Pharmaceutical composition comprising edaravone for use in reducing levels of il-6 and TNF-alpha inflammatory markers and reducing time to withdrawal of oxygen therapy in patients with infectious diseases

Abstract

The disclosure refers to use of pharmaceutical compositions comprising edaravone. The use of a pharmaceutical composition comprising edaravone in a patient with an infectious disease, wherein in the event of a condition resulted from systemic inflammatory response syndrome during the infectious disease, includes additional introduction of a pharmaceutical composition comprising edaravone as a drug to the drug therapy. The technical result achieved by the claimed disclosure resides in additional reduction in the levels of IL-6 and TNF-α inflammation markers, reducing the duration of therapy of an infectious disease, reducing the time to withdrawal of oxygen therapy implemented in the event of oxygen deficiency in a patient with an infectious disease accompanied by the condition resulted from systemic inflammatory response syndrome.

Description

[0001] Description USE OF A PHARMACEUTICAL COMPOSITION COMPRISING EDARAVONE TO REDUCE LEVELS OF IL-6 AND TNF-α INFLAMMATORY MARKERS AND REDUCE TIME TO WITHDRAWAL OF OXYGEN THERAPY IN PATIENTS WITH INFECTIOUS DISEASES Technical Field The disclosure relates to the field of medicine, namely, to the use of pharmaceutical compositions comprising edaravone, in particular, to reduce the levels of IL-6 and TNF-α inflammatory markers and to reduce the time to withdrawal of oxygen therapy that is implemented in the event of oxygen deficiency in a specific course of an infectious disease that is accompanied by a systemic inflammatory response syndrome. Background Art Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186, Radicut) is a powerful low molecular weight free radical scavenger developed by Mitsubishi Tanabe Pharma Corporation (Osaka, Japan). Free radicals, such as reactive oxygen species (ROS), are currently considered as potential targets for therapeutic intervention, as they play an important role in the pathogenesis of a variety of diseases (e.g., cardiovascular disease and stroke). This approach was confirmed by the data obtained in numerous clinical and experimental studies in which edaravone demonstrated neurovascular protective effects in ischemic strokes and inflammatory processes in the heart, blood vessels and brain. Edaravone has been widely used since April 2001 in Japan in patients with acute ischemic stroke. The US Food and Drug Administration (USFDA) has approved a pharmaceutical composition comprising edaravone for the treatment of adults with amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) in two dosage forms: RADICAVA ORS oral suspension and RADICAVA intravenous (IV) infusion. The mechanism of therapeutic action of edaravone is not fully understood, but its ability to scavenge free hydroxyl radicals and peroxynitrite radicals, that are largely associated with neuronal damage / death in cerebrovascular disorders, is generally and widely accepted. Additionally, edaravone exhibits a neuroprotective and antioxidant effect and delays the progression of a disease, limiting the degree of lipid peroxidation, which develops as a result of the formation of free radicals and damage of the cell membrane due to oxidative stress. In general, it can be noted that additional study of edaravone, pharmaceutical compositions comprising edaravone, as well as methods of their use, is necessary, since edaravone affects a large complex of biochemical reactions that take place in the human body. Thus, one of the topical directions in modern medicine requiring the invention of new methods of the use and control is the therapy of infectious diseases. Infectious diseases are disorders triggered by disease-causing pathogens, such as causative agents (microorganisms, in particular, viruses, various bacteria, protozoa, parasitic fungi, helminths), biological products of causative agents (exotoxins, endotoxins), or pathogenic proteins (prions). All disease-causing pathogens show resemblance in their ability to be transmitted from infected organisms to healthy organisms. Some infectious diseases have a propensity for mass spread, which can progress to a significant scale and simultaneously affect the lives of millions of people. Therefore, in the countries with developed medicine, the subject of human infectology is primarily the so-called infectious communicable diseases. The danger of the infectious diseases is determined by their characteristic features: ^ specific etiology, according to the influence of the disease-causing pathogen; ^ contagiousness, which, in some cases, can lead to spread on an epidemic or pandemic scale; ^ cyclical course of the disease; ^ complications arising in many cases. In infectious diseases, both specific complications, that are directly related to the effect of the etiological factor of the disease, and non-specific complications, that do not depend on the causative factor, can develop. Inflammatory processes, that accompany the course of most of the infectious diseases, make a significant contribution to the development of the complications. In the context of an infectious disease, inflammation is a protective reaction that prevents the spread of disease-causing pathogens throughout the body; sometimes the inflammatory process contributes to pathogen destruction. Inflammation is characterized by external symptoms and microstructural changes. External symptoms include pain, swelling, hyperemia, increase in local or systemic temperature, dynamic changes in the structure and function of the affected organ and / or tissue. Microstructural changes include exudative-vascular reaction, migration of white blood cells, fibroblasts and other cells, that participate in post-inflammatory recovery, to the area of inflammation. In infectious diseases, the so-called inflammatory markers are an important epizootological category. Levels of the inflammatory markers are an indicator of an infectious disease suitable for registration and correlation in any type of the course, from manifested to hidden. Assessment of the levels of the inflammatory markers, for example IL-6 and TNF-α, enables reliable monitoring of the dynamics of the infectious disease course. IL-6 (Interleukin-6, IL-6) is a pleiotropic protein with a wide range of functions, the level of which increases (up to 100 times) during acute inflammatory reactions, mechanical injuries, burns, infections, tumor processes, stress, and brain death. IL-6 stimulates the synthesis of C-reactive protein (CRP) and acute phase proteins. TNF-α (α-tumor necrosis factor, tumor necrosis factor, TNF, cachexin, cachectin) is an extracellular multifunctional pro-inflammatory protein synthesized mainly by monocytes and macrophages. It affects lipid metabolism, coagulation, resistance to insulin, functioning of the endothelium, stimulates the production of IL-1, IL-6, IL-8, interferon-gamma, activates white blood cells, and is one of the important factors of protection against intracellular parasites and viruses. TNF-α was first detected in the serum of mice injected with BCG vaccine and endotoxin. Serum from these mice had a cytotoxic and cytostatic effect on particular transformed cell lines, and also caused hemorrhagic necrosis and reduction of inoculated tumors in mice. TNF-α also activates the nuclear transcription factor NF-B. Excessive production of TNF-α causes hemodynamic disorders (reduces myocardial contractility, minute blood volume, diffusely increases capillary permeability) and has a cytotoxic effect on body cells. Both markers are used to monitor the dynamics of the infectious disease course, since a decrease in their levels reflects a positive course of a therapy. Inflammation can manifest itself in different degrees of severity; the pronounced inflammatory process is characterized by a certain number of characteristic clinical manifestations united under the term "systemic inflammatory response syndrome" (SIRS). According to the protocol established by the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM), systemic inflammatory response syndrome is diagnosed if a patient has at least two of the following four symptoms: ^ body temperature above 38 °C or below 36 °C; ^ heart rate above 90 per minute; ^ respiratory rate more than 20 / min or PaCO2 (partial pressure of carbon dioxide in the arterial blood) less than 32 mm Hg (4.3 kPa); ^ the number of white blood cells is more than 12x109 / L or less than 4x109 / L, or the presence of 10% or more of immature forms of cells. In turn, the systemic inflammatory response syndrome in infectious diseases can cause or be accompanied by a number of dangerous complications for the body, such as acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis. Acute respiratory distress syndrome (the accepted abbreviation ARDS) is a type of respiratory failure characterized by the rapid onset of an inflammatory process in the lungs, that causes the accumulation of fluid in the lungs and a decrease in the level of oxygen in the blood. In more than half of the cases, ARDS develops precisely as a result of a severe course of the infectious diseases, in particular, with mediated lung damage caused by the systemic inflammatory response syndrome. A decrease in the level of oxygen in the blood and the entry into the bloodstream of certain proteins (cytokines) produced by damaged lung cells and white blood cells, in turn, can lead to the development / intensification of inflammation and complications in other organs, as well as multiple organ failure. At this stage, the general condition of the body deteriorates very quickly, and multiple organ failure can be observed already a few days after the onset of ARDS. In ARDS, shortness of breath, usually, quick and shallow breath, spots or bluish tint (cyanosis) on the skin, symptoms of disorders of other organs, such as the heart and brain, may be observed and experienced. Patients are held in the intensive care unit because they may need artificial lung ventilation and / or oxygen therapy, as well as drug therapy, to eliminate the causes of respiratory failure. Hypercytokinemia (cytokine storm, cytokine cascade) is an acute and potentially fatal form of systemic inflammatory response syndrome that develops due to an overreaction of the body's immune system. The essence of this condition is the excessive and uncontrolled production of a large number of inflammatory mediators (cytokines and other chemical mediators) by immune cells in the inflammation area. This process leads to the destruction of cells in the inflammation area, with simultaneous spread of the inflammation to neighboring tissues; as it develops, the inflammation becomes systemic, affecting the entire body. Hypercytokinemia can develop, for example, during a severe course of a viral infectious disease, when the body's immune system, in response to the rapid spread of the virus, tries to stop this process "at any cost". As a result, an excessive inflammatory reaction simultaneously helps to eliminate the pathogen and harms the body itself. In hypercytokinemia, various types of drug therapy are implemented according to the patient's condition: immunosuppression along with measures to affect the infection or another factor that caused this disorder, intensive therapy in case of unstable hemodynamics, supportive therapy in case of malfunction of certain organs and correction of coagulopathy. Cytokine release syndrome is a form of systemic inflammatory response syndrome that can be triggered by a variety of factors, including infectious diseases. The process begins when a significant number of white blood cells are activated and these white blood cells release pro-inflammatory cytokines, which, in turn, activate even more white blood cells. Cytokine release syndrome develops when a certain number of white blood cells, including B lymphocytes, T lymphocytes, natural killer cells, macrophages, dendritic cells, and monocytes, become activated and release proinflammatory cytokines, the most prominent of which is interleukin-6 (IL-6). This occurs when the immune system fights against pathogens, since cytokines direct immune cells, such as T lymphocytes and macrophages, to the site of the infection. Cytokine release syndrome differs from hypercytokinemia in the duration of the inflammatory process development (in the case of cytokine release syndrome, it is a week or more) and the lower severity of the inflammatory process. In most patients, the cytokine release syndrome develops in a mild or moderate form and is accompanied by symptoms such as nausea, chills, fever, rash, headache, hypotension, shortness of breath. With a rapid increase in the number of cytokines and a sharp manifestation of symptoms, the cytokine release syndrome progresses into hypercytokinemia. Sepsis is a pathological process based on generalized inflammation that develops in response to an infection of various nature (bacterial, viral, fungal), which leads to acute organ dysfunction. Sepsis is characterized by development of an inflammatory process in an individual organ, and, in fact, is a form of systemic inflammatory response syndrome. Organ dysfunction is assessed using the SOFA (Sequential Organ Failure Assessment) scale. Sepsis develops when the primary source is associated with blood or lymphatic vessels. In this case, there is a potential for hematogenous dissemination of the infection and the formation of secondary septic areas (metastases), from which pathogens periodically enter the blood. Severe sepsis leads to multiple organ failure or dysfunction, such as acute respiratory failure, coagulation and other hematological / hemodynamic disorders, acute renal failure, cerebral coma, acute adrenal deficiency. The condition that develops in the event of serious hemodynamic changes and low blood pressure (arterial hypotension) during severe sepsis is called septic shock. With no immediate actions, sepsis leads to multiple organ failure and death. Among the particularly threatening infectious diseases that can be accompanied by the dangerous complications described above, are the coronavirus disease COVID- 19, influenza and Ebola fever. Coronavirus disease COVID-19 (COVID-19) is an infectious respiratory disease caused by the positive-sense single-stranded RNA virus SARS-CoV-2. The mechanism of the development of COVID-19 consists in the damage of the type II alveolar cells of the lungs (alveolocytes) by the SARS-CoV-2 virus resulted in release of inflammatory markers. With excessive synthesis of inflammatory markers, in particular IL-6 and TNF- α, hypercytokinemia caused by hyperactivation of the immune system may develop in the inflammation area, and the disease may progress to a critical stage. Elevated levels of IL-6 and TNF-α cause external manifestations of the disease with different degrees of severity of COVID-19, which have a negative impact on the quality of life, in particular, persistent fever and non-specific symptoms such as weight loss, pain in the joints and muscles, fatigue, headache. COVID-19 continues to be a cause of global public health concern, as well as an urgent focus for efforts to develop new means of controlling the spread of the virus and therapies for the disease. A list of the most important consequences related to COVID- 19 includes the following: - General impact on public health: COVID-19 causes a range of symptoms, from mild to severe, with possible fatalities. Complications such as pneumonia, acute respiratory distress syndrome, and multiple organ failure develop in severe forms of the disease. Certain populations, including the elderly, the chronically ill, and the immunocompromised populations, are at higher risk of developing severe form of the disease and complications even though many people experience an asymptomatic or mild form of COVID-19. - Rapid spread: COVID-19 is a contagious disease and spreads easily from human to human, mainly through airborne transmission. Such extreme contagiousness has led to a single outbreak developing into a global pandemic, with the virus spreading across countries and continents in a short period of time. The high transmissibility of the pathogen presents significant challenges in controlling viral spread in the absence of rigorous containment measures. - Overburdened health care facilities: a surge in the number of COVID-19 cases in a short period of time means that the region's resources would be insufficient to provide qualified medical care to all the people who need it. The influx of patients who, in