История разработки в России кислород-продуцирующих антигипоксантов, кислородных взрывателей и генераторов кислорода

Полный текст

1. Introduction

Ideas about antihypoxants as substances capable of increasing the body's resistance to oxygen deficiency first began to form in St. Petersburg in the middle of the 20th century. The founder of this pharmacological field is the head of the Department of Pharmacology of the Military Medical Academy (1941-1959), Professor Nikolay Lazarev (1895-1974) [1]. He was the first to suggest that there is a special body condition characterized by increased resistance to many damaging factors, including lack of oxygen. Nikolai Lazarev postulated that resistance to adverse factors can be increased by "training" the body to them. To do this, he suggested using unfavorable factors repeatedly. Additionally, he suggested that the body's resistance to adverse factors could be increased by introducing special drugs into the body, which he called adaptogens.

Then this scientific direction was developed by the staff of the Department of Pharmacology of the S.M. Kirov Military Medical Academy under the supervision of Professor Vasily Mikhailovich Vinogradov (1924-2003) [2]. In the 1960s, F.Y. Rachinsky successfully synthesized the first antihypoxants (gutimine, amtizol, bemitil, almid, and etomerzol), and the staff of the department L.V. Pastushenkov, A.V. Pastushenkov, A.E. Alexandrova, I.D. Boldina, T.O. Basieva showed that these substances can have antihypoxic, antioxidant, and universal adaptive effects.

The results of the research allowed the team of employees led by Professor Vasily Vinogradov to continue developing not only antihypoxants, but also actoprotectors (from Latin actus — movement), drugs that enhance and preserve the physical performance of the body in adverse conditions. At the same time, researchers have developed an antidote to carbon monoxide [3]. It has been reported that antihypoxants have advantages over oxygen, such as the ability to prolong the life of the body in the absence of oxygen in the inhaled air, with respiratory obstruction and/ or inability to bind oxygen to the hemoglobin of red blood cells. Over the years, a significant contribution to the development of these ideas has been made by the results of research conducted by O.Y. Uryupov, Yu.G. Bobkov, A.V. Smirnov, S.A. Vorobyov, L.A. Bezyaeva, A.L. Zyuban, V.P. Natalenko, T.V. Sambukova, V.F. Katkov, E.B. Shustov, I.S. Morozov, A.S. Losev, Yu.N. Korolev, I.V. Zarubina, and others. The research resulted in the development of bemitil, which was introduced into clinical practice in the Russian Federation [4, 5].

From 2000 to 2022, the Department of Pharmacology at the Military Medical Academy was headed by Professor Petr Shabanov. Under his leadership, the staff of the department continued to study the pharmacological activity of such antihypoxants and actoprotectors as bemitil, mexidol and its analogues [6-9]. The results of the conducted studies have shown that the main problems of the resistance of a warm-blooded organism to hypoxemia are due to the resistance of its brain to hypoxia. It was found that hypoxic damage to brain cells directly depends on the intensity of aerobic metabolism occurring in the mitochondria and on the local temperature of the brain tissue.

In parallel, from the middle of the second half of the 20th century, at the Izhevsk State Medical Academy, on the initiative of Alexander Urakov, research began on the possibility of changing the mechanism of action of "old" (well-known) medicines by changing their physico-chemical properties [10, 11]. It has been shown that the pharmacological activity of "old" (known) medicines can be changed by increasing their temperature from +24 - +26 °C to temperature +37 - +42 ° C and above; by replacing the acidic activity of the drug with alkaline activity; by changing the osmotic activity of  drug solution (for example, by replacing its hypotonic activity with hypertensive activity); as well as by saturating medicinal solutions with various gases [10-21]. This area of research and development of new drugs was first called thermopharmacology or temperature pharmacology, and then physico-chemical pharmacology. Later it developed into physico-chemical materials science [22-27]. Soon, research carried out in Izhevsk by graduate students and students under the guidance of Professor Alexander Urakov led to the discovery of the possibility of physico-chemical conversion of the "old" (well-known) hydrogen peroxide drug from antiseptics to oxygen-producing pyolytics, bleaching agents and antihypoxants [28, 29]. The emergence of the new coronavirus pandemic COVID-19 in the 20s of the 21st century has exacerbated the problem of combating hypoxic damage to brain cells, which has united the efforts of many researchers around the world, including Russia [30, 31]. In the Russian Federation, this problem united the efforts of researchers from St. Petersburg, Moscow and Izhevsk, which accelerated the development of oxygen-producing antihypoxants and led to the discovery of two new groups of drugs: oxygen fuzes and oxygen generators.

The purpose of the article is to describe the chronology of the development of oxygen-producing antihypoxants, oxygen fuzes, and oxygen generators in Russia.

