, including tocilizumab (TCZ) are used off-label for the treatment of patients with severe COVID-19, including life-threatening conditions. The role of IL-6 in the pathogenesis of CSS during COVID-19 is important however, a number of related issues are not yet clear. These issues include the indications for treatment with IL-6 inhibitors, as well as the estimation of risk associated with the disease, outcomes, treatment options, and adverse drug reactions. The development of personalized immunomodulatory therapy, with respect to the role of cytokines in pathogenesis, requires the studies that aimed to find other relevant therapeutic targets for the treatment of CSS in patients with COVID-19. These therapeutic targets include inhibition of IL-1, IL-6, TNFα, GM-CSF, IFNγ, IL-17, IL-18, and also activation of the complement system. The challenge of CSS in patients with COVID-19 is identifying the correct scientific targets and developing clinical trials aimed to evaluate the pathogenesis and treat immune-mediated inflammatory diseases (IMIDs). Hopefully, the significant efforts of scientists and physicians across the globe will improve the prognosis in COVID-19 patients and provide useful information on IMIDs required to support the struggle for treating potential viral outbreaks, and treatment of well-known IMIDs.

[Efficacy and safety of narlaprevir/ritonavir and daclatasvir non interferon combination in population of Russian patients with chronic hepatitis C].

AIM: Evaluate efficacy and safety of a combination of direct - acting antivirals narlaprevir/ritonavir with daclatasvir in patients with viral hepatitis C. MATERIALS AND METHODS: The study enrolled adult patients with HCV genotype 1b infection without demonstrated NS5A resistance - associated substitutions Y93C/H/N/S and/or L31F/M/V/I. Patients were treated with narlaprevir 200 mg QD, ritonavir 100 mg QD and daclatasvir 60 mg QD. Treatment duration was 12 weeks. Proportion of patients achieving sustained virological response 12 weeks after treatment (SVR12) was the primary efficacy endpoint. RESULTS AND DISCUSSION: In total, 105 (75.0%) patients were treatment with the study combination. Patients' age varied from 21 to 69 years, the mean age being 43.2±10.9 years. There were slightly more women (55.2%), and 69 patients (65.7%) had comorbidities. SVR 12 was 89.5% (95% CI 82.0-94.7%). In 10 of 11 patients with treatment failures NS5A resistance - associated substitutions in residues 31 and/or 93 were found, as well as less clinically relevant substitutions L28M, P58S, R30Q, Q62K. Adverse events (AEs) were found in less than one half of patients (45 patients, or 42.9% in the safety population). Almost all recorded AEs were mild to moderate. CONCLUSION: Efficacy of treatment with a combination of narlaprevir/ritonavir and daclatasvir in treatment - naïve patients with HCV genotype 1b was close to 90%. This combination was found to be safe and well - tolerated.

Pharmacokinetics of the New Hepatitis C Virus NS3 Protease Inhibitor Narlaprevir following Single-Dose Use with or without Ritonavir in Patients with Liver Cirrhosis.

In this study we sought to evaluate narlaprevir (NVR) pharmacokinetics (PK) after a single dose with or without ritonavir (RTV) in cirrhotic versus healthy subjects. NVR at 200 mg was administered to 8 healthy and 8 cirrhotic subjects, and NVR at 100 mg with RTV at 100 mg was administered to 8 healthy and 8 cirrhotic subjects. PK analysis was performed. The geometric mean maximum concentration of a drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUC0-∞) were 563.1 ng/ml and 4,701.8 ng · h/ml in cirrhotic patients versus 364.8 ng/ml and 1,917.1 ng · h/ml in healthy volunteers, respectively. The geometric mean ratios of the PK parameters of cirrhotic subjects to healthy volunteers were 1.54-fold (90% confidence interval [CI] = 1.05 to 2.27) for Cmax and 2.45-fold (90% CI = 1.56 to 3.85) for AUC0-∞ The geometric mean Cmax and AUC0-∞ in cirrhotic and healthy subjects were similar: 1,225.7 ng/ml for Cmax and 15,213.1 ng · h/ml for AUC0-∞ in cirrhotic subjects and 1,178.9 ng/ml for Cmax and 14,257.2 ng · h/ml for AUC0-∞ in healthy volunteers. The corresponding geometric mean ratios were 1.04 (90% CI = 0.67 to 1.62) for Cmax and 1.07 (90% CI = 0.72 to 1.58) for AUC0-∞ Higher exposures in cirrhotic subjects were safe and well tolerated. We found that NVR exposures after a 200-mg single dose were higher in cirrhotic subjects than in healthy subjects and that a 100-mg single dose of NVR boosted with RTV at 100 mg resulted in no significant PK differences between cirrhotic and healthy subjects.