particular, require hospitalization and intensive therapy leads to a shortage of hospital beds, drugs, medical equipment and personnel. As a result, the overall quality of medical care, both for patients with COVID-19 and for people with other diseases, decreases. - Long-term health effects: some people who has recovered from COVID-19 continue to experience negative effects that last for a long time, which is known as "long-term COVID" or "post-COVID-19 syndrome" (post-acute effects of SARS- CoV-2 - PASC). Symptoms can include constant fatigue, shortness of breath, brain fog, muscle weakness, organ damage and mental health problems. Long-term COVID significantly affects quality of life and also requires medical care and supportive therapy. - Economic and social consequences: the COVID-19 pandemic has had far- reaching consequences that go beyond the medical or public health sector. Quarantines, travel restrictions and business closures aimed at curbing the spread of the virus have led to job losses, reduced economic activity and financial hardship for individuals and companies. Social distancing measures and restrictions on gatherings disrupted the processes of social interaction, education and negatively affected the mental well-being of people, which led to increased isolation and increased cases of psychological stress. - Vulnerable populations: certain populations are at risk of lapsing into COVID-19. The issue affects the elderly, people with chronic diseases, weakened immunity, and people with limited access to health care resources. These populations are at higher risk of lapsing into severe disease, complications, and death due to COVID- 19, which highlights the need for their targeted protection and support. According to official statistics published daily on the Worldometer web resource (see https: / / www.worldometers.info / coronavirus / ), during the COVID-19 pandemic, as of 2023-08-24, more than 694 million people got ill, and more than 6.9 million of them died. The actual number is probably higher due to unreported and asymptomatic cases. Currently, evidence-based specific treatment for COVID-19 does not exist. The treatment depends on factors such as age, general health, availability of specific medical care and vaccination status. Currently, taking preventive measures such as vaccination, sticking to good hygiene, wearing masks, and following public health guidelines and recommendations are measures to reduce the risks and protect individuals and communities from the dangers of COVID-19. Influenza is an acute respiratory viral disease caused by influenza viruses, transmitted mainly by airborne way. At present, more than 2,000 variants of the influenza virus have been identified, differing in their antigenic spectrum. The influenza virus primarily affects the upper respiratory tract, as well as the bronchi, and in some cases, the lungs. Influenza is associated with high mortality during pandemics, epidemics, and sporadic outbreaks. The frequency of complications in the flu is relatively small, but they can pose a significant danger to the human's health. There are several main types of complications in the flu that include bacterial pneumonia, hemorrhagic pneumonia, formation of lung abscess, and acute respiratory distress syndrome. Being an infectious disease, influenza is accompanied by excessive production of IL-6 and TNF-α inflammatory markers, which in severe stages of the disease can lead to the development of a cytokine storm. Thus, studies have repeatedly shown a correlation between elevated levels of inflammatory markers and the degree of flu, in particular, high levels of IL-6 and TNF-α are observed in patients with moderate and severe flu. What is particularly dangerous in such a development is the fact that the activity of IL-6 and TNF- α in their excessive production can lead to the destruction of organs and tissues with the subsequent development of multiple organ failure and the death of the patient, as was observed during the pandemic of the Spanish, Asian and Hong Kong flu. According to data from the Public Health Center of the Ministry of Health of Ukraine, 3.9 million cases of influenza and SARS were registered in Ukraine during 2022 / 2023 epidemic season, wherein the incidence rate was 9,582.5 per 100,000 population. During the season, 9.6% of the population of Ukraine sought medical care for respiratory infections. The main driver of the epidemic process is the pediatric population, due to the high risk of infection in this age group: the proportion of children in the population of sick people in 2022 / 2023 epidemic season was on average 26.3%, the proportion of adults was about 5.9%. Thus, the fight against influenza remains an extremely urgent and important problem for public health. The danger of the disease resides in the following: - Seasonal outbreaks: influenza is seasonal, outbreaks occur every year, especially during autumn and winter months in regions with a temperate climate. At this time, significant morbidity and increased mortality, particularly among vulnerable populations such as the elderly, young children, pregnant women, and those with chronic medical conditions, is observed. During this period, children usually attend educational institutions, which further contributes to the spread of the disease, therefore, temporary quarantine restrictions are applied, is applicable. - Global impact: influenza affects people worldwide and represents a global health problem. The virus can spread rapidly and cause mass outbreaks of the disease, affecting the economy and the general functioning of society. Influenza poses a particular threat in densely populated areas and communities with limited medical resources to help people. - Health burden: influenza causes significant health damage, resulting in hospitalizations, doctor appointments, and work or school days-off. The flu can worsen chronic conditions such as asthma, diabetes and heart disease, and pose a risk of complications (pneumonia, bronchitis, ear and nose infections). - High contagiousness: influenza is highly contagious, and the virus mutates and changes its strains over time. This ability to change complicates the development of long-term immunity to influenza and requires the development of new vaccines every year. - Pandemic potential: influenza can develop into a pandemic, as demonstrated by historical outbreaks such as 1918 flu pandemic, commonly known as the Spanish Flu. Pandemics arise when a new strain of influenza virus, to which the population has practically no immunity, appears. These events can lead to significant number of diseases, deaths, and social disruptions on a global scale. A type of flu, informally known as bird flu, is caused by influenza A viruses that infect birds and can also infect humans. Bird flu is similar to other types of animal flu in that it is caused by a strain of the virus adapted to a specific host. The type that poses the greatest risk is highly pathogenic avian influenza (HPAI). Until the 1990s, HPAI caused high mortality in poultry, but infections were sporadic and effectively controlled. After the world poultry population increased significantly in the 1990s, avian influenza outbreaks became more common because of the high density and frequent movement of flocks due to intensive poultry farming. Between 1996 and 2008, there were at least 11 outbreaks of HPAI among poultry, with 4 of these outbreaks involving millions of birds. Human infection with avian influenza type A / H5N1 was first registered in 1997 in Hong Kong. Since 2003, more than 700 human cases of Asian HPAI H5N1 have been reported to the World Health Organization (WHO), mainly from 15 countries in Asia, Africa, the Pacific, Europe and the Middle East, with a total of more than 60 countries affected. In the period from the beginning of 2013 to the beginning of 2017, WHO registered 916 laboratory-confirmed cases of human infections with a different strain of bird flu, namely H7N9. On January 9, 2017 China's National Health and Family Planning Commission reported 106 cases of H7N9 to WHO that took place from late November to late December, including 35 deaths and 2 potential cases of human-to-human transmission, 80 of those 106 stated that they visited markets where live birds were. Public health measures such as annual vaccination campaigns, promotion of good respiratory hygiene, and maintenance of robust surveillance systems are currently taken to combat influenza. In addition, ongoing researches and new developments are vital to improving the effectiveness and availability of influenza vaccines and antiviral pharmaceutical compositions Overall, influenza control remains relevant to protect public health, prevent outbreaks, and mitigate the impact of this infectious respiratory disease. Ebola fever (the disease caused by Ebola virus, Ebola hemorrhagic fever) is an acute viral highly contagious, rare but extremely dangerous, disease. The infection is transmitted through direct or indirect contact with the blood, body fluids, or secretions (feces, urine, saliva, semen) of infected people, but only when they have symptoms. Ebola cannot be transmitted through the air. The gates for the infection are the mucous membranes of the respiratory tract and microtraumas of the skin. The disease is characterized by rapid generalization of the infectious process with the development of general intoxication, multiple organ failure, followed by the development of severe shock and death. The disease usually has a high mortality rate, with the last Ebola outbreak ranging from 55% to 60%. The exceptionally high fatality rate, combined with the virtual absence of approved antiviral therapy and vaccination, makes Ebola an extremely dangerous threat to humanity. The Ebola virus is an effective inducer of inflammatory markers, including IL-6 and TNF-α. The scientific data that have been accumulated to date confirm the ability of the pathogen to trigger an excessive and uncontrolled inflammatory reaction that becomes systemic, that is, to provoke the development of a cytokine storm, which ultimately leads to a fatal outcome in more than half of the cases of the infection. According to the report of the Centers for Disease Control and Prevention, the total number of cases exceeds 27,000, including more than 11,000 deaths. The disease is more common on the African continent, so far in the USA, only 4 people have been diagnosed with Ebola. Currently, there are several types of combination therapy for people suffering from Ebola, however, development of an Ebola vaccine and improvement of existing treatment regimens are complicated by the fact that the disease is caused by four different types of viruses and there are significant difficulties in obtaining current samples of the virus and their research. The following use of pharmaceutical compositions in a patient with an infectious disease are known. There is a known use of pharmaceutical compositions comprising antibiotics or antiviral active agents in a patient with an infectious disease, in which either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non-drug supportive therapy is implemented (see https: / / www.dovidnyk.org / dir / 27 / 155 / 1700.html). According to the known use, a patient, during the course of an infectious disease, is exposed to the following affects provided by the drug therapy (pharmacotherapy) within the combination therapy: ^ influence upon the causative agent and its toxins (etiotropic stage); ^ influence upon certain elements of the infectious process and homeostasis of the macroorganism; ^ elimination and reduction of disease symptoms. The main disadvantage is that the known use does not consider one of the important features of the infectious diseases such as the systemic inflammatory response syndrome, and the influence upon the conditions resulted from development of systemic inflammatory response syndrome during an infectious disease. Thus, the disadvantage of the known use is its focus on etiotropic component of the therapy, i.e., on the destruction and removal of the causative agent and the products of its vital activity from the body, and ignoring the dangerous phenomena in the pathogenesis of the infectious diseases such as conditions resulted from systemic inflammatory response syndrome during an infectious disease, such as uncontrolled release of inflammatory markers. Another disadvantage of the known use is the issue of resistance of the causative agents of various infectious diseases to pharmaceutical compositions comprising antibiotics / antiviral agents, which at today's stage of the development of medicine poses a tangible threat to the effectiveness of therapy and the patient's life. The mentioned disadvantage of the pharmaceutical compositions comprising antibiotics / antiviral agents is especially dangerous in case of rapid progression of an infectious disease and rapid development of immunological complications. In addition, the disadvantage of the known use is complicated dosing and complicated estimation of the optimal duration of the therapy, since long-term use of the pharmaceutical compositions comprising antibiotics / antiviral agents can lead to allergic and toxic reactions, development of candidiasis, intestinal dysbacteriosis and vitamin deficiency, and insufficient doses of the pharmaceutical compositions comprising antibiotics / antiviral agents can lead to habituation of the pathogen and development of resistance. Another disadvantage of the known use is the need for control and strict adherence to the rules established in the instructions when implementing the therapy aimed at the immunological status of the body, since in some cases development of complications such as anaphylactic shock, serum sickness, double anaphylactic reaction, is likely. There is also a known method of reduction of the levels of the markers in a condition developing as a result of systemic inflammatory response syndrome such as cytokine storm during an infectious disease (see https: / / www.techinsider.ru / science / 1582691-citokinovyi-shtorm-samoubiistvo-ili-borba / and https: / / volgograd.medsi.ru / spravochnik-zabolevaniy / tsitokinovyy-shtorm / ). It is known that in the case of cytokine storm, either drug therapy or combination therapy is implemented; a patient is held in the intensive care unit due to the possible need for artificial lung ventilation (ALV). Pharmaceutical compositions that target and completely stop cytokine storm are not known, therefore a combination of the pharmaceutical compositions with different mechanisms of action is used in the drug therapy: ^ Monoclonal antibodies to interleukins and interleukin antagonists. ^ Anti-inflammatory agents (glucocorticoids). ^ Agents that reduce the immune response (immunoglobulins). In addition to ALV, other procedures such as plasmapheresis and hemosorption can also be implemented. Thus, when the specified medical therapy is implemented, a decrease in the level of various inflammatory markers is achieved (indicators of complete blood count and blood chemistry tests, C-reactive protein, cytokines, in sepsis - procalcitonin, presepsin). The disadvantage of the known method is that the pharmaceutical compositions used as a part of the drug therapy for cytokine storm have an inhibitory effect on the patient's immune system resulting in a high risk of developing a complication such as a secondary infection, most often bacterial one. To reduce the negative consequences of the drug therapy directed against cytokine storm, pharmaceutical compositions with antiviral, antibacterial, anticoagulation, antishock, and antihypertensive effects are added to the drug therapy. The known disadvantages of the use of antibacterial / antiviral compositions are listed above. Moreover, the simultaneous use of a large number of the pharmaceutical compositions for a long time increases the likelihood of the patient developing additional negative side effects, such as arterial hypertension and tissue hypoxia, ischemic lesions, tachycardia, bradycardia, arrhythmia, palpitations, increased contraction of the heart muscle (myocardium), acute heart failure, decreased systolic pressure, urinary retention, respiratory failure or breathing difficulty, shortness of breath, paresthesia of the lower extremities, allergic reactions, and others. There is also a known method of reducing the time to withdrawal of oxygen therapy implemented in the case of oxygen deficiency developed in a patient during infectious diseases, in the event of a condition resulted from systemic inflammatory response syndrome, that includes use of