It has been shown that the inhalation of gaseous NO (exogenous nitric oxide) leads to the formation of nitrosonium cations (NO+) in the circulating blood of humans and animals during the oxidation of NO, which can have a detrimental effect on pathogenic viruses and bacteria. When thiols enter the blood simultaneously with NO inhalation, they form S-nitrosothiols with NO+ and cause hypotensive effect in animals. The biological effect of endogenous NO, which is produced in cells and tissues with the participation of NO synthases in animals and humans, is mediated by the dinitrosyl iron complexes (DNIC) formed with thiol-containing ligands. As NO and NO+ donors, these complexes have a variety of regulatory and cytotoxic effects on the animal and human body. In particular, the NO+ released by DNIC was shown to suppress SARS-CoV-2 infection in Syrian hamsters.

The article consistently examines the discovery of the biophysical properties of nitric oxide (NO) and provides some scientific data on the metabolism of NO.
The aim was to consider NO as a biological marker in the diagnostic algorithm and its therapeutic use.
Conclusion. The experience accumulated to date indicates the effectiveness of NO in such areas as transplantology, cardiology, endocrinology, andrology, sports medicine, etc. The experience of using NO in patients with post-COVID syndrome and pulmonary embolism is reviewed. It is necessary to organize multicenter studies to assess the effectiveness of NO therapy more deeply and develop criteria for selecting its dosage and duration of treatment.

The aim of this review was to demonstrate the significant successes of domestic neonatology, thanks to which infant mortality rates have dropped unprecedentedly, mostly due to a decrease in early neonatal and overall neonatal mortality in the last 3 decades. The noted achievements are primarily due to the implementation of the National Project “Health”. Within this project, a large number of perinatal centers were commissioned and a multi-level system of providing care to pregnant women from high-risk groups was introduced, equipped with high-quality diagnostic and treatment equipment and life-saving drugs.
Conclusion. Over the past decades, significant successes have been noted by domestic manufacturers in the creation of high-tech medical equipment, consumables and medications used in neonatology, some of which are one-of-a-kind on the global arena.

Acute and chronic neonatal pulmonary hypertension accompany all critical syndromes in newborns, both congenital and acquired. Use of all selective vasodilators for newborns and premature infants is off-label in the Russian Federation.
The aim of the paper is to structure data on the pathogenesis of acute and chronic neonatal pulmonary hypertension in newborns and premature infants; to determine the pathogenetic and clinical aspects of the use of inhaled nitric oxide in neonatology; and to describe the experience of using a fundamentally new technology for generating nitrogen oxide from air with the Tianox apparatus.
Conclusion. Inhaled nitric oxide is a proven, high-quality rescue technology for acute and chronic neonatal pulmonary hypertension in newborns and preterm infants. Inhalantion of nitric oxide with the use of a nitric oxide generator is an affordable and the most thoroughly developed technique in this population.

To evaluate the effect of NO added to the oxygenator during CPB on the liver and kidneys in pigs.
Methods. The experiment was conducted on 10 pigs undergoing cardiac surgery using cardiopulmonary bypass (CPB). Animals of the experimental group (CPB-NO; n = 5) received NO with the gas mixture supplied to the oxygenator at 100 ppm. Animals of the control group (CPB-control; n = 5) did not receive NO via the oxygenator. The surgery lasted 4 hours and was followed by 12-hour postoperative monitoring. To assess the liver and kidney injury, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) were determined at baseline, at weaning from the CPB, 6 and 12 hours after weaning from the CPB. A pathomorphological study of the liver and kidneys was also performed.
Results. A long period of CPB deliberately used in our experiment caused liver injury. In the CPB-control group, an increase in the ALT concentration was found: 43 (34; 44) U/l at baseline to 82 (53; 99) U/l 12 hours after CPB, p < 0.05. AST concentration in the CPB-control group increased from 25 (17; 26) U/l at baseline to 269 (164; 376) U/l 12 hours after CPB (p < 0.05). We found no significant increase in ALT and AST concentrations in the CPB-NO group. There were no significant differences in ALT and AST concentrations between CPB-NO and CPB-control groups at all study time points. In the CPB-control group, an increase in the creatinine level was found from 131 (129; 133) μmol/l at baseline to 273 (241; 306) μmol/l 12 hours after CPB (p < 0.05). We found no significant increase in creatinine levels in the CPB-NO group. Creatinine levels in the CPB-NO group were significantly lower than in the CPB-control group 12 h after weaning from CPB: 183 (168; 196) vs 273 (241; 306) μmol/l (p < 0.008). We found no significant differences between the study groups by the NGAL level. Morphology revealed characteristic alterative changes in tissues, circulatory disorders, and inflammatory infiltration of varying degrees of severity, which in combination is a manifestation of the acute damaging effect of CPB. In the CPB-NO group, the severity of pathological changes, measured in points, was lower than in the CPB-control group, but no statistically significant differences were found.
Conclusion. NO added to the oxygenator gas mixture reduces liver and kidney injury during prolonged CPB. Further research is required.