New sterically-hindered o-quinones annelated with metal-dithiolates: regiospecificity in oxidative addition reactions of a bifacial ligand to the Pd and Pt complexes.

An unusual reactivity of sterically hindered o-quinones with an annelated dithiete ring towards coordination at a dithiolene site has been discovered. New Pd and Pt dithiolate complexes have been synthesized. The reaction proceeds regioselectively, and the quinone site of the parent ligand is not affected even while using an excess of the metal complex. Both Pt and Pd complexes display a square planar surrounding for the metal ion and have very similar NMR, IR and UV/Vis spectra. Surprisingly, being coordinated at the dithiolene site to the metal, the ligand exhibits activity like an o-quinone, it could be reduced with different metals resulting in the corresponding o-semiquinonates which were confirmed by EPR spectroscopy. It was shown that an unpaired electron exhibits HFC with the phosphorus nuclei of phosphine ligands coordinated to the metal ions at the dithiolene site of the molecule.

[Suppression of vascular endothelium hyperpermeability by cell-permeating peptide inhibitors of myosin light chain kinase].

Novel peptides originating from the peptide inhibitor of myosin light chain kinase, L-PIK (Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys), have been studied for ability to attenuate the thrombin-induced hyperpermeability of endothelial cell monolayer in culture. Peptides [NalphaMeArg1]-Lys-Lys-Tyr-Lys-Tyr-Arg-(D)Arg8-Lys and H-Arg(NO2)Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH2 (designated PIK2 and PIK4, respectively) appeared to be the most effective inhibitors of endothelial cell monolayer hyperpermebility, and surpassed other known peptide inhibitors of myosin light chain kinase derived from original L-PIK. Our results validate PIK2 and PIK4 as the leading molecules for the development of novel drugs intended to counteract pathological hyperpermeability of vascular endothelium.

[On classification of medicinal diets].

The article touches upon the questions of classification of medicinal diets. The major attention is given the system of diets, made on the basis of "numer" diets first proposed by M. Pevzner. The system is based on the daily food sets for patients, who are grouped into profile units of hospitals on nosologic principle. In the author's opinion, this system allows to use in diets more widely and differently of foods, from the sets, which envisages big effectiviness of dietary nutrition at its high organoliptic quality.

[Principle stages of scientific activity of the clinics for dietary nutrition affiliated to the Institute of Nutrition within 1930-2005 years].

The article gives a brief account of activities of clinics for dietary nutrition affiliated to the Institute of Nutrition within 1930-2005 years.

[Clinical value of soluble tumor necrosis factor-alpha receptors in patients with systemic lupus erythematosus]. / Klinicheskoe znachenie rastvorimykh retseptorov faktora nekroza opukholi al'fa u bol'nykh sistemnoi krasnoi volchankoi.

The study was undertaken to examine the clinical value of serum levels of soluble receptors of tumor necrosis factor-alpha with a molecular mass of 55 kDa (rTNF-alpha-55R) in patients with systemic lupus erythematosus (SLE). The serum level of rTNF-alpha-55R was measured by enzyme immunoassay (a "Quantikine" set, R&D System, USA) in 73 patients with SLE and 22 donors. In the patients, the mean level of rTNF-alpha-55R was significantly higher than that in donors. Higher serum levels of rTNF-alpha-55R were noted in 43.8% of the patients with SLE. There was a correlation between the level of rTNF-alpha-55R and the progression of SLE (p < 0.05), the exacerbation (p < 0.05), and the clinical manifestations of the disease (cardiac valvular apparatus damage, active lupus nephritis). rTNF-alpha-55R are a marker of the progression and exacerbation of SLE and reflects that there is a prognostically poor factor, i.e. the involvement of the kidneys in a pathological process.

[Level of soluble tumor necrosis factor receptor type I in patients with systemic scleroderma]. / Uroven' rastvorimogo retseptora I tipa faktora nekroza opukholi u bol'nykh sistemnoi sklerodermiei.