conservative oxygen therapy as a part of the combination therapy (see Young P et al; ICU-ROX Investigators the Australian Intensive Care Society Clinical Trials Group. “Conservative Oxygen Therapy for Mechanically Ventilated Adults With Sepsis: A Post hoc Analysis of Data From the Intensive Care Unit Randomized Trial Comparing two Approaches to Oxygen Therapy (ICU-ROX)." Intensive Care Med.2020 Jan;46(1):17-26.). The oxygen therapy is used in cases where the patient develops a condition that causes a low level of oxygen in the blood (e.g., ARDS, pneumonia). The issue is that there is currently no clear opinion on the optimal regimen of oxygen dosing to the patient due to conflicting data in clinical practice. Because oxygen is a chemically active substance that can also cause harm due to its pronounced oxidizing properties, the oxygen therapy is an important risk factor for a patient who is already in critical condition. Hyperoxia (oxygen poisoning) can lead to absorptive atelectasis, central nervous system intoxication, decreased cardiac output, and systemic vasoconstriction. To limit the negative impact of oxygen and, accordingly, reduce the risks of hyperoxia in a patient receiving the oxygen therapy, the authors of the article suggested using conservative oxygen therapy as opposed to the conventional one (also referred to as liberal oxygen therapy). The difference between conservative and conventional schemes of the oxygen therapy resides in the final goal, namely achieving the levels of the levels at which therapy can be ceased: ^ conservative – PaO2 (partial pressure of oxygen in the arterial blood) 55–70 mm Hg or SpO2 (blood oxygen saturation) 88–92%. ^ conventional - PaO290–105 mm Hg or SpO2greater than 96%. The authors of the article showed that patients having sepsis (a group of 149 patients were included in the study registered in the ICU-ROX database and were held in the intensive care unit with ALV based on the diagnosed infection), who received the conservative oxygen therapy, spent less time in the department of the intensive care compared with patients, who received the conventional oxygen therapy. The disadvantage of the proposed method is unsatisfactory final results. The primary endpoint was 90-day mortality. Key secondary outcomes were all- cause mortality, a number of days in intensive care unit and hospital, ventilator-free days, vasopressor-free days, and proportion of patients, who received renal replacement therapy in the intensive care unit. According to the obtained results, no statistically significant differences in the therapy group were observed in any of the indicated mortality endpoints. However, point estimates of the effect of the therapy on mortality rates were higher in patients who received the conservative oxygen therapy at each time point. There were also no statistically significant differences between treatment groups for other secondary endpoints. Point estimates of the therapy effect consistently favored conventional oxygen therapy (e.g., the number of ventilator-free days was greater in the conventional oxygen group). Thus, there is an unsatisfied need for new agents and uses in infectious diseases, in cases where a patient has complications due to systemic inflammatory response syndrome. Summary of Invention The objective of the disclosure is to develop new uses in infectious diseases, in cases where a patient develops complications due to systemic inflammatory response syndrome, that contribute to increasing the effectiveness of the therapy of an infectious disease, accelerating the recovery of a patient and improving quality of life. Another objective is to ensure a more effective reduction of the levels of the inflammatory markers in a patient with an infectious disease, in the event of a condition resulted from systemic inflammatory response syndrome. The third objective is to reduce the time of use / to withdrawal of oxygen therapy implemented in the case of oxygen deficiency in a patient with an infectious disease, in the event of a condition resulted from systemic inflammatory response syndrome, reduce the duration of use of specialized equipment and qualified medical personnel involvement in the implementation of the oxygen therapy, and reduce the burden on the health care system. In addition, the objective is to expand the range of treatment methods / aids for use in infectious diseases, in cases where a patient develops complications due to systemic inflammatory response syndrome. The first objective is achieved by a use of a pharmaceutical composition comprising edaravone in a patient with an infectious disease, wherein in the event of a condition resulted from systemic inflammatory response syndrome during the infectious disease, either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non-drug supportive therapy is implemented, and the drug therapy is implemented by administering at least one drug to the patient, wherein the drug therapy additionally includes use of a pharmaceutical composition comprising edaravone as a drug. According to one of the embodiments, the infectious disease is COVID-19, influenza, bird flu, Ebola fever. According to one of the embodiments, the condition resulted from the systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis. According to one of the embodiments, the pharmaceutical composition comprising edaravone is in a dosage form of a solution for injection or solution for infusion containing 0.3 - 1.5 mg of edaravone in 1 mL of the solution. According to one of the embodiments, the pharmaceutical composition comprising edaravone additionally comprises at least one excipient selected from cysteine hydrochloride, sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. According to one of the embodiments, the pharmaceutical composition comprising edaravone is administered to the patient once or twice a day in an amount to provide a daily dose of edaravone of 30-60 mg. The second objective is achieved by a method of reduction of levels of IL-6 and TNF-α inflammatory markers in a patient with an infectious disease in the event of a condition resulted from the systemic inflammatory response syndrome during the infectious disease, wherein either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non-drug supportive therapy is implemented, and drug therapy is implemented by administering at least one drug to the patient, wherein the drug therapy additionally includes use of a pharmaceutical composition comprising edaravone as a drug, and the drug therapy or combination therapy is implemented for at least 14 days, and the levels of the IL-6 and TNF-α inflammatory markers are further reduced by at least 10% more than the levels of the IL- 6 and TNF-α inflammatory markers achieved after implementing the drug therapy or combination therapy that does not include a pharmaceutical composition comprising edaravone. According to one of the embodiments, the infectious disease is COVID-19, influenza, bird flu, Ebola fever. According to one of the embodiments, the condition resulted from the systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis. According to one of the embodiments, the pharmaceutical composition comprising edaravone is in a dosage form of a solution for injection or solution for infusion containing 0.3 - 1.5 mg of edaravone in 1 mL of the solution. According to one of the embodiments, the pharmaceutical composition comprising edaravone additionally comprises at least one excipient selected from cysteine hydrochloride, sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. According to one of the embodiments, the pharmaceutical composition comprising edaravone is administered to the patient once or twice a day in an amount to provide a daily dose of edaravone of 30-60 mg. The third objective is achieved by a method of reducing a time to withdrawal of oxygen therapy that is implemented in oxygen deficiency in a patient with an infectious disease, in the event of a condition resulted from systemic inflammatory response syndrome during the infectious disease, wherein either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non- drug supportive therapy is implemented, and drug therapy is implemented by administering at least one drug to the patient, wherein the drug therapy additionally includes use of a pharmaceutical composition comprising edaravone as a drug. According to one of the embodiments, the infectious disease is COVID-19, influenza, bird flu, Ebola fever. According to one of the embodiments, the condition resulted from the systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis. According to one of the embodiments, the pharmaceutical composition comprising edaravone is in a dosage form of a solution for injection or solution infusion containing 0.3 - 1.5 mg of edaravone in 1 mL of the solution. According to one of the embodiments, the pharmaceutical composition comprising edaravone additionally comprises at least one excipient selected from cysteine hydrochloride, sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. According to one of the embodiments, the pharmaceutical composition comprising edaravone is administered to the patient once or twice a day in an amount to provide a daily dose of edaravone of 30-60 mg. In this disclosure, the term "drug therapy" means the treatment of a disease by administering to a patient a pharmaceutical composition in any form. In this disclosure, the term “combination therapy" means exposure of a patient to a combination of the drug therapy and methods of the non-drug therapy or methods of the non-drug supportive therapy. In this disclosure, the term "methods of the non-drug therapy" refers to exposure of a patient to any physico-chemical methods that provide a certain therapeutic effect after the cessation of exposure, without any use of pharmaceutical compositions. In this disclosure, the term "methods of the non-drug supportive therapy" refers to exposure of a patient to any physico-chemical methods that provide a certain therapeutic effect only during exposure, without any use of pharmaceutical compositions, e.g., oxygen support, in case of oxygen deficiency in patients with acute respiratory distress syndrome (sometimes referred to as oxygen therapy), consists in supplying a patient with oxygen to increase the oxygen saturation of the blood, in case of withdrawal of the oxygen supply to a patient, the oxygen saturation of the blood decreases after a short time. In this disclosure, the term "oxygen deficiency" refers to a decrease in the level of oxygen in human blood. Oxygen deficiency is determined through the blood oxygen saturation index (SpO2): the proportion of oxygen-saturated hemoglobin relative to the total hemoglobin in the blood. The level of blood oxygen saturation in a healthy human is 95% or more. The authors of this disclosure unexpectedly discovered that the pharmaceutical composition comprising edaravone can be effectively used to achieve the claimed objectives. Edaravone was chosen by the authors due to its features: it has a low molecular weight, is water-soluble and lipophilic, and can remain in the body in an effective concentration for up to 12 hours. Further, an important constituent of the edaravone effect is activation of natural antioxidant systems in tissues and positive effects on ferroptosis, another type of programmed cell death provoked by oxidative stress. The results of experimental studies have shown that the introduction of the pharmaceutical composition comprising edaravone to the known drug therapy or combination therapy prescribed for conditions resulted from systemic inflammatory response syndrome during infectious diseases allows achieving an unexpected result, namely, a decrease in the levels of the IL-6 and TNF-α inflammatory markers, reduce in the time required to alleviate the condition resulted from systemic inflammatory response syndrome, as well as reduce the time to withdrawal of the oxygen therapy in a patient in need of oxygen. Since an increase in the level of TNF-α is observed in severe infectious diseases, sepsis (primarily gram-negative) and septic shock, the actions directed on changes in its levels, as well as the levels of IL-6, were proposed by the authors of this disclosure to improve the conditions of patients in cases where complications develop due to systemic inflammatory response syndrome. Another indicator that was taken into account is the duration of providing the oxygen therapy to a patient with oxygen deficiency. This value directly depends on the patient's condition, i.e., how much the body needs additional oxygen supply. In addition, quicker withdrawal of the oxygen therapy has a positive effect on a patient, since excess oxygen is toxic to a patient who is already in a critical condition, e.g., is held in an intensive care unit. Although hypoxia is dangerous, research data suggest that exposure of the alveolar epithelium to an above-normal concentration of oxygen leads to the formation of free radicals. Thus, the introduction of the pharmaceutical composition comprising edaravone into the combination therapy of a patient provides an additional advantage in mitigating the side effects of the oxygen therapy, making it safer for a patient in a critical condition due to the free radical scavenging properties of edaravone. Another important resulting factor is alleviation of the issue of health care system overload, particularly regarding oxygen supplies and oxygen therapy systems, which was observed during the COVID-19 pandemic. The pharmaceutical composition for the use according to the claimed disclosure may comprise edaravone in different concentrations, preferably from 0.3 to 1.5 mL / mL. The recommended concentration of edaravone for administration to a human is 0.3 mg / mL. Accordingly, more concentrated pharmaceutical compositions comprising edaravone require additional dilution to a concentration of 0.3 mL / mL before administration of the pharmaceutical composition to a human. Dilution can be accomplished using solvents acceptable for administration to a human by intravenous infusion, for example, 0.9% sodium chloride solution. The pharmaceutical composition for use according to the claimed disclosure additionally comprises excipients acceptable for use as a part of the pharmaceutical compositions in the dosage form of a solution for infusion or the dosage form of a solution for injection, where the pharmaceutical composition is intended for administration to a human by intravenous infusion. In particular, the disclosure offers to include to the formulation of the pharmaceutical composition comprising edaravone, in the dosage form of s solution for injection or in the dosage form of s solution for infusion, the following acceptable excipients: sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid and water for injections. The pharmaceutical composition for use according to the claimed disclosure in the dosage form of a solution for infusion can additionally comprise cysteine hydrochloride as an anhydrous salt or as a hydrate. Brief Description of Drawings [Fig.1] represents a diagram of the median duration to withdrawal of the oxygen therapy in the studied groups. [Fig.2] represents a diagram of the median total score of the patient’s condition in the studied groups according to the modified WHO Scale for 28 days. [Fig.3] represents a diagram of graphic interpretation of IL-6 dynamics. [Fig.4] represents a diagram of graphic interpretation of TNF-α dynamics. Modes for Carrying out the Invention To determine the effectiveness of the use of the pharmaceutical composition comprising edaravone (hereinafter abbreviated as PC) along with combination therapy in a course of an infectious disease in a patient characterized by development of the condition resulted from systemic inflammatory response syndrome during the infectious disease, clinical studies were conducted on the infectious disease such as the coronavirus disease (COVID-19). A distinction of COVID-19 is that during the course of this disease, specific conditions often develop, namely conditions resulted from development of systemic inflammatory response syndrome during the infectious disease, in particular, these conditions are acute respiratory distress syndrome and hypercytokinemia. Example 1 Study on the use of the pharmaceutical composition comprising edaravone. Study design: Prospective, multicenter, double-blind, randomized, placebo- controlled, parallel-group clinical trial. 