The aim of the study was to evaluate the impact of various technologies for the use of gaseous nitric oxide on the state of the lungs and heart during heart valve surgery under cardiopulmonary bypass (CPB).
Methods. The study included 93 patients of both sexes. All patients underwent heart valve surgery and combined surgical interventions under CPB. The patients were divided into 4 groups. Group 1 (control, n = 30) used the standard protocol for anesthetic and perfusion management. Group 2 (n = 30) received inhalation of nitric oxide (20 ppm) within 3 days before surgery, as well as before and after CPB. Group 3 (n = 30) inhaled nitric oxide (40 ppm) throughout surgery with the medication delivered through inspiratory part of the ventilator and combined with perfusion of the pulmonary artery and reduced volume ventilation during CPB. Group 4 (n = 33) received nitric oxide (40 ppm) via oxygenator of the heart-lung machine. We assessed changes in the functional parameters of the lungs at different phases of surgery, performed a morphological examination of the lungs in the initial phase (before CPB), at the peak of ischemia, and after reperfusion. The state of the myocardium after surgery was assessed by troponin I (cTnI) activity at the beginning of the operation, after transfer to the ICU, at 12, 24 and 48 hours after the surgery. Myocardial damage index (MDI) was calculated according to the following formula: MDI = TnIlate / TnIearly. The clinical outcomes of the surgeries were evaluated.
Results. There were no statistically significant differences in the functional state of the lungs with various options for inhalation delivery and administration via the CPB circuit. The most intact indicators of the functional state of the lungs were seen in patients of Group 3 who received inhaled nitric oxide throughout surgery and combined mechanical ventilation with the addition of nitric oxide and perfusion of the pulmonary artery during CPB. Morphological examination of the lungs showed that inhalation of nitric oxide before CPB does not prevent the development of morphological disorders. Morphological changes found in Group 3 were the smallest. The supply of nitric oxide into the CPB circuit statistically significantly improved the restoration of pulmonary blood flow during reperfusion. The cTnI level statistically significantly increased in all groups of patients, however, it was statistically significantly lower in Groups 2, 3, and 4 compared with Group 1 at the end of surgery, in Groups 3 and 4 compared with Groups 1 and 2 after 12 and 24 hours, and in Group 3 after 48 hours. The most favorable changes in the MDI were seen in Group 3; statistically significantly lower MDI was registered 12 and 48 hours after surgery in this group compared with Groups 1, 2, and 4. A lower complication rate, a shorter duration of ventilation and stay in the ICU were observed in Groups 3 and 4.
Conclusion. Nitric oxide has a protective effect on the lungs and heart when used during anesthesia and cardiopulmonary bypass in heart valve surgery. It preserves the lung function and morphology and statistically significantly reduces cTnI level and myocardial damage index in the postoperative period. The extent of the protective effect depends on the nitric oxide exposure time and is most pronounced when nitric oxide is used throughout the surgery, including during CPB.

Cardiac surgery is associated with high risks of complications, and these risks increase when it comes to aortic surgery because of the technical complexity of the surgeries, the use of cardiopulmonary bypass (CPB) and “circulatory arrest” (CA) that leads to ischemia-reperfusion damage. Abdominal complications in cardiovascular surgery are not the most common complications but are associated with high mortality. Protecting the gastrointestinal (GI) organs from ischemia-reperfusion injury is still a serious problem. According to a study of the organoprotective properties of nitric oxide (NO), its effectiveness in the treatment of diseases of the cardiovascular system, lungs, and kidneys has been proven, and observational results have shown that patients who were administered NO were less prone to complications from the gastrointestinal tract.
The aim of the study was to evaluate the protective properties of NO for the intestines during simulated surgery under CPB and hypothermic CA. Methods. The study was conducted on sheep (n = 24). The animals were divided into 4 groups: the “CPB” group with the standard CPB protocol, the “CPB + NO” group with CPB and NO administration, the “CPB + CA” group with the standard CPB and CA protocol, and the group “CPB + CA + NO” with CPB and CA and NO administration. Instrumental and laboratory parameters were monitored at all stages of the experiment to assess the effectiveness and safety of CPB and CA simulation. In intestinal biopsy samples, the changes in the defecation rate, the concentration of a biochemical marker of intestinal ischemia (intestinal enterocyte fatty acid binding protein – i-FABP), and tissue concentrations of adenosine triphosphate (ATP) and lactate were assessed.
Results. A higher rate of defecation was established (p = 0.046) in the “CPB + NO” group after CPB compared to the “CPB” group. The concentration of i-FABP in the CPB + NO group after CPB was lower compared to that in the CPB group (p = 0.002), and it was lower in the “CPB + CA + NO” group compared to the “CPB + CA” group (p = 0.033). 1 hour after CPB, the tissue concentration of ATP in intestinal biopsies in the “CPB + NO” group was higher than in the CPB group (p = 0.005).
Conclusion. When modeling CPB and CA in the experiment, a positive effect of NO therapy on the intestine was noted: the functional state improved, the concentration of i-FABP decreased, and the concentration of ATP in intestinal biopsies increased.