AIM: To study content and clinical correlations of sTNF-RI in patients with systemic sclerosis (SS). MATERIAL AND METHODS: Thirty nine SS patients were examined with enzyme immunoassay for serum levels of sTNF-RI and soluble adhesion molecules (sSAM) sVSAM-1, sISAM-1 and sR-selectine using R&D System kits (USA). The control group consisted of 14 healthy subjects (donors). Content of sTNF-RI and sSAM was considered as elevated if it exceeded relevant mean values by 1SD. RESULTS: sTNF-RI content was significantly higher in the patients than in the controls (p = 0.0001) and was similar in patients with diffuse and limited forms of the disease. A rise in sTNF-RI correlated with a rise in pulmonary artery pressure. In patients with pulmonary hypertension or restrictive pulmonary affection sTNF-RI was higher than in patients free of pulmonary hypertension or impaired external respiration function. A marked correlation was found between sTNF-RI and sVSAM-1. Patients with high CRP had significantly higher sTNF-RI level than patients with normal CRP. CONCLUSION: SS is characterized by elevated content of sTNF-RI. This content may serve a diagnostic marker of the disease progression.

[System approach and system analysis in dietology]. / Sistemnyi podkhod i sistemnyi analiz v dietologii.

There is analysis of using of two variants of the auto-program of dietotherapy in the article: numeric system and basis system. They belong the same kind of building type, but are different in the type of functioning principle. Numeric system is built upon nosological principle taking into consideration the clinicopathogenetic features of disease. The basic diets built upon metabolic principle that a matter is adaptation of chemical content, alimentary and food value of diet for concrete mechanism of metabolic disturbance. At the same time metabolic conveyor is considered as system organization of the separate functional systems that are in the permanent dynamic and the interacting with each other. This organization is combined on the principle of auto regulation and set in correction and recovery of disturbed homeostasis as a whole. Selection of practical using of mentioned principles of diets is a right of the specialist-dieitian. Auto-program of diet building should help him in that and simplify the organization of dietotherapy.

[Clinical value of soluble adhesion molecules in systemic scleroderma]. / Klinicheskoe znachenie rastvorimykh molekul adgezii pri sistemnoi sklerodermii.

The aim of the trial was to study clinical significance of estimation of cell adhesion soluble molecules (CASM) in scleroderma systematica (SS). Quantitation of CASM VCAM-1, ICAM-1 and R-selectin was made with enzyme-immunoassay (R&D System kits, USA) in 38 patients with SS (11 with limited SS and 27 with diffuse SS). The levels of VCAM-1, ICAM-1 and R-selectin was elevated in 30 (79%), 17 (45%) and 20 (53%) patients, respectively. Mean values of VCAM-1 and ICAM-1 in patients were significantly higher than in healthy donors. R-selectin was also higher but insignificantly. A mean CASM level and a relative number of patients with elevated count of CASM in patients with diffuse and limited forms of SS did not differ. In 15 patients with active (progressive) course of the disease the level of VCAM-1 was significantly higher than in patients with chronic (non-progressive) course of SS while concentrations of ICAM-1 and R-selectine were almost the same. Thus, SS patients have elevated levels of CASM. CASM VCAM-1 concentration is the most sensitive marker of SS activity compared to other CASM.

[Soluble receptors of TNF-alpha with molecular mass 55 kDa in rheumatoid arthritis: clinical role]. / Rastvorimye retseptory FNOalfa s molekuliarnoi massoi 55 kDa pri revmatoidnom artrite: klinicheskoe znachenie.

UNLABELLED: To evaluate clinical implications of the serum level of soluable receptors of tumor necrosis factor alpha (TNFa) with molecular mass 55 kDa (rTNF-55R) in rheumatoid arthritis, serum levels of rTNF-55R and rTNF-75R were measured with the use of radioimmunoassay in 76 RA patients, 38 donors and in 25 RA patients, 10 donors, respectively. RESULTS: Elevated serum level of rTNF-55R was recorded in 55.3% RA patients. This level correlated with basic clinical and laboratory parameters of RA, the disease activity, values of DAS indices. It is concluded that a serum level of rTNF-55R adequately reflects clinico-laboratory activity of RA and its measurement can be used for assessment of RA activity and treatment efficiency.

[Soluble vascular adhesion-1 molecule in Sneddon syndrome: clinical and prognostic value]. / Rastvorimaia sosudistaia molekula adgezii-1 pri sindrome Sneddona: klinicheskoe i prognosticheskoe znachenie.