144 hospitalized male and female patients aged 18-67 years with diagnosed COVID-19 along with systemic inflammatory response syndrome took part in the study and were divided into two treatment groups: First group - Main group: size - 72 patients. Therapy - administration of the PC + combination therapy (therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). Second group - Placebo group: size - 72 patients. Therapy - administration of the placebo + combination therapy (therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). Inclusion criteria: 1. Diagnosed coronavirus disease (COVID-19). 2. Prescribed non-invasive oxygen therapy (nasal catheter, mask, non-invasive lung ventilation (NILV)). 3. At the time of screening, two or more of the following (systemic inflammatory response syndrome criteria): a. respiratory rate more than 20 breaths / min and / or partial pressure of carbon dioxide in arterial blood PaCO2 < 32 mm Hg with spontaneous breathing indoors; b. heart rate (HR) > 90 bpm; c. the number of white blood cells > 12.0 x 109 / L or < 4.5 x 109 / L; d. body temperature > 38 °C or < 36 °C. 4. At the time of screening, the patient had symptoms of pneumonia and / or respiratory failure (increased frequency of respiratory movements above the physiological norm, hemoptysis, blood oxygen saturation index (SpO2) when measured with a pulse oximeter ≤92%) with radiologically confirmed pneumonia. Exclusion criteria Patients who had at least one of the following criteria were not included in the study: - Hospitalization more than 24 hours before randomization. - Known hypersensitivity to the studied pharmaceutical composition and its components. - Pregnancy or breastfeeding. - Severe disturbance of consciousness (does not respond to external stimulation). - The need for artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO). - Detected severe heart failure. - Levels of alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT) more than three times higher than the upper limit of normal. - Glomerular filtration rate (GFR) less than 60 mL / min. - Suspected / confirmed bacterial infection. - Diagnosed severe chronic obstructive pulmonary disease, decompensated diabetes, cancer, active tuberculosis, presence of human immunodeficiency virus (HIV) regardless of immunological status, hepatitis regardless of etiology. - The patient received immunosuppressive drug therapy with antibodies for the past 5 months, including intravenous immunoglobulin. - At the time of screening, the patient was using oral corticosteroids in a dose that exceeds the prednisone dose of 10 mg (or its equivalent) per day. - At the time of the screening, the patient was using anti-rheumatic disease- modifying pharmaceutical compositions / immunosuppressive drug therapy, including IL-6 inhibitors, or Janus kinase inhibitors within the last 30 days. - The patient's history included inflammatory bowel disease, diverticulitis, peptic ulcer disease. - The patient had a history of alcohol or drug addiction. Scheme of the therapy prescription Patients of the main group received the PC along with combination therapy. Two versions of the PC were used: 1. in the dosage form of a solution for injection that comprised 1.5 mg of edaravone in 1 mL of the solution, and additionally comprised excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. Before administration, the PC content was dissolved in a solution of 100 mL of 0.9% sodium chloride to achieve a concentration of 0.3 mg / mL. 2. in the dosage form of a solution for infusion that comprised 0.3 mg of edaravone in 1 mL of the solution, and additionally comprised excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. The PC according to this version did not need to be dissolved and was ready for direct administration to the patient. The PC in both versions was administered twice a day, in the morning and in the evening, by intravenous infusion for 30 minutes. The daily dose of edaravone was 60 mg – twice per 30 mg. Patients with COVID-19 with systemic inflammatory response syndrome in the placebo group received placebo along with combination therapy. As a placebo, 0.9% sodium chloride solution, 10 mL, twice a day, in the morning and in the evening, was administered by intravenous infusion for 30 minutes. The use of the PC and placebo started as early as possible after hospitalization of the patients, the duration of the therapy was 14 days. Combination therapy The patients having participated in the study received the drug therapy or combination therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). The combination therapy included non-steroidal anti-inflammatory pharmaceutical compositions, low molecular weight heparins (LMWH), systemic corticosteroids, electrolyte solutions, and oxygen therapy. Study endpoints Primary endpoints: 1. Time to withdrawal of the oxygen therapy (nasal catheter, oxygen mask, NILV), confirmed by the following indicators during the observation period from 1 to 28 days: a. stable improvement of the general condition. b. decrease in respiratory rate - <24 / min. c. decrease in heart rate - <110 / min. d. compensated pH - >7.35 (H+ <45 nmol / L). e. SpO2 - >90% with FiO2 <4 L / min. 2. Time to improve of a patient's condition by 1 point according to the modified WHO Clinical Progression Scale. 3. The integral assessment of the patients’ condition was expressed in the sum of points received during the observation period (28 days), wherein the sum of the points of the assessed patients’ condition is determined with the modified WHO Clinical Progression Scale (hereinafter abbreviated as modified WHO Scale), where 10 points is a healthy patient, 0 points is death: 0 points: death; 1 point: ALV, partial pressure of oxygen in the blood or in the arterial blood (PaO2) / fraction of inspired oxygen (FiO2) < 150, vasopressors, dialysis or ECMO; 2 points: ALV, PaO2 / FiO2< 150 (PaO2 / FiO2< 200) or vasopressors; 3 points: intubation or ALV, PaO2 / FiO2 ≥ 150 or PaO2 / FiO2 ≥ 200; 4 points: hospitalization, oxygen therapy with NILV; 5 points: hospitalization, oxygen therapy with a mask or nasal catheter; 6 points: hospitalization, no oxygen therapy; 7 points: symptoms are present, external assistance is required; 8 points: symptoms are present, external assistance is not required; 9 points: no symptoms, viral RNA is detected during testing based on polymerase chain reaction (PCR testing); 10 points: no symptoms, viral RNA is not detected during testing based on polymerase chain reaction (PCR testing); Secondary endpoints: 1. Duration of hospitalization. 2. Proportion of the patients with no acute respiratory distress syndrome from the moment of hospitalization (up to the 28th day of the study). 3. Proportion of the patients with no need in artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO) - up to the 28th day of the study (onset / no onset). 4. Proportion of the patients with clinical recovery on day 6, 14, 28 (recovered / not recovered). 5. Proportion of the patients with axillary temperature up to 36.9 °C on day 6, 14. 6. Level of TNF-α on day 4, 6, 10, 14 compared with day 1. 7. Level of IL-6 on day 4, 6, 10, 14 compared with day 1. 8. Proportion of the patients with negative SARS-CoV-2 (qualitative) PCR test on day 6, 14, 20 (negative / positive). Examination methods used in the study: X-ray of chest. Laboratory studies: 1. Test for detection of the virus (SARS-CoV-2) in nasopharyngeal swab samples on day 6, 14, 20. 2. Complete blood count with white blood cell level, with mandatory estimation of red blood cell levels and platelet levels on day 1 and 10. 3. Blood chemistry test on day 1, 6, 14 that included the following categories: creatinine, blood urea nitrogen; ALAT; ASAT; bilirubin; total protein; lactate dehydrogenase (LDH); ferritin; procalcitonin; alkaline phosphatase; D-dimer; C- reactive protein; TNF-α; interleukins IL-1β; IL-6; IL-10. 4. Automatic calculation of glomerular filtration rate (GFR) on day 1, 6, 14. 5. Coagulogram on day 1, 6, 14; prothrombin index (PTI); international normalized ratio (INR); thrombin time (TH); fibrinogen; antithrombin III. 6. Complete urinalysis on day 1, 4, 6, 10, 14. 7. Assessment of the respiratory system indicators: respiratory rate (RR), SpO2, need in the oxygen therapy and method of such therapy, FiO2 if the oxygen therapy is used. 8. Arterial blood gas test, day 0, at the discretion of the researcher to verify the inclusion criterion: PaСO2. 9. Arterial blood gas test when deciding to withdraw the oxygen therapy: pH; SaO2(percentage of available binding sites on hemoglobin that are bound with oxygen in arterial blood); PaO2. 10. Calculation of the PaO2 / FiO2value when deciding to withdraw the oxygen therapy. Instrumental examinations: measurement of HR, blood pressure (BP), RR, blood oxygen saturation and body temperature parameters, electrocardiography (ECG). Stages of the study: screening, randomization, period of the therapy according to the protocol (up to 14 days) and period of the observation after the therapy - from 14 days (28 days in total). An outline of the study design is provided in Table 1. Table 1. Outline of study design Appointment Day of therapy Actions Assessment 0 0 Screening, randomization, complete examination, assessment of data 1 1 Collection of clinical Therapy Assessment of respiratory data, data of laboratory prescription: PC, system indicators, examinations placebo, assessment of the combination therapy possibility of oxygen therapy withdrawal (if applicable) 2, 3, 7, 8, 9, 2, 3, 7, Assessment of clinical Use of PC, Assessment of respiratory 11, 12, 13 8, 9, 11, data in dynamics, adjustment of system indicators, 12, 13 registration of combination assessment of the information about therapy, collection possibility of oxygen changes in the course of PC safety data therapy withdrawal (if and therapy applicable) 4, 6, 10, 14 4, 6, 10, Collection of clinical Use of PC, Assessment of respiratory 14 data, collection of adjustment of system indicators, laboratory examination combination assessment of the data therapy, collection possibility of oxygen of PC safety data, therapy withdrawal (if assessment of PC applicable) tolerability 15-19, 21-27 15-19, Collection of clinical data Collection of PC Assessment of respiratory 21-27 safety data system indicators, assessment of the possibility of oxygen therapy withdrawal (if applicable) 20 20 Collection of clinical Collection of PC Assessment of respiratory data, collection of safety data system indicators, laboratory examination assessment of the data possibility of oxygen therapy withdrawal (if applicable) 28 a phone 28 Information about the call, if a patient patient's health has already condition, the presence been of complaints, the discharged presence of undesirable phenomena The population during the treatment included 144 patients with positive PCR- confirmed COVID-19 (SARS-CoV-2) that received the prescribed therapy (72 in the main group and 72 in the placebo group). The relevant patients underwent a medical examination by a doctor in the medical department. Baseline characteristics such as age, gender, comorbidities, duration of the symptoms, and severity of the disease at admission were recorded at enrollment. All patients were diagnosed with COVID-19 using a baseline PCR nasopharyngeal swab. The groups were statistically homogeneous in terms of gender and age, as well as in comorbidities - information about the patients in the groups is provided in Table 2. Table 2. General characteristics of the patients participating in the study Total Main group Placebo Indicator (n = 144) (n = 72) group (n = 72) n (%) n (%) n (%) Gender Male 54 38 28 39 26 36 Female 90 63 44 61 46 64 Age (years), median ± standard deviation 48.57 ± 49.42 47.72 ± 15.45 (SD) 14.80 ±14.29 < 40 years 36 25 20 28 16 22 40–65 years 92 64 44 61 48 67 > 65 years 16 11 8 11 8 11 Comorbidities Diabetes 34 24 22 31 12 17 Hypertension 58 40 32 44 26 36 Dyslipidemia 50 35 32 44 18 25 Ischemic heart disease 4 3 2 3 2 3 Oncology 0 0 0 0 0 0 HIV 0 0 0 0 0 0 Chronic cerebrovascular diseases 4 3 0 0 2 6 Chronic liver diseases 0 0 0 0 0 0 Chronic kidney diseases 10 7 4 6 6 8 Miscellaneous 58 40 26 36 32 44 Results of the therapy Primary results Compared with the placebo group, participants in the PC group more often reported a shorter time to withdrawal of the oxygen therapy, earlier negative virological tests, a shorter time to improvement by 1 point according to the modified WHO Scale, normalization of the temperature, an enhanced sum of the points of the Integral assessment of patient's condition according to the modified WHO Scale within 28 days. 1. The analysis of the primary end point - time to withdrawal of the oxygen therapy (hours) with a follow-up period from 1 to 28 days confirms a predominant effectiveness of the therapy in the main group compared with the placebo group. There were statistically significant differences in the time to withdrawal of the oxygen therapy that in the main group was 18 to 358 hours (median - 72 hours) and in the placebo group - 21 to 388 hours (median - 99 hours). The difference in median time was 27 hours (95% confidence interval CI -45 to -12, p = 0.001) (Table 3, diagram in [Fig.1] ). Following abbreviations were used in the tables and text below: minimum – min, maximum – max. Table 3. Analysis of the effectiveness of the therapy according to the primary results Main group Placebo group (n = 72) (n = 72) Indicator 95% CI median 95% CI median р Recovery min max min max rate (95% CI) Assessment of the 3.02 4.96 4.0 4.5 6.1 5.4 <0.001 1.23 effectiveness based on the time (1.04–1.49) to improvement of the patient's condition by 1 point according to the modified WHO Scale Time to withdrawal of the 18 358 72 21 388 99 <0.001 Difference oxygen therapy (hours) during (95% CI) observation period 1 to 28 days –27 (–45 to –12) Integral assessment of the 146 234 223 135 202 186 <0.001 Difference patient's condition according to (95% CI) the modified WHO Scale for 28 days 37 (47–25) 2. According to the analysis results, it can be stated that there was a statistically significant difference between the groups in terms of the time to improvement of a patient's condition by 1 point according to the modified WHO Scale. The patients in the main group, according to the analysis results, had a shorter time to improvement of a patient's condition by 1 point according to the modified WHO Scale than the patients in the placebo group. The patients in the main group had a median improvement of the condition of 4 days (95% CI 3.02 to 4.96) compared with 5.4 days (95% CI 4.5 to 6.1) for the patients in the placebo group (recovery rate 1.23; 95% CI 1.04 to 1.49; P<0.001 according to logarithmic test) (Table 3). 3. An integral assessment of the patient’s condition was conducted according to the modified WHO Scale, measured daily and expressed in the sum of the points for the entire observation period, 28 days. Integral assessment of the patient’s condition according to the modified WHO Scale for 28 days showed a more significant improvement in the patient’s condition in the main group, 146 to 234 points, with a median of 223 points (95% CI 146 – 234), compared with the placebo group, 135 to 202 points, with a median of 186 points (95% CI 135 – 202); P < 0.04 (Table 3, diagram in [Fig.2] ). Secondary results 1. Based on the analysis results, there were statistically significant (p <0.01) differences between the groups according to the results of the PCR test on day 6 and 14. This is evidence of greater effectiveness of the therapy in the main group compared with the placebo group. The proportion of the patients with a negative PCR test on day 6 was 81.0% in the main group and 54% in the placebo group; on day 14, PCR was negative in 94% of the main group and 75% of the placebo group. A positive estimated treatment effect (>1) of 1.56 (95% CI 1.12 – 3.7) on day 6 and 1.24 (95% CI 1.08 – 2.2) on day 14, shows an advantage of use of the PC therapy + combination therapy compared with use of the combination therapy alone (Table 4). Table 4. Analysis of the estimated treatment effect based on the results of the PCR test on day 6, 14 and 20 of the study Indicator Results Main group Placebo group Estimated treatment Р - n % n % effect (95% CI) value PCR on day 1 positive 72 100 72 100 PCR on day 1 negative 0 0 0 0 PCR on day 6 positive 14 19 33 46 PCR on day 6 negative 58 81 39 54 1.56 (1.12-3.7) <0.01* PCR on day 14 positive 4 6 19 26 PCR on day 14 negative 68 94 54 75 1.24 (1.08-2.2) <0.04* PCR on day 20 positive 0 0 3 4 PCR on day 20 negative 72 100 69 96 1.09 (1.02-1.77) <0.19 Note. Significant difference in indicators (p<0.05) 2. According to the analysis results, a significant difference was noted between the groups in terms of the assessed compliance with the norm of the body temperature on day 6. There was a greater effectiveness in the main group compared with the placebo group, statistically significant (p <0.01). Thus, the proportion of the patients with a normal axillary body temperature on day 6 was 85% in the main group and 68.0% in the placebo group; the positive value of the estimated treatment effect is 1.39 (95% CI 1.11 – 2.5). A more pronounced effectiveness of edaravone therapy was additionally confirmed when assessing axillary temperature on day 14. The proportion of the patients with normal axillary body temperature was 100% in the main group and 89.0% in the placebo group; the positive value of the estimated treatment effect is 1.17 (95% CI 1.08 – 2.1) (Table 5). 