Perioperative management of cardiac surgery leads to significant morphofunctional impairment of the lungs, cardiopulmonary bypass (CPB) being the principal contributor. The pathophysiological mechanisms associated with cardiopulmonary bypass include ischaemic-reperfusion injury, oxidative stress and systemic inflammation. Nitric oxide is able to limit the associated damage.
Aim of the study: to investigate the effect of nitric oxide supply on morphofunctional state of sheep lungs under simulated cardiopulmonary bypass. Methods. 12 sheep of Altai breed were divided into 2 equal groups. Classical techniques of pulmonary ventilation and cardiopulmonary bypass were simulated in the CPB group. The sheep of the CPB + NO group were supplied with 80 ppm nitric oxide (via respiratory circuit or extracorporeal circulation circuit) during mechanical ventilation and cardiopulmonary bypass. The gas supply started immediately after tracheal intubation and continued until the end of the experiment. In both groups, the cardiopulmonary bypass time was 90 min, after which the sheep were switched to spontaneous circulation and observed for 60 min. Subsequently, blood was sampled, and the animals were withdrawn from the experiment with subsequent collection of histologic specimens.
Results. Statistically significant intergroup differences in P / F-index level before the end of the experiment were found (p = 0.041). Nitric oxide supply was associated with decreased infiltrate density in the lung parenchyma (p = 0.006) and increased alveolar area (p < 0.001).
Conclusion. Supply of NO during modelling of cardiopulmonary bypass in experimental animals improves the morphological and functional state of the lungs by reducing inflammation, vascular changes and damage to the respiratory part of the lungs (structure of alveoli, alveolar passages and pneumocytes). Clinical studies are needed to investigate pulmonoprotective properties of NO in humans.

Nitric oxide (NO), a reactive nitrogen species, is a molecule of high physiological and pathological importance. Physiological mechanisms mediated by NO mainly include angiogenesis, growth, puberty, and senescence. NO has vital roles in normal reproduction, including steroidogenesis, gametogenesis, and the regulation of germ-cell apoptosis. In males, NO is a key player in steroidogenesis, erectile functions, sperm capacitation, and acrosome reaction. Moreover, NO is also a regulator of Sertoli cell-germ cell interaction and maintenance of the blood-testis barrier. In pathological conditions such as infections, increased nitric oxide synthase activities stimulate the excessive synthesis of NO which acts as a proinflammatory mediator inducing oxidative stress, detrimental to reproductive functions in males. Excessive NO synthesis disrupts gonadal functions and induces germ cell apoptosis and oxidative damage to the germ cells. This review elucidates how the differences in NO expression levels account for its beneficial and adverse impacts on male fertility.

