[New opportunities for preventive anti-inflammatory therapy in the management of patients with moderate and severe COVID-19].

The specific feature of new coronavirus infection (COVID-19) is high risk of hyperinflammatory response or cytokine storm development, which underly the pathogenesis of several life-threatening conditions and determine the disease outcomes. Pathophysiological features of COVID-19 justify the search of effective drugs capable to control the hyperinflammatory response. AIM: To evaluate the efficacy and safety of Aterixen (1-[2-(1-Мethylimidazol-4-yl)-ethyl]perhydroazin-2,6-dion) for achieving clinical improvement in adult patients hospitalized with moderate and severe COVID-19. MATERIALS AND METHODS: Multicenter, adaptive, randomized, double-blind, placebo-controlled, phase III study to evaluate the efficacy and safety of Aterixen , tablets, 100 mg, in patients with COVID-19. The study analysis included 116 patients who, by randomization, were divided into 2 groups: 57 patients were included in the Aterixen drug group and 59 patients were in the placebo group. RESULTS AND CONCLUSION: Obtained results have shown high efficacy and statistically significant superiority of Aterixen over placebo. Thus, it allows us to consider it as viable medication for COVID-19 pathogenetic therapy.

[BCG, muramylpeptides, trained immunity (part II): a low molecular weight alternative to multicomponent bacterial immunostimulants for prevention of respiratory infections during a pandemic].

During a pandemic, nonspecific immunoprophylaxis of SARS-CoV-2 infection and other acute respiratory infections (ARI), which can worsen the course of COVID-19, is increasingly in demand in addition to specific immunization. BCG vaccine appears to be one of the candidate immunostimulants in this regard. At the same time, other microbe-derived preparations capable of inducing a state of trained immunity deserve attention. BCG and other bacterial immunostimulatory agents containing a large number of biologically active subunits have long been considered as objects of search for promising pharmacological substances. The review analyzes the linkages between BCG, mycobacterial adjuvants, bacterial lysates, trained immunity, muramylpeptides (MPs) and NOD2 receptors in light of the choice of a low molecular weight alternative to multicomponent bacterial immunostimulants for ARI prevention during the COVID-19 pandemic. The search for key molecules by which bacteria stimulate innate and adaptive immune responses proceeds in a spiral. On different loops of this spiral, MPs have repeatedly reproduced the nonspecific effects of multicomponent bacterial adjuvants, vaccines and immunostimulants. MPs and peptidoglycans containing MPs determine the adjuvant properties of the cell walls of mycobacteria and their peptide-glycolipid fraction (wax D). MPs were able to replace Mycobacterium tuberculosis in complete Freunds adjuvant. MPs determine the NOD2-dependent ability of BCG to induce trained immunity. Probably, MPs provide NOD2-mediated long-term prophylactic action of bacterial lysates. All of the above has prompted revisiting the previously obtained evidence of the efficacy of glucosaminylmuramyl dipeptide (GMDP) as a NOD2 agonist in treatment/prevention of respiratory infections. We speculate here that MPs, in particular GMDP, at rational dosing regimens will be able to reproduce many aspects of the nonspecific effects of BCG and multicomponent bacterial immunostimulants in preventing ARI during the COVID-19 pandemic and in the post-pandemic period.

[BCG, muramylpeptides, trained immunity (part I): linkages in the light of the COVID-19 pandemic].

It has long been known that Bacillus CalmetteGurin (BCG) vaccine provides nonspecific protection against many non-mycobacterial infections, which has been discussed in the last decade through the prism of the concept of trained immunity. Within the framework of this concept, a persistent increase in resistance to various pathogens, which occurs after an infectious disease or exposure to certain microbial agents, is associated with epigenetic reprogramming of innate immune cells and their bone marrow progenitors. The COVID-19 pandemic has drawn attention of scientists and practitioners to BCG as an inducer of trained immunity. A number of epidemiological studies have suggested a negative association between the coverage of the population with BCG vaccination and the burden of SARS-CoV-2 infection. A series of independent clinical studies of the effectiveness of this vaccine in non-specific prevention of COVID-19 has been initiated in different countries. Recently, the key role of cytosolic NOD2 receptors in BCG-induced trained immunity has been proven. This actualizes the search for effective immunoactive preparations for prevention of respiratory infections in the pandemic among low molecular weight peptidoglycan fragments of the bacterial cell wall, muramylpeptides (MPs), which are known to be NOD2 agonists. The review highlights the proven and proposed linkages between BCG, MPs, NOD2 and trained immunity in the light of the COVID-19 pandemic. Analysis of the data presented indicates the prospects for preclinical and clinical studies of MPs as potential drugs for nonspecific prevention of SARS-CoV-2 infection and/or other respiratory infections in risk groups during the pandemic. First of all, attention should be paid to glucosaminylmuramyl dipeptide, approved for clinical use in Russia and a number of post-Soviet countries for the complex treatment and prevention of acute and recurrent respiratory infections.