3. When analyzing the effectiveness based on the proportion of the patients with clinical recovery on day 6, 14 and 28, the best indicators at all points were observed in the main group. The greatest results in the time to recovery were observed on day 14, when the proportion of the patients clinically recovered in the main group was 61.1% compared with 40.3% in the placebo group, the estimated treatment effect is 1.43 (95% CI 1.2 – 1.7, p<0.01) (Table 5). Table 5. Analysis of the estimated treatment effect based on the values of axillary temperature on day 6, 14 and proportion of the patients with clinical recovery on day 6, 14 of the study Indicator Results Main group Placebo Estimated Р - value group treatment effect n % n % (95% CI) Analysis of the effectiveness based on proportion of the patients with axillary temperature up to ° 36.9, day 6, 14 t ° on day 6 normal 61 85 49 68 1.39 (1.11-2.5) <0.01* t ° on day 6 increased 11 15 23 32 t ° on day 14 normal 72 100 64 89 1.17 (1.08-2.1) <0.04* t on day 14 increased 0 0 8 11 Analysis of the effectiveness based on proportion of the patients with clinical recovery on day 6, 14 and 28, difference 95% CI recovery on day 6 recovered 2 2.8 0 0.0 0.7 (0.6-0.7) <0.16 recovery on day 14 recovered 44 61.1 29 40.3 1.43 (1.2-1.7) <0.01* recovery on day 28 recovered 72 100 68 94.4 1.05 (0.9-1.1) <0.05* Note. Significant difference in indicators (p<0.05) 4. The patients in the main group had a shorter time to hospital discharge compared with the patients in the placebo group: median of 14 days compared with 19 days in the placebo group, recovery rate is 1.3495% CI 1.15 to 1.51% p <0.01 (Table 6). 5. There were more patients with no acute respiratory distress syndrome in the main group: 36% (median), compared with 24% (median) in the placebo group, difference 12% (95% CI -17 to -6), p<0.04%, which indicates the ability of edaravone to reduce the activity of pro-inflammatory molecules and active radicals and reduce the intensity of the inflammatory process (Table 6). 6. This conclusion regarding the ability of edaravone to reduce the development of systemic inflammatory response syndrome is confirmed by the results of the analysis of the patient need in need for artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO): 96% of the patients in the main group compared with 86% of the placebo group did not need them (a difference is 10%, 95 % CI – 15 to -6; p<0.015) (Table 6). Table 6. Analysis of secondary endpoints Main group (n = 72) Placebo group (n = 72) Indicator 95% CI 95% CI Recovery min max median min max median р rate (95% CI) Evaluation of the effectiveness based on 8 27 14 7 29 18 <0.0 1.34 the time to hospital 01* (1.15 to 1.51) discharge (days) Evaluation of the Difference effectiveness based on (95% CI) proportion of the patients with no acute 29 44 36 16 30 24 <0.04* respiratory distress -12 syndrome since (-17 to -6) hospitalization, (%) Evaluation of the effectiveness based on proportion of the 89 98 96 79 90 -10 patients (%) with no 86 <0.015* (-15 to -6) need in ALV or ECMO, (%) Note. Significant difference in indicators (p<0.05) The pharmaceutical composition comprising edaravone, either in the form of a solution for injection or in the form of a solution for infusion, has shown a good level of safety and tolerability. Therapy tolerability did not differ in the main group and the placebo group. Adherence to the prescribed therapy was high. The conducted study revealed a positive effect of the pharmaceutical composition comprising edaravone, when used along with the combination therapy in the treatment of hospitalized patients with COVID-19 and systemic inflammatory response syndrome (the inclusion criteria coincide with the criteria for systemic inflammatory response syndrome, and are indications for hospitalization of the patients with coronavirus disease according to the Order of the Ministry of Health of Ukraine). The analysis of the data in Tables 2-6 demonstrates that the use of the pharmaceutical composition comprising edaravone along with combination therapy, in comparison with the combination therapy alone, allows achieving a pronounced anti- inflammatory effect, extinguishing and mitigating the development of systemic inflammatory response syndrome in the treatment of COVID-19, one of which is acute respiratory distress syndrome. The results of the analysis of the primary endpoints testify the greater effectiveness of the use of the PC along with combination therapy: the time to withdrawal of the oxygen therapy was shortened by an average of 1 day - 27 hours (median), from 99 hours in the placebo group to 72 hours in the main group; the time to improvement of a patients’ condition by 1 point according to the modified WHO Scale decreased from 5.4 days to 4 days; the integrated assessment of the patients’ condition according to the modified WHO Scale during 28 days showed a more significant improvement in the patients’ condition in the main group, where the median is 223 points, compared with the placebo group with a median of 186 points. The demonstrated effect of the use of the pharmaceutical composition comprising edaravone confirms the ability of the PC to exert an anti-inflammatory effect in a patient with an infectious disease. This is additionally confirmed by the results of the analysis of secondary endpoints: the presence of statistically significant (p <0.01) differences between the groups based on the results of the PCR test on day 6 and on 14. The proportion of the patients with a negative PCR test on day 6 was 81.0% in the main group and 54% in the placebo group; on day 14, PCR was negative in 94% of the main group and 75% of the placebo group. There was a significant difference between the groups in terms of the assessed compliance with the norm of the body temperature on day 6. Thus, the proportion of the patients having a normal axillary body temperature on day 6 was 85% in the main group and 68.0% in the placebo group. In the analysis of the time to recovery, the largest difference between the groups was apparent on day 14, when the proportion of the patients clinically recovered in the main group was 61.1%, compared with 40.3% in the placebo group, the estimated treatment effect was 1.43. Median hospital discharge in the main group was 5 days shorter: 14 days compared with 19 days in the placebo group. There were more patients with no acute respiratory distress syndrome in the main group: 36% (median), compared with 24% (median) in the placebo group, difference 12% (95% CI -17 to -6), p<0.04%, which indicates the ability of edaravone to reduce the activity of pro-inflammatory mediators and reduce the intensity of the inflammatory process. Example 2 Study on the reduction of the levels of the IL-6 and TNF-α inflammatory markers Study design: Prospective, multicenter, double-blind, randomized, placebo- controlled, parallel-group clinical trial. 144 hospitalized male and female patients aged 18-67 years with diagnosed COVID-19 along with systemic inflammatory response syndrome took part in the study and were divided into two treatment groups: The first group - Main group: size - 72 patients. Therapy - administration of the PC + combination therapy (therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). Second group - Placebo group: size - 72 patients. Therapy - administration of the placebo + combination therapy (therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). Inclusion criteria: 1. Diagnosed coronavirus disease (COVID-19). 2. Prescribed non-invasive oxygen therapy (nasal catheter, mask, non-invasive lung ventilation (NILV)). 3. At the time of screening, two or more of the following (systemic inflammatory response syndrome criteria): a. respiratory rate more than 20 breaths / min and / or partial pressure of carbon dioxide in arterial blood PaCO2 < 32 mm Hg with spontaneous breathing indoors; b. heart rate (HR) > 90 bpm; c. the number of white blood cells > 12.0 x 109 / L or < 4.5 x 109 / L; d. body temperature > 38 °C or < 36 °C. 4. At the time of screening, the patient had symptoms of pneumonia and / or respiratory failure (increased frequency of respiratory movements above the physiological norm, hemoptysis, blood oxygen saturation index (SpO2) when measured with a pulse oximeter ≤92%) with radiologically confirmed pneumonia. Exclusion criteria Patients who had at least one of the following criteria were not included in the study: - Hospitalization more than 24 hours before randomization. - Known hypersensitivity to the studied pharmaceutical composition and its components. - Pregnancy or breastfeeding. - Severe disturbance of consciousness (does not respond to external stimulation). - The need for artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO). - Detected severe heart failure. - Levels of alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT) more than three times higher than the upper limit of normal. - Glomerular filtration rate (GFR) less than 60 mL / min. - Suspected / confirmed bacterial infection. - Diagnosed severe chronic obstructive pulmonary disease, decompensated diabetes, cancer, active tuberculosis, presence of human immunodeficiency virus (HIV) regardless of immunological status, hepatitis regardless of etiology. - The patient received immunosuppressive drug therapy with antibodies for the past 5 months, including intravenous immunoglobulin. - At the time of screening, the patient was using oral corticosteroids in a dose that exceeds the prednisone dose of 10 mg (or its equivalent) per day. - At the time of the screening, the patient was using anti-rheumatic disease- modifying pharmaceutical compositions / immunosuppressive drug therapy, including IL-6 inhibitors, or Janus kinase inhibitors within the last 30 days. - The patient's history included inflammatory bowel disease, diverticulitis, peptic ulcer disease. - The patient had a history of alcohol or drug addiction. Scheme of the therapy prescription The patients of the main group received the PC along with combination therapy. Two versions of the PC were used: 1. in the dosage form of a solution for injection that comprised 1.5 mg of edaravone in 1 mL of the solution, and additionally comprised excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. Before administration, the PC content was dissolved in a solution of 100 mL of 0.9% sodium chloride to achieve a concentration of 0.3 mg / mL. 2. in the dosage form of a solution for infusion that comprised 0.3 mg of edaravone in 1 mL of the solution, and additionally comprised excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. The PC according to this version did not need to be dissolved and was ready for direct administration to the patient. The PC in both versions was administered twice a day, in the morning and in the evening, by intravenous infusion for 30 minutes. The daily dose of edaravone was 60 mg – twice per 30 mg. The patients with COVID-19 and systemic inflammatory response syndrome in the placebo group received placebo along with the combination therapy. As a placebo, 0.9% sodium chloride solution, 10 mL, twice a day, in the morning and in the evening, was administered by intravenous infusion for 30 minutes. The use of the PC and placebo started as early as possible after hospitalization of the patients, the duration of the therapy was 14 days. Combination therapy The patients having participated in the study received the drug therapy or combination therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). The combination therapy included non-steroidal anti-inflammatory pharmaceutical compositions, low molecular weight heparins (LMWH), systemic corticosteroids, electrolyte solutions, and oxygen therapy. Study endpoints Primary endpoints: 1. Time to withdrawal of the oxygen therapy (nasal catheter, oxygen mask, NILV), confirmed by the following indicators during the observation period from 1 to 28 days: a. Stable improvement of the general condition. b. Decrease in respiratory rate - <24 / min. c. Decrease in heart rate - <110 / min. d. Compensated pH - >7.35 (H+ <45 nmol / L). e. SpO2 - >90% with FiO2 <4 L / min. 2. Time to improve of a patient's condition by 1 point according to the modified WHO Scale. 3. The integral assessment of the patient’s condition was expressed in the sum of points received during the observation period (28 days), wherein the sum of the points of the assessed patient’s condition was determined with the modified WHO Scale, where 10 points is a healthy patient, 0 points is death: 0 points: death; 1 point: ALV, partial pressure of oxygen in the blood or in the arterial blood (PaO2) / fraction of inspired oxygen (FiO2) < 150, vasopressors, dialysis or ECMO; 2 points: ALV, PaO2 / FiO2 < 150 (PaO2 / FiO2 < 200) or vasopressors; 3 points: intubation or ALV, PaO2 / FiO2≥ 150 or PaO2 / FiO2≥ 200; 4 points: hospitalization, oxygen therapy with NILV; 5 points: hospitalization, oxygen therapy with a mask or nasal catheter; 6 points: hospitalization, no oxygen therapy; 7 points: symptoms are present, external assistance is required; 8 points: symptoms are present, external assistance is not required; 9 points: no symptoms, viral RNA is detected during testing based on polymerase chain reaction (PCR testing); 10 points: no symptoms, viral RNA is not detected during testing based on polymerase chain reaction (PCR testing); Secondary endpoints: 1. Duration of hospitalization. 2. Proportion of the patients with no acute respiratory distress syndrome from the moment of hospitalization (up to the 28th day of the study). 3. Proportion of the patients with no need in artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO) - up to the 28th day of the study (onset / no onset). 4. Proportion of the patients with clinical recovery on day 6, 14, 28 (recovered / not recovered). 5. Proportion of the patients with axillary temperature up to 36.9 °C on day 6, 14. 6. Level of TNF-α on day 4, 6, 10, 14 compared with day 1. 7. Level of IL-6 on day 4, 6, 10, 14 compared with day 1. 8. Proportion of the patients with negative SARS-CoV-2 (qualitative) PCR test on day 6, 14, 20 (negative / positive). Examination methods used in the study: X-ray of chest. Laboratory studies: 1. Test for detection of the virus (SARS-CoV-2) in nasopharyngeal swab samples on day 6, 14, 20. 2. Complete blood count with white blood cell level, with mandatory estimation of red blood cell levels and platelet levels on day 1 and 10. 3. Blood chemistry test on day 1, 6, 14 that included the following categories: creatinine, blood urea nitrogen; ALAT; ASAT; bilirubin; total protein; lactate dehydrogenase (LDH); ferritin; procalcitonin; alkaline phosphatase; D-dimer; C- reactive protein; TNF-α; interleukins IL-1β; IL-6; IL-10. 4. Automatic calculation of glomerular filtration rate (GFR) on day 1, 6, 14. 5. Coagulogram on day 1, 6, 14; prothrombin index (PTI); international normalized ratio (INR); thrombin time (TH); fibrinogen; antithrombin III. 6. Complete urinalysis on day 1, 4, 6, 10, 14. 7. Assessment of the respiratory system indicators: respiratory rate (RR), SpO2, need in the oxygen therapy and the method of such therapy, FiO2 if oxygen therapy is used. 8. Arterial blood gas test, day 0, at the discretion of the researcher to verify the inclusion criterion: PaСO2. 9. Arterial blood gas test when deciding to withdraw the oxygen therapy: pH; SaO2; PaO2. 10. Calculation of the PaO2 / FiO2 value when deciding to withdraw the oxygen therapy. Instrumental examinations: measurement of HR, blood pressure (BP), RR, blood oxygen saturation and body temperature parameters, electrocardiography (ECG). Stages of the study: screening, randomization, period of the therapy according to the protocol (up to 14 days) and period of the observation after the therapy - from 14 days (28 days in total). An outline of the study design is provided in Table 7.