Nitric oxide (NO) plays a significant role in the development of tumor processes, offering potential therapeutic options and serving as a target for influencing tumor growth.
The aim of this review was to study the role of nitric oxide in the development of cancer, identify key signaling pathways in which NO is involved, mechanisms and methods of nitric oxide delivery in tumor therapy, as well as its impact as a therapeutic target.
Results. Different isoforms of nitric oxide synthase (NOS) regulate nervous functions, vascular functions, and inflammatory processes. Elevated levels of induced nitric oxide synthase (iNOS) are associated with tumor development, and its inhibitors can suppress tumor growth. Research indicates that the effect of NO on tumors depends on the concentration and duration of exposure. Low concentrations stimulate the growth and metastases of tumor cells, whereas high concentrations exert an anti-tumor effect, enhancing therapy sensitivity. NO also impacts angiogenesis, metastases, and immune response. The application of NO in tumor treatment is challenging due to its short half-life and rapid diffusion. Developing various NO delivery methods, like gaseous NO and nanoparticles, holds promise for improving the effectiveness and control of distribution. Silicon and goldbased nanoparticles demonstrate potential for NO delivery, enhancing immune response and showing synergism with chemotherapy. Inhibitors of iNOS suppress tumor growth. Their combined usage with other agents, such as chemotherapy, displays promising results in tumor growth control. Further research and clinical trials are essential to determine optimal conditions for employing NO and iNOS inhibitors in cancer treatment. Overall, studying the influence of NO and iNOS on tumor processes represents a crucial area for developing novel treatment methods, underscoring the therapeutic potential of these molecules as agents and targets to enhance oncological outcomes.
Conclusion. Nitric oxide and various isoforms of NOS, in particular induced NOS, play a vital role in the regulation of oncological processes. Research confirms the promise of nitric oxide in oncology as a potential antitumor agent. The use of iNOS inhibitors shows potential in controlling tumor growth, especially when combined with other drugs such as chemotherapy. In addition, the development of NO delivery methods is an area of active research that may improve the efficiency of NO distribution in the body and tumor.

Nitric oxide (NO) is a biologically active molecule approved for the treatment of persistent pulmonary hypertension in newborns in the USA, Japan, and most European countries in 1999 – 2008. Inhaled NO is currently used to treat a spectrum of cardiopulmonary disorders, including pulmonary hypertension in children and adults. A commercially available NO delivery system uses pressurized cylinders as a source of NO. Current cylinder-based delivery systems are widely used around the world, but they are bulky, expensive and dependent on a reliable supply chain. The aim of the work was to present an original domestic generator for NO inhalation therapy. Over the past few years, to overcome the limitations of the balloon technology, specialists from the Federal State Unitary Enterprise “Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics” have developed a plasma-chemical NO generator that produces NO from ambient air using a nonequilibrium spark discharge plasma. In this case, a diffuse discharge mode is implemented, which ensures the most efficient synthesis of NO with the participation of excited nitrogen molecules (N²⁺) according to a chain mechanism similar to the Zeldovich – Semenov chain reaction. The result is a high-quality NO-containing gas mixture that does not contain toxic by-products (electrode material, ozone, etc.) usually formed in the known systems of this type. Conclusion. Based on the developed generator, the Federal State Unitary Enterprise “Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics” designed and created the world’s first commercially available device for inhalation therapy, “Tianox”. The device was approved for circulation on the territory of the Russian Federation by order of the Federal Service for Surveillance in Healthcare (2020) based on the results of technical and clinical tests. Serial production of “Tianox” meets the requirements of ISO 13485-2016 and GOST ISO 13485-2017.

For the first time, the effectiveness and safety of high doses of inhaled nitric oxide (iNO) in patients with community-acquired pneumonia (CAP) has been demonstrated.
The aim of the study was to examine the effectiveness and safety of adding iNO to standard treatment for patients with CAP.
Methods. A pilot, single-center, prospective, randomized, open-label clinical trial was conducted, which included patients (n = 120) hospitalized with CAP. Randomization was carried out using the blind envelope method. Patients in the main group (n = 60) received iNO through nasal cannulas using the Tianox iNO therapy device (AIT-NO-Ol according to TU 32.50. 21-001-07623615-2017) in addition to the therapy according to the standard of care at the study center. Inhalations were carried out with high doses of NO, namely 200 ppm for 15 minutes 3 times a day, regardless of food intake. Patients in the control group (n = 60) received only the therapy recommended by the standard of care at the study center. Clinical and laboratory parameters were assessed and safety of the therapy was monitored during the study.
Results. No significant differences were identified between the main group and the control group in demographic, clinical, laboratory and instrumental data at baseline. Patients receiving iNO as an adjunct to standard therapy had a more significant improvement in clinical symptoms starting from the 3rd day and better oxygenation parameters on the 7th day of therapy. There was a more significant decrease in the level of C-reactive protein on the 5th and 7th days of therapy and a more significant decrease in the level of leukocytes on the 5th day in the main group. The duration of hospitalization in the main group was significantly shorter than that in the control group. NO inhalation was not associated with any side effects and was well tolerated.
Conclusion. The use of high doses of NO has a positive effect on the clinical status, markers of inflammation, reduces the length of hospitalization, and demonstrates good tolerability and safety in patients with CAP.