Clinical significance of a soluble vascular adhesion-1 molecule (pVCAM-1) in Sneddon's syndrome (SS) was studied in 48 SS patients by examination of serum pVCAM-1 level using enzyme immunoassay (R&D, USA). High serum concentration of pVCAM-1 registered in 62.6% of SS patients was associated with extracerebral thromboses, not with severity of cerebral vessel damage. Lethal outcomes for 2 years of follow-up occurred more frequently in patients with a high basal level of pVCAM-1 than in patients with normal level. Thus, development of the pathological process in SS is associated with elevated concentration of serum pVCAM-1 and may serve an additional laboratory indicator of developing extrabrain thrombotic disorders and marker of unfavourable prognosis.

[Soluble adhesion molecules in antiphospholipid syndrome associated with systemic lupus erythematosus and in primary antiphospholipid syndrome]. / Rastvorimye molekuly adgezii pri antifosfolipidnom sindrome, sviazannom s sisemnoi krasnoi volchankoi, i pervichnom antifosfolipidnom sindrome.

AIM: To evaluate clinical implications of measurements of the level of soluble cell molecules of adhesion (sCMA) in systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS) and primary APS (PAPS). MATERIAL AND METHODS: Serum levels of sP-selectine, sE-selectine, sVCAM-1 were determined with enzyme immunoassay (R&D, USA) in 23 SLE with APS, 15 SLE patients free of APS and 19 patients with PAPS. RESULTS: Mean levels of sE-selectine and sVCAM-1 in SLE patients with APS, PAPS and SLE was higher than in donors. Elevated mean levels of sP-selectine were observed only in SLE patients free of APS. These patients also showed a correlation between sVCAM-1 level and the disease activity (p < 0.01). CONCLUSION: The development of immunopathological process in APS is associated with increased concentration of sCMA.

[Concept of balanced nutrition and it's significance in studying the mechanisms of the therapeutic effects of food]. / Kontseptsiia sbalansirovannogo pitaniia i ee znachenie v izuchenii mekhanizmov lechebnogo deistviia pishchi.

In the article the data of study of mechanism of remedial effect of food are presented. The main attention is given to the concept of the balanced nutrition as the basic theory of modern nutritionogy, including a diet treatment.

[Soluble receptors of TNF-alpha in rheumatoid arthritis]. / Rastvorimye retseptory faktora nekroza opukholi pri revmatoidnom artrite.

The serum level of soluble TNF-alpha receptors with molecular mass 55 kDa (sTNF-a55R) was measured by enzyme immunoassay with commercial kits in 30 patients with rheumatoid arthritis (RA) and 38 healthy donors. High sTNF-a55R serum levels were registered in 90% of RA patients. These levels correlated with RA activity by DAS. Thus, assay for sTNF-a55R can be used for assessing RA activity.

Cardiac troponin and beta-type myosin heavy chain concentrations in patients with polymyositis or dermatomyositis.

Cardiac troponin T (cTnT), cardiac troponin I (cTnI), myosin heavy chains (MHC), myoglobin, creatine kinase (CK), and creatine kinase isoenzyme MB (CKMB), were measured in blood samples from 39 polymyositis (PM) or dermatomyositis (DM) patients without clinical evidence for cardiac involvement to evaluate their clinical usefulness in this patient population. MHC, myoglobin, and CKMB were frequently elevated and correlated with each other and with disease severity. Undetectable cTnI in all but one patient indicated that MHC was released from skeletal muscle, thereby providing the first laboratory evidence of frequent slow-twitch muscle fibre-necrosis in patients with PM or DM. CKMB was elevated in 51%, cTnT in 41%, and cTnI in only 2.5% of patients. cTnI did not correlate with other markers or with disease severity scores. The close correlations found between cTnT and skeletal muscle damage markers and the relationship between cTnT with disease severity without clinical evidence for myocardial damage suggest a release of cTnT from skeletal muscle. The relationship of cTnT with disease severity indicates a possible role of the marker for risk stratification. However, the prognostic values of cardiac troponins and other muscle damage markers in PM/DM patients remain to be compared in prospective outcome trials.

Dissolution of uranium dioxide in supercritical fluid carbon dioxide.

Uranium dioxide can be dissolved in supercritical CO2 with a CO2-philic TBP-HNO3 complexant to form a highly soluble UO2(NO3)(2).2TBP complex; this new method of dissolving UO2 that requires no water or organic solvent may have important applications for reprocessing of spent nuclear fuels and for treatment of nuclear wastes.