[0002] Table 7. Outline of study design Appointment Day of therapy Actions Assessment 0 0 Screening, randomization Complete examination, assessment of data 1 1 Collection of clinical Therapy Assessment of respiratory data, data of laboratory prescription: PC, system indicators, examinations placebo, Assessment of the combination therapy possibility of oxygen therapy withdrawal (if applicable) 2, 3, 7, 8, 9, 2, 3, 7, Assessment of clinical Use of PC, Assessment of respiratory 11, 12, 13 8, 9, 11, data in dynamics, adjustment of system indicators, 12, 13 Registration of combination Assessment of the information about therapy, collection possibility of oxygen changes in the course of PC safety data therapy withdrawal (if and therapy applicable) 4, 6, 10, 14 4, 6, 10, Collection of clinical data Use of PC, Assessment of respiratory 14 Collection of laboratory adjustment of system indicators, examination data combination Assessment of the therapy, collection possibility of oxygen of PC safety data, therapy withdrawal (if assessment of PC applicable) tolerability 15-19, 21-27 15-19, Collection of clinical data Collection of PC Assessment of respiratory 21-27 safety data system indicators, Assessment of the possibility of oxygen therapy withdrawal (if applicable) 20 20 Collection of clinical data Collection of PC Assessment of respiratory Collection of laboratory safety data system indicators, examination data Assessment of the possibility of oxygen therapy withdrawal (if applicable) 28 a phone 28 information about the call, if a patient patient's health has already condition, the presence been of complaints, the discharged presence of undesirable phenomena The population during the treatment included 144 patients with positive PCR- confirmed COVID-19 (SARS-CoV-2) that received the prescribed therapy (72 in the main group and 72 in the placebo group). The relevant patients underwent a medical examination by a doctor in the medical department. Baseline characteristics such as age, gender, comorbidities, duration of the symptoms, and severity of the disease at admission were recorded at enrollment. All the patients were diagnosed with COVID-19 using a baseline PCR nasopharyngeal swab. The groups were statistically homogeneous in terms of gender and age, as well as in comorbidities - information about the patients in the groups is provided in Table 8. Table 8. General characteristics of the patients participating in the study Total Main group Placebo Indicator (n = 144) (n = 72) group (n = 72) n (%) n (%) n (%) Gender Male 54 38 28 39 26 36 Female 90 63 44 61 46 64 Age (years), median ± standard deviation 48.57 ± 49.42 47.72 ± 15.45 (SD) 14.80 ±14.29 < 40 years 36 25 20 28 16 22 40–65 years 92 64 44 61 48 67 > 65 years 16 11 8 11 8 11 Comorbidities Diabetes 34 24 22 31 12 17 Hypertension 58 40 32 44 26 36 Dyslipidemia 50 35 32 44 18 25 Ischemic heart disease 4 3 2 3 2 3 Oncology 0 0 0 0 0 0 HIV 0 0 0 0 0 0 Chronic cerebrovascular diseases 4 3 0 0 2 6 Chronic liver diseases 0 0 0 0 0 0 Chronic kidney diseases 10 7 4 6 6 8 Miscellaneous 58 40 26 36 32 44 Results of the therapy The dynamics of the inflammatory markers shows the advantage of the use of the main group therapy. The level of IL-6 shows a more pronounced downward trend in the main group, starting from day 4 (-59.61 pg / mL), steadily continuing to decrease (-79.44 pg / mL on day 14). In the placebo group, the level decreased slower, starting from day 6 of stagnation (76 - 77 pg / mL) of the IL-6 level and even with increase of the median on day 14 to 82.65 pg / mL. The difference in median values between 1 and 14 days in the main group is 79.44, in the placebo group -37.34. The estimated treatment effect in the main group on day 14 was 1.2 (95% CI 1.02 to 1.35) (Table 9, diagram in [Fig.3] ). As for the TNF-α level, a tendency to a more pronounced downward trend in the main group was noticeable, although there were no statistically significant differences between the groups (Table 9, diagram in [Fig.4] ). Table 9. Secondary analysis of IL-6 and TNF-α inflammatory markers Main group (n = 72) Placebo group (n = 72) Indica Da medi differenc differenc min max a e with mi medi Recovery rate tor y na n max e with р day 1 ana day 1 (95% CI) day 1 2 16.1 8.55 2 13.7 8.5 Level day 2 10.4 6.5 -2.05 2 15.4 7.65 -0 0.6 of 4 .85 0.5 (0.4 to 0.75)TNFα, day 2 10.5 6.1 -2.45 2 16.1 6.65 -1.85 0. 0.6 pg / mL 6 5 (0.45 to 0.75) N = 0 to 8.2 day 2 8.2 5.7 -2.85 2 8.1 6.15 -2.35 0. 0.7 pg / mL 10 5 (0.5 to 0.83) day 2 13.8 0.8 14 5.15 -3.4 3.2 7.3 6.05 -2.45 0.5 (0.5 to 0.95) day 6.72 298. 124.5 119.9 1 4 9.45 307.67 0.2 Level 5 9 of IL– day 2.54 155.89 79.60 -44.95 6.76 210.6 86.00 -33.99 0.2 1.05 6, 4 (0.9 to 1.2)pg / mL day 3.09 78.3 64.94 -59.6 1.1 N = 0 6 1 56.67 89.96 77.41 -42.58 0.05* (0.95 to 1.25) to 7.0 day 2.19 254.6 54.45 -70.10 25.71 108.54 76.4 1.15 pg / mL 10 2 -43.57 0.05* (0.98 to 1.2) day 5.78 105.63 45.11 -79.44 44. 1.2 14 67 145.82 82.65 -37.34 0.01* (1.02 to 1.35) Note. Significant difference in indicators (p<0.05) The above conclusion regarding the effectiveness of the use of the pharmaceutical composition comprising edaravone is confirmed by the dynamics of the inflammatory markers: more pronounced and stable dynamics of IL-6 reduction was in the main group, starting from day 4 (-59.61 pg / mL), with a stable continuation of the reduction (-79.44 pg / mL on day 14), the difference was 11%. In the placebo group, the level decreases slower, starting from day 6 of stagnation of the IL-6 level and even with an increase in the median on day 14 to 82.65 pg / mL was observed. The difference in median values between 1 and 14 days in the main group was 79.44, in the placebo group - 37.34, the difference was 33%, the estimated treatment effect in the main group on day 14 was 1.2 (95% CI 1.02 - 1.35). Example 3 Study design: Prospective, multicenter, double-blind, randomized, placebo- controlled, parallel-group clinical trial. 144 hospitalized male and female patients aged 18-67 years with diagnosed COVID-19 along with systemic inflammatory response syndrome took part in the study and were divided into two treatment groups: The first group - Main group: size - 72 patients. Therapy - administration of the PC + combination therapy (therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). Second group - Placebo group: size - 72 patients. Therapy - administration of the placebo + combination therapy (therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). Inclusion criteria: 1. Diagnosed coronavirus disease (COVID-19). 2. Prescribed non-invasive oxygen therapy (nasal catheter, mask, non-invasive lung ventilation (NILV)). 3. At the time of screening, two or more of the following (systemic inflammatory response syndrome criteria): a. respiratory rate more than 20 breaths / min and / or partial pressure of carbon dioxide in arterial blood PaCO2 < 32 mm Hg with spontaneous breathing indoors; b. heart rate (HR) > 90 bpm; c. the number of white blood cells > 12.0 x 109 / L or < 4.5 x 109 / L; d. body temperature > 38 °C or < 36 °C. 4. At the time of screening, the patient had symptoms of pneumonia and / or respiratory failure (increased frequency of respiratory movements above the physiological norm, hemoptysis, blood oxygen saturation index (SpO2) when measured with a pulse oximeter ≤92%) with radiologically confirmed pneumonia. Exclusion criteria: The patients who had at least one of the following criteria were not included in the study: - Hospitalization more than 24 hours before randomization. - Known hypersensitivity to the studied pharmaceutical composition and its components. - Pregnancy or breastfeeding. - Severe disturbance of consciousness (does not respond to external stimulation). - The need for artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO). - Detected severe heart failure. - Levels of alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT) more than three times higher than the upper limit of normal. - Glomerular filtration rate (GFR) less than 60 mL / min. - Suspected / confirmed bacterial infection. - Diagnosed severe chronic obstructive pulmonary disease, decompensated diabetes, cancer, active tuberculosis, presence of human immunodeficiency virus (HIV) regardless of immunological status, hepatitis regardless of etiology. - The patient received immunosuppressive drug therapy with antibodies for the past 5 months, including intravenous immunoglobulin. - At the time of screening, the patient was using oral corticosteroids in a dose that exceeds the prednisone dose of 10 mg (or its equivalent) per day. - At the time of the screening, the patient was using anti-rheumatic disease- modifying pharmaceutical compositions / immunosuppressive drug therapy, including IL-6 inhibitors, or Janus kinase inhibitors within the last 30 days. - The patient's history included inflammatory bowel disease, diverticulitis, peptic ulcer disease. - The patient had a history of alcohol or drug addiction. Scheme of the therapy prescription. The patients of the main group received the PC along with combination therapy. Two versions of the PC were used: 1. in the dosage form of a solution for injection that comprised 1.5 mg of edaravone in 1 mL of the solution, and additionally comprised excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. Before administration, the PC content was dissolved in a solution of 100 mL of 0.9% sodium chloride to achieve a concentration of 0.3 mg / mL. 2. in the dosage form of a solution for infusion that comprised 0.3 mg of edaravone in 1 mL of the solution, and additionally comprised excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections. The PC according to this version did not need to be dissolved and was ready for direct administration to the patient. The PC in both versions was administered twice a day, in the morning and in the evening, by intravenous infusion for 30 minutes. The daily dose of edaravone was 60 mg – twice per 30 mg. The patients with COVID-19 and systemic inflammatory response syndrome in the placebo group received placebo along with the combination therapy. As a placebo, 0.9% sodium chloride solution, 10 mL, twice a day, in the morning and in the evening, was administered by intravenous infusion for 30 minutes. The use of the PC and placebo started as early as possible after hospitalization of the patients, the duration of the therapy was 14 days. Combination therapy The patients having participated in the study received the drug therapy or combination therapy according to the Protocol "Provision of medical assistance for the treatment of coronavirus disease (COVID-19)" approved by the Order of the Ministry of Health of Ukraine dated April 2, 2020 No.762 (as amended by the Order of the Ministry of Health of Ukraine dated April 10, 2020 No.852) with changes). The combination therapy included non-steroidal anti-inflammatory pharmaceutical compositions, low molecular weight heparins (LMWH), systemic corticosteroids, electrolyte solutions, and oxygen therapy. Study endpoints Primary endpoints: 1. Time to withdrawal of the oxygen therapy (nasal catheter, oxygen mask, NILV), confirmed by the following indicators during the observation period from 1 to 28 days: a. Stable improvement of the general condition. b. Decrease in respiratory rate - <24 / min. c. Decrease in heart rate - <110 / min. d. Compensated pH - >7.35 (H+ <45 nmol / L). e. SpO2- >90% with FiO2<4 L / min. 2. Time to improve of a patient's condition by 1 point according to the modified WHO Scale. 3. The integral assessment of the patient’s condition was expressed in the sum of points received during the observation period (28 days), wherein the sum of the points of the assessed patient’s condition was determined with the modified WHO Scale, where 10 points is a healthy patient, 0 points is death: 0 points: death; 1 point: ALV, partial pressure of oxygen in the blood or in the arterial blood (PaO2) / fraction of inspired oxygen (FiO2) < 150, vasopressors, dialysis or ECMO; 2 points: ALV, PaO2 / FiO2 < 150 (PaO2 / FiO2 < 200) or vasopressors; 3 points: intubation or ALV, PaO2 / FiO2≥ 150 or PaO2 / FiO2≥ 200; 4 points: hospitalization, oxygen therapy with NILV; 5 points: hospitalization, oxygen therapy with a mask or nasal catheter; 6 points: hospitalization, no oxygen therapy; 7 points: symptoms are present, external assistance is required; 8 points: symptoms are present, external assistance is not required; 9 points: no symptoms, viral RNA is detected during testing based on polymerase chain reaction (PCR testing); 10 points: no symptoms, viral RNA is not detected during testing based on polymerase chain reaction (PCR testing); Secondary endpoints: 1. Duration of hospitalization. 2. Proportion of the patients with no acute respiratory distress syndrome from the moment of hospitalization (up to the 28th day of the study). 3. Proportion of the patients with no need in artificial lung ventilation (ALV) or extracorporeal membrane oxygenation (ECMO) - up to the 28th day of the study (onset / no onset). 4. Proportion of the patients with clinical recovery on day 6, 14, 28 (recovered / not recovered). 5. Proportion of the patients with axillary temperature up to 36.9 °C on day 6, 14. 6. Level of TNF-α on day 4, 6, 10, 14 compared with day 1. 7. Level of IL-6 on day 4, 6, 10, 14 compared with day 1. 8. Proportion of the patients with negative SARS-CoV-2 (qualitative) PCR test on day 6, 14, 20 (negative / positive). Examination methods used in the study: X-ray of chest. Laboratory studies: 1. Test for detection of the virus (SARS-CoV-2) in nasopharyngeal swab samples on day 6, 14, 20. 2. Complete blood count with white blood cell level, with mandatory estimation of red blood cell levels and platelet levels on day 1 and 10. 3. Blood chemistry test on day 1, 6, 14 that included the following categories: creatinine, blood urea nitrogen; ALAT; ASAT; bilirubin; total protein; lactate dehydrogenase (LDH); ferritin; procalcitonin; alkaline phosphatase; D-dimer; C- reactive protein; TNF-α; interleukins IL-1β; IL-6; IL-10. 4. Automatic calculation of glomerular filtration rate (GFR) on day 1, 6, 14. 5. Coagulogram on day 1, 6, 14; prothrombin index (PTI); international normalized ratio (INR); thrombin time (TH); fibrinogen; antithrombin III. 6. Complete urinalysis on day 1, 4, 6, 10, 14. 7. Assessment of the respiratory system indicators: respiratory rate (RR), SpO2, need in the oxygen therapy and the method of such therapy, FiO2 if oxygen therapy is used. 8. Arterial blood gas test, day 0, at the discretion of the researcher to verify the inclusion criterion: PaСO2. 9. Arterial blood gas test when deciding to withdraw the oxygen therapy: pH; SaO2; PaO2. 10. Calculation of the PaO2 / FiO2 value when deciding to withdraw the oxygen therapy. Instrumental examinations: measurement of HR, blood pressure (BP), RR, blood oxygen saturation and body temperature parameters, electrocardiography (ECG). Stages of the study: screening, randomization, period of the therapy according to the protocol (up to 14 days) and period of the observation after the therapy - from 14 days (28 days in total). An outline of the study design is provided in Table 10.