According to the literature, the risk of death in patients with chronic obstructive pulmonary disease (COPD) increases with both frequency and severity of the disease exacerbations. However, the clinical burden and healthcare resource utilization associated with severe COPD exacerbations in the Russian population have not been adequately studied.
The aim of this study was to assess the clinical burden of severe COPD in Russia by examining the relationship between frequency of severe exacerbations, clinical outcomes, and healthcare utilization among the Russian patients.
Methods. The EXACOS International Study on Exacerbations and Outcomes was an observational, cross-sectional study that collected retrospective data from medical records over a five-year period. The study population included a broad range of COPD patients monitored by pulmonologists. The purpose of the study was to assess the frequency of severe exacerbations that were defined as hospitalizations (with or without admission to an intensive care unit) or emergency department visits due to worsening of COPD symptoms.
Results. A total of 326 patients with COPD were included (mean age: 64.8 years, 87.1% male). Most participants had moderate (137 (42.0%)) or severe COPD (135 (41.4%)), as well as comorbidities (275 (84.4%)). The most common comorbidities included hypertension, heart failure, and diabetes. During the study period, 120 (40.0%), 158 (48.5%), and 247 (75.8%) patients received courses of oral corticosteroids, injectable corticosteroids and antibiotics, respectively. 250 (76.7%) patients experienced at least one severe COPD exacerbation, with a total of 1,026 events; and 102 (31.3%) had more than 3 exacerbations. The annual number of exacerbations increased from 128 in 2019 to 294 in 2021 (p < 0.0001), and the proportion of patients with severe exacerbations also increased from 23.6% in 2009 to 54.7% in 2021.
Conclusion. The high clinical burden of severe COPD exacerbations among the Russian population indicates a significant need for further research into factors leading to these events, modification of these factors and optimization of therapy to prevent the exacerbations.

The study of the efficacy of biological therapy in patients with severe bronchial asthma in real world settings is a relevant task since observational research programs allow answering questions that fall out of focus with a strict selection of patients in RCT. Multicenter studies are prioritized because they allow combining and systematizing additional previously undescribed data in a wider population.
The aim of the BEST study (Real World Evidence of Benralizumab in Eosinophilic Severe AsThma in Russia) was to confirm the clinical effectiveness of benralizumab regarding change of disease control and quality of life (QoL) level associated with respiratory status in patients with eosinophilic phenotype of uncontrolled severe asthma in real clinical practice in Russia.
Methods. An open-label non-randomised multicenter study was conducted involving 59 adult patients with severe eosinophilic asthma. Benralizumab was prescribed according to indications used in routine practice in addition to maintenance therapy. The duration of follow-up was 56 weeks. Disease control level was assessed using the Asthma Control Questionnaire-5 (ACQ-5), and QoL associated with respiratory status was assessed using the St. George’s Respiratory Questionnaire (SGRQ). Patients’ Global Impression of Change (PGIC) and Patients’ Global Impression of Severity (PGIS) were used for subjective assessments of the well-being of patients. The frequency of exacerbations, usage of systemic corticosteroids (SCS), and functional parameters were also evaluated.
Results. The use of benralizumab led to a clinically significant improvement in ACQ-5 and SGRQ scores, a significant decrease in the frequency of exacerbations and a significant increase in pre- and post-bronchodilation FEV1 and FVC. There was an improvement in the well-being of patients according to the PGIC and PGIS scales. The SCS dose did not change. The therapeutic effect of benralizumab occurred quickly and persisted throughout the whole study, demonstrating the most significant changes in effectiveness values by the 56th week of treatment.
Conclusion. The use of benralizumab in real clinical practice significantly improved the control of severe eosinophilic asthma and QoL of patients and was associated with a favorable safety profile.

Inhaled nitric oxide (iNO) is being considered as a potential therapeutic intervention for COVID-19 and post-COVID syndrome due to its various mechanisms such as vasodilation, antiviral activity, antithrombotic and anti-inflammatory effects. There is currently a lack of information on patient selection criteria, optimal dosing, duration and timing of administration, and methods of administration. These factors are of substantial importance for the efficacy of iNO therapy.
Aim. To discuss the physiological basis of using inhaled nitric oxide for treating patients with COVID-19 and post- COVID syndrome, analyze the research findings, and present the achievements in nitric oxide synthesis technology in medicine.
Conclusion. The early initiation and use of high-dose iNO appears to be an effective and safe treatment strategy for patients with COVID-19, as it targets the basic pathological mechanisms of the disease. iNO may also be a promising therapeutic option for patients with post-COVID syndrome. However, the optimal dosing regimen, continuous or intermittent, warrants further investigation. Recent advances in nitric oxide synthesis technology are of great significance for the broad practical application of iNO therapy.