2. MATERIALS AND METHODS

Methods and terminology

An unstructured literature review was conducted in the E-library, CyberLeninka, РИНЦ (In Russ.), Scopus, Web of Science, MedLine, PubMed, Yandex, Google, the Cochrane Library, EMBASE and Global Health databases using the search terms “old”, “new”, “drugs”, "medicinal product", "medicinal solution", "injection", "pharmacological preparation", “antihypoxants”, “repurposing”, “conversion”, “re-profile”, “physical-chemical properties”, "temperature", “local temperature”, "hypothermia", “local hypothermia", “cooling”, “hyperthermia”, “local hyperthermia”, “heating”, “warming", "warm", "warm medicine", "therapeutic hypothermia", “hibernation”, "targeted temperature management", “thermal imager”, “infrared imager”, “infrared thermography”, “acidic”, “alkaline activity”, “osmotic activity”, “hypotonic activity”, “hypertensive activity”, “carbonated”, “sparkling”, “oxygenated”, “air bubble”, “cold boiling”, “hydrogen peroxide”, “catalase”, “catalytic”, “producing”, “generator”, “oxygen”, “oxygen content”, “oxygen tension”, “oxygen-producing antihypoxants”, “hypoxia”, “hypoxemia”, “lack of oxygen”, “ischemia”, “brain”, “cells”, “mitochondria”, “aerobic metabolism”, “survival”, “viability”, “resilience”, “damage”, “reversible”, “irreversible”, “death” and various combinations of the above-mentioned terms. No time limits were chosen for the research. All types of articles, dissertations, and descriptions of inventions in Russian and English were included. In addition, the information in the “References” section of the selected scientific articles was studied.

The information contained in the description of inventions was searched using the following databases: FIIP (In Russ.), RUPTO, USPTO, Google Patents, EAPATIS, Espacenet, PATENTSCOPE, PatSearch, and DWPI. In addition, analogues and prototypes indicated in the selected inventions were studied.

The search for clinical studies was carried out by NU, while PS, and AU searched for theoretical, laboratory, biochemical, experimental and/or biophysical studies. The structured approach proved impractical due to the wide scope of the review, which included both the results obtained before the advent of temperature pharmacology and the advent of thermal imagers, and in the modern era, when monitoring the dynamics of local temperature using infrared thermography began to be widely implemented in laboratory, experimental research and clinical trials.

The article uses various terms to describe the physical-chemical properties of medicines, such as warm, heated, cold, at room temperature, hypotonic, normotonic and hypertensive, acidic, alkaline, carbonated.  We assumed that "hypothermia" is a condition of human tissues with a temperature of less than 36.0°C. We have used the term "hypothermia" to describe any decrease in the general or local temperature of any part of the body below normal temperature. We also assumed that the temperature of all parts of the body changes cyclically, since there is a circadian rhythm. In addition, we assumed that the local temperature of body parts depends on their blood circulation, inflammation, local irritant and drug effects, and their temperature when applied topically.

In addition, the article presents some data on the resistance to hypoxia of warm-blooded and cold-blooded animals, in particular, aquarium fish under various temperature conditions. Attention is also focused on the dependence of metabolic rate on temperature according to the Arrhenius law. The principal possibility of using the catalase enzyme as a new pharmacological target for oxygen-producing antihypoxates containing hydrogen peroxide is shown. This is due to the fact that, in our opinion, tissue protection from lack of oxygen can be improved in the future due to advances in artificial hibernation and local therapeutic hypothermia.

Warnings and side effects of oxygen-producing antihypoxants, oxygen fuses and oxygen generators

Although the review article highlights the advantages of oxygen-producing antihypoxants and oxygen generators in hypoxemia caused by lack of oxygen in the air and/or respiratory obstruction, there is very little direct clinical evidence for this [32-35]. Laboratory and experimental studies describing the mechanisms of the antihypoxic effect of oxygen-producing antihypoxants was studied on an experimental biological model of acute respiratory obstruction in isolated lungs and in live-bred rabbits. Due to the lack of sufficient clinical data, it is necessary to take into account the possible side effects that may occur when using intrapulmonary warm alkaline solutions of hydrogen peroxide with a normal air content and with their saturation with oxygen gas at an excess pressure of up to 0.3 atm.

The most unpredictable side effects and complications can occur with intrapulmonary injections of oxygen-saturated warm alkaline solutions of hydrogen peroxide. The fact is that oxygen-saturated warm alkaline solutions for intrapulmonary injections are not included in the medical standard, the technology of intrapulmonary injections has not been developed, and there are no syringes for intrapulmonary injections of carbonated solutions.