[0003] Table 10. Outline of study design Appointment Day of therapy Actions Assessment 0 0 Screening, randomization Complete examination, assessment of data 1 1 Collection of clinical Therapy Assessment of respiratory data, data of laboratory prescription: PC, system indicators, examinations placebo, Assessment of the combination therapy possibility of oxygen therapy withdrawal (if applicable) 2, 3, 7, 8, 9, 2, 3, 7, Assessment of clinical Use of PC, Assessment of respiratory 11, 12, 13 8, 9, 11, data in dynamics, adjustment of system indicators, 12, 13 Registration of combination Assessment of the information about therapy, collection possibility of oxygen changes in the course of PC safety data therapy withdrawal (if and therapy applicable) 4, 6, 10, 14 4, 6, 10, Collection of clinical data Use of PC, Assessment of respiratory 14 Collection of laboratory adjustment of system indicators, examination data combination Assessment of the therapy, collection possibility of oxygen of PC safety data, therapy withdrawal (if assessment of PC applicable) tolerability 15-19, 21-27 15-19, Collection of clinical data Collection of PC Assessment of respiratory 21-27 safety data system indicators, Assessment of the possibility of oxygen therapy withdrawal (if applicable) 20 20 Collection of clinical data Collection of PC Assessment of respiratory Collection of laboratory safety data system indicators, examination data Assessment of the possibility of oxygen therapy withdrawal (if applicable) 28 a phone 28 information about the call, if a patient patient's health has already condition, the presence been of complaints, the discharged presence of undesirable phenomena The population during the treatment included 144 patients with positive PCR- confirmed COVID-19 (SARS-CoV-2) that received the prescribed therapy (72 in the main group and 72 in the placebo group). The relevant patients underwent a medical examination by a doctor in the medical department. Baseline characteristics such as age, gender, comorbidities, duration of the symptoms, and severity of the disease at admission were recorded at enrollment. All the patients were diagnosed with COVID-19 using a baseline PCR nasopharyngeal swab. The groups were statistically homogeneous in terms of gender and age, as well as in comorbidities - information about the patients in the groups is provided in Table 11. Table 11. General characteristics of the patients participating in the study Total Main group Placebo Indicator (n = 144) (n = 72) group (n = 72) n (%) n (%) n (%) Gender Male 54 38 28 39 26 36 Female 90 63 44 61 46 64 Age (years), median ± standard deviation 48.57 ± 49.42 47.72 ± 15.45 (SD) 14.80 ±14.29 < 40 years 36 25 20 28 16 22 40–65 years 92 64 44 61 48 67 > 65 years 16 11 8 11 8 11 Comorbidities Diabetes 34 24 22 31 12 17 Hypertension 58 40 32 44 26 36 Dyslipidemia 50 35 32 44 18 25 Ischemic heart disease 4 3 2 3 2 3 Oncology 0 0 0 0 0 0 HIV 0 0 0 0 0 0 Chronic cerebrovascular diseases 4 3 0 0 2 6 Chronic liver diseases 0 0 0 0 0 0 Chronic kidney diseases 10 7 4 6 6 8 Miscellaneous 58 40 26 36 32 44 Results of the therapy The analysis of the primary end point - time to withdrawal of the oxygen therapy (hours) with a follow-up period from 1 to 28 days - confirmed a predominant effectiveness of the therapy in the main group compared with the placebo group. There were statistically significant differences in the time to withdrawal of the oxygen therapy that in the main group is 18 to 358 hours (median -72 hours) and in the placebo group - 21 to 388 hours (median - 99 hours). The difference in median time was 27 hours (95% confidence interval CI -45 to -12, p = 0.001) (Table 12, diagram in [Fig.1] ). Table 12. Analysis of the effectiveness of the therapy based on the primary results Main group Placebo group (n = 72) (n = 72) Indicator 95% CI median 95% CI median р Recovery min max min max rate (95% CI) Assessment of the 3.02 4.96 4.0 4.5 6.1 5.4 <0.001 1.23 effectiveness based on (1.04–1.49) the time to improvement of the patient's condition by 1 point according to the modified WHO Scale Time to withdrawal of the 18 358 72 21 388 99 <0.001 Difference oxygen therapy (hours) (95% CI) during observation period –27 1 to 28 days (–45 to –12) The results of the primary endpoints analysis testify the greater effectiveness of the use of the PC along with combination therapy: the time to withdrawal of the oxygen therapy was shortened by an average of 1 day - 27 hours (median), from 99 hours in the placebo group to 72 hours in the main group. The technical result achieved by the introduction of the pharmaceutical composition comprising edaravone into the therapy resides in the following: - additional decrease in the levels of the IL-6 and TNF-α inflammatory markers in a patient with an infectious disease, in the event of a condition resulted from systemic inflammatory response syndrome; - reducing the duration of the therapy of an infectious disease that is accompanied by a condition resulted from systemic inflammatory response syndrome; - reducing the time to withdrawal of the oxygen therapy that is implemented in the case of the oxygen deficiency in a patient with an infectious disease, in the event of the condition resulted from systemic inflammatory response syndrome; - reduction of the burden on the health care system: use of the resources of qualified experts, specialized premises, medical therapy aids, equipment for the oxygen therapy; - improvement of the quality of life of people by spending less time in intensive care facilities and / or needlessness in artificial lung ventilation, etc. The described examples of the embodiments only illustrate the disclosure and do not limit it any manner.

