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WO2025104696A1 - Composition pharmaceutique comprenant de l'édaravone destinée à être utilisée dans la réduction des taux de marqueurs inflammatoires de l'il-6 et du tnf-alpha et la réduction du temps de retrait de l'oxygénothérapie chez des patients atteints de maladies infectieuses - Google Patents

Composition pharmaceutique comprenant de l'édaravone destinée à être utilisée dans la réduction des taux de marqueurs inflammatoires de l'il-6 et du tnf-alpha et la réduction du temps de retrait de l'oxygénothérapie chez des patients atteints de maladies infectieuses Download PDF

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WO2025104696A1
WO2025104696A1 PCT/IB2024/061418 IB2024061418W WO2025104696A1 WO 2025104696 A1 WO2025104696 A1 WO 2025104696A1 IB 2024061418 W IB2024061418 W IB 2024061418W WO 2025104696 A1 WO2025104696 A1 WO 2025104696A1
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therapy
edaravone
drug
pharmaceutical composition
patient
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Mykola GUMENIUK
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Sia "emteko Holding"
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Sia "emteko Holding"
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • 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- ⁇ 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.
  • 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.
  • ROS reactive oxygen species
  • US Food and Drug Administration 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.
  • ALS amyotrophic lateral sclerosis
  • IV RADICAVA intravenous
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • IL-6 Interleukin-6, IL-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.
  • CRP C-reactive protein
  • TNF- ⁇ ⁇ -tumor necrosis factor, tumor necrosis factor, TNF, cachexin, cachectin
  • monocytes and macrophages mainly by monocytes and macrophages.
  • TNF- ⁇ TNF- ⁇ 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- ⁇ also activates the nuclear transcription factor NF-B.
  • TNF- ⁇ chronic myocardial contractility
  • minute blood volume minute blood volume
  • capillary permeability 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).
  • SIRS systemic inflammatory response syndrome
  • 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.
  • 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.
  • cytokines proteins
  • 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.
  • 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
  • cytokine storm cytokine cascade
  • cytokine cascade cytokine storm, cytokine cascade
  • cytokine cascade cytokine storm, cytokine cascade
  • 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.
  • IL-6 interleukin-6
  • 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.
  • Coronavirus disease COVID-19 (COVID-19) is an infectious respiratory disease caused by the positive-sense single-stranded RNA virus SARS-CoV-2.
  • 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.
  • inflammatory markers in particular IL-6 and TNF- ⁇
  • 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- ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • HPAI highly pathogenic avian influenza
  • 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 civilization.
  • the Ebola virus is an effective inducer of inflammatory markers, including IL-6 and TNF- ⁇ .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a complication such as a secondary infection, most often bacterial one.
  • 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.
  • 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.
  • 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.
  • 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).
  • ARDS a condition that causes a low level of oxygen in the blood
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • the infectious disease is COVID-19, influenza, bird flu, Ebola fever.
  • the condition resulted from the systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis.
  • 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.
  • 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.
  • 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- ⁇ 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- ⁇ inflammatory markers are further reduced by at least 10% more than the levels of the IL- 6 and TNF- ⁇ inflammatory markers achieved after implementing the drug therapy or combination therapy that does not include a pharmaceutical composition
  • the infectious disease is COVID-19, influenza, bird flu, Ebola fever.
  • the condition resulted from the systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis.
  • 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.
  • 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.
  • 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.
  • the infectious disease is COVID-19, influenza, bird flu, Ebola fever.
  • the condition resulted from the systemic inflammatory response syndrome during the infectious disease is acute respiratory distress syndrome, hypercytokinemia, cytokine release syndrome, sepsis.
  • 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.
  • 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.
  • 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.
  • drug therapy means the treatment of a disease by administering to a patient a pharmaceutical composition in any form.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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- ⁇ dynamics.
  • PC edaravone
  • 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.
  • NILV non-invasive lung ventilation
  • 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.
  • ABV artificial lung ventilation
  • ECMO extracorporeal membrane oxygenation
  • alanine aminotransferase AAT
  • ASAT aspartate aminotransferase
  • GFR Glomerular filtration rate
  • HAV human immunodeficiency virus
  • the patient was using oral corticosteroids in a dose that exceeds the prednisone dose of 10 mg (or its equivalent) per day.
  • 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.
  • 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.
  • excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections.
  • 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.
  • modified WHO Clinical Progression 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, PaO 2 /FiO 2 ⁇ 150 (PaO 2 /FiO 2 ⁇ 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
  • 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- ⁇ ; interleukins IL-1 ⁇ ; 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.
  • 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,
  • 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.
  • the pharmaceutical composition comprising edaravone 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 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.
  • 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.
  • 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.
  • Example 2 Study on the reduction of the levels of the IL-6 and TNF- ⁇ 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.
  • NILV non-invasive lung ventilation
  • 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.
  • ABV artificial lung ventilation
  • ECMO extracorporeal membrane oxygenation
  • alanine aminotransferase AAT
  • ASAT aspartate aminotransferase
  • GFR Glomerular filtration rate
  • HAV human immunodeficiency virus
  • the patient was using oral corticosteroids in a dose that exceeds the prednisone dose of 10 mg (or its equivalent) per day.
  • 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.
  • 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.
  • excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections.
  • 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.
  • 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, PaO 2 /FiO 2 ⁇ 150 or PaO 2 /FiO 2 ⁇ 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
  • 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- ⁇ ; interleukins IL-1 ⁇ ; 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.
  • 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.
  • 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).
  • 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] ).
  • 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.
  • NILV non-invasive lung ventilation
  • 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.
  • ABV artificial lung ventilation
  • ECMO extracorporeal membrane oxygenation
  • alanine aminotransferase AAT
  • ASAT aspartate aminotransferase
  • GFR Glomerular filtration rate
  • HAV human immunodeficiency virus
  • the patient was using oral corticosteroids in a dose that exceeds the prednisone dose of 10 mg (or its equivalent) per day.
  • 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.
  • 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.
  • excipients such as sodium metabisulfite, sodium chloride, sodium hydroxide, phosphoric acid, water for injections.
  • 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.
  • 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, PaO 2 /FiO 2 ⁇ 150 or PaO 2 /FiO 2 ⁇ 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
  • 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- ⁇ ; interleukins IL-1 ⁇ ; 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.
  • 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.
  • 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- ⁇ 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.