Claims

Claims 1. A use of a pharmaceutical composition comprising edaravone in a patient with an infectious disease, characterized in that in the event of a condition resulted from systemic inflammatory response syndrome during the infectious disease, either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non-drug supportive therapy is implemented, and the drug therapy is implemented by administering at least one drug to the patient, wherein the drug therapy additionally includes use of a pharmaceutical composition comprising edaravone as a drug.

2. The use according to claim 1, characterized in that the infectious disease is COVID-19, influenza, bird flu, Ebola fever.

3. The use according to any of claims 1-2, characterized in that the condition resulted from systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis.

4. The use according to any of claims 1-3, characterized in that the pharmaceutical composition comprising edaravone is in a dosage form of a solution for injection or solution for infusion containing 0.3 - 1.5 mg of edaravone in 1 mL of the solution.

5. The use according to claim 4, characterized in that the pharmaceutical composition comprising edaravone additionally comprises at least one excipient selected from cysteine hydrochloride, sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections.

6. The use according to any of claims 1-5, characterized in that the pharmaceutical composition comprising edaravone is administered to the patient once or twice a day in an amount to provide a daily dose of edaravone of 30-60 mg.

7. A method of reduction of levels of IL-6 and TNF-α inflammatory markers in a patient with an infectious disease in the event of a condition resulted from systemic inflammatory response syndrome during the infectious disease, wherein either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non-drug supportive therapy is implemented, and drug therapy is implemented by administering at least one drug to the patient, characterized in that the drug therapy additionally includes use of a pharmaceutical composition comprising edaravone as a drug, and the drug therapy or combination therapy is implemented for at least 14 days, and the levels of the IL-6 and TNF-αinflammatory markers are further reduced by at least 10% more than the levels of the IL-6 and TNF-α inflammatory markers achieved after implementation of the drug therapy or combination therapy that does not include a pharmaceutical composition comprising edaravone.

8. The use according to claim 7, characterized in that the infectious disease is COVID-19, influenza, bird flu, Ebola fever.

9. The use according to any of claims 7-8, characterized in that the condition resulted from systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis.

10. The use according to any of claims 7-9, characterized in that the pharmaceutical composition comprising edaravone is in a dosage form of a solution for injection or solution for infusion containing 0.3 - 1.5 mg of edaravone in 1 mL of the solution.

11. The use according to claim 10, characterized in that the pharmaceutical composition comprising edaravone additionally comprises at least one excipient selected from cysteine hydrochloride, sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections.

12. The use according to any of claims 7-11, characterized in that the pharmaceutical composition comprising edaravone is administered to the patient once or twice a day in an amount to provide a daily dose of edaravone of 30-60 mg.

13. A method of reducing a time to withdrawal of oxygen therapy that is implemented in oxygen deficiency in a patient with an infectious diseases, in the event of a condition resulted from systemic inflammatory response syndrome during the infectious disease, wherein either drug therapy or combination therapy that includes drug therapy and methods of non-drug therapy or methods of non-drug supportive therapy is implemented, and drug therapy is implemented by administering at least one drug to the patient, characterized in that the drug therapy additionally includes use of a pharmaceutical composition comprising edaravone as a drug.

14. The use according to claim 13, characterized in that the infectious disease is COVID-19, influenza, bird flu, Ebola fever.

15. The use according to any of claims 13-14, characterized in that the condition resulted from systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis.

16. The use according to any of claims 13-15, characterized in that the pharmaceutical composition comprising edaravone is in a dosage form of a solution for injection or solution for infusion containing 0.3 - 1.5 mg of edaravone in 1 mL of the solution.

17. The use according to claim 16, characterized in that the pharmaceutical composition comprising edaravone additionally comprises at least one excipient selected from cysteine hydrochloride, sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections.

18. The use according to any of claims 13-17, characterized in that the pharmaceutical composition comprising edaravone is administered to the patient once or twice a day in an amount to provide a daily dose of edaravone of 30-60 mg.

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