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Abstract

La divulgation concerne l'utilisation de compositions pharmaceutiques comprenant de l'édaravone. L'utilisation d'une composition pharmaceutique comprenant de l'édaravone chez un patient atteint d'une maladie infectieuse, dans le cas d'un état résultant d'un syndrome de réponse inflammatoire systémique pendant la maladie infectieuse, comprend l'introduction supplémentaire d'une composition pharmaceutique comprenant de l'édaravone en tant que médicament pour la thérapie médicamenteuse. Le résultat technique obtenu par la divulgation revendiquée réside dans une réduction supplémentaire des taux de marqueurs d'inflammation d'IL-6 et de TNF-α, réduisant la durée de thérapie d'une maladie infectieuse, réduisant le temps de retrait de l'oxygénothérapie mise en œuvre en cas de déficience en oxygène chez un patient atteint d'une maladie infectieuse accompagnée de l'état résultant du syndrome de réponse inflammatoire systémique.
PCT/IB2024/061418 2023-11-17 2024-11-15 Composition pharmaceutique comprenant de l'édaravone destinée à être utilisée dans la réduction des taux de marqueurs inflammatoires de l'il-6 et du tnf-alpha et la réduction du temps de retrait de l'oxygénothérapie chez des patients atteints de maladies infectieuses Pending WO2025104696A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004143068A (ja) * 2002-10-23 2004-05-20 Mitsubishi Pharma Corp インフルエンザ脳炎・脳症の予防及び／又は治療のための医薬
CN115011562A (zh) * 2022-04-24 2022-09-06 华农（肇庆）生物产业技术研究院有限公司 一种鸡新城疫禽流感二联疫苗及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004143068A (ja) * 2002-10-23 2004-05-20 Mitsubishi Pharma Corp インフルエンザ脳炎・脳症の予防及び／又は治療のための医薬
CN115011562A (zh) * 2022-04-24 2022-09-06 华农（肇庆）生物产业技术研究院有限公司 一种鸡新城疫禽流感二联疫苗及其制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Abstracts", DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, HEINEMANN WILLIAM MEDICAL BOOKS, LONDON, GB, vol. 54, 7 May 2012 (2012-05-07), pages 5 - 212, XP071148819, ISSN: 0012-1622, DOI: 10.1111/J.1469-8749.2012.04283.X *
MOSLEMI MOHAMMADREZA ET AL: "Evaluating the effect of Edaravone on clinical outcome of patients with severe COVID-19 admitted to ICU: a randomized clinical trial", INFLAMMOPHARMACOLOGY, KLUWER ACADEMIC PUBLISHERS, DORDRECHT, NL, vol. 30, no. 4, 20 June 2022 (2022-06-20), pages 1277 - 1282, XP037906089, ISSN: 0925-4692, [retrieved on 20220620], DOI: 10.1007/S10787-022-01001-2 *
YOUNG P ET AL.: "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., vol. 46, no. 1, January 2020 (2020-01-01), pages 17 - 26, XP037120189, DOI: 10.1007/s00134-019-05857-x

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