 

3. RESULTS

It has been established that the cause of biological death of all critically ill patients is hypoxic damage to brain cells [9, 30, 36-39]. Therefore, the assessment of the supply of oxygen to brain tissues and the effective delivery of oxygen to the brain are the most important tasks of clinical medicine. However, methods for assessing the oxygen supply of brain tissue, brain resistance to hypoxia, and direct oxygen delivery to the brain have not yet been developed [40]. Moreover, the diagnosis of cerebral hypoxia in patients in hospital settings today is based on indirect signs [41]. Hypoxemia is traditionally used as one of the indirect signs of brain hypoxia in medical institutions around the world - a reduced oxygen content in the body's blood (without specifying blood vessels, but excluding the blood vessels of the brain). However, it should be borne in mind that in practical medicine, oxygen content is assessed using a pulse oximeter, which does not indicate the oxygen content in arterial or venous blood. The fact is that the pulse oximeter allows you to assess the total presence of hemoglobin bound to oxygen molecules in the thickness of the soft tissues of the peripheral parts of the body. Usually, a pulse oximeter is worn on a finger (index or middle), or on the patient's earlobe [42]. But the diagnosis of hypoxemia using a pulse oximeter is very informative. This has been shown by the experience of treating patients affected by a new coronavirus infection complicated by acute respiratory syndrome [43, 44]. At the same time, in clinical conditions, oxygen gas remains the number one antihypoxant for a long time, which is injected into the lungs of patients by inhalation using breathing masks, intubation tubes, and breathing apparatus providing artificial lung ventilation (ALV). As a criterion for the adequacy of the oxygen dose administered by medical professionals into the patient's body, an indicator of the hemoglobin content associated with oxygen is used, which is recorded using a pulse oximeter and is called the "blood oxygenation index" or "blood saturation index" [45].

Nevertheless, despite oxygen gas injected into the lungs with ALV, in some cases severe hypoxemia can not only persist, but also increase, leading to brain hypoxia and death of the patient from hypoxic damage to his brain cells [32, 46]. Evidence of this lack of inhaled oxygen administered using a traditional ventilator is the death of more than 7 million people during the COVID-19 pandemic due to respiratory obstruction [31, 47, 48]. Therefore, reliable and effective oxygenation of blood with oxygen through the lungs in case of respiratory obstruction remains an unsolved problem in modern clinical practice.

It has been reported that many elderly patients with nonspecific bilateral pneumonia caused by COVID-19 may develop respiratory obstruction due to the filling of the peripheral airways with thick sputum and purulent masses [31]. The accumulation of sputum and pus in the respiratory tract does not irritate them, just as blood spilled into the tissues from damaged blood vessels does not irritate soft tissues [49]. The absence of local irritant effects in sputum, pus and blood makes their accumulation in the peripheral areas of the respiratory tract almost " intangible" to the patient and does not cause him to cough. Therefore, older people do not seek to get rid of these biological masses. As a result, they develop hypoxemia. In turn, the expectorants known today, which are part of the medical standard, are not intended for injection into the respiratory tract. Therefore, modern expectorants do not provide an urgent change in the state of dense biological masses inside the respiratory tract and their enrichment with oxygen gas [50-52]. At the same time, researchers in the Russian Federation have shown that thick pus and blood can be instantly converted into oxygen foam by local interaction with a warm alkaline solution of hydrogen peroxide [30-34, 53-56].

These ideas formed the basis for the development in Russia of oxygen-producing antihypoxants, medical "gas fuses" and medical oxygen generators, the original mechanism of action of which, when applied locally, made it possible to raise the effectiveness of eliminating hypoxemia in respiratory obstruction and lack of oxygen in the air to the maximum possible height [54-57].

 

3.1. History of development of oxygen-producing antihypoxants based on hydrogen peroxide

 

The proposal to use warm hydrogen peroxide solutions as a basis for the creation of a new group of oxygen-producing antihypoxants intended for topical application for the purpose of oxygen enrichment of a selected biological object belongs to the head of the Department of General and Clinical Pharmacology of the Izhevsk State Medical Academy, Professor Alexander Urakov [30, 34]. He was the first to suggest the use of local oxygenation of biological objects not with oxygen gas but with a warm solution of hydrogen peroxide. In particular, Alexander Urakov was the first to suggest using hydrogen peroxide solution for injection into a selected portion of venous blood (in a container with preserved donor blood) for the purpose of its oxygenation, into a selected area of soft tissues (skin, subcutaneous fatty tissue, lung tissue, myocardium, brain) in order to enrich them with oxygen, in the respiratory tract for inhalation in the form of an aerosol in order to transform sputum, mucus and pus into oxygen foam, oxygenation of blood through the lungs and expectoration, as well as for irrigation of chronic wounds in order to oxygenate pus and enrich granulations with oxygen [33, 55, 58-61]. The fact is that all of these tissues contain the enzyme catalase, which breaks down hydrogen peroxide into water and molecular oxygen at a tremendous rate [31]. Chemical calculations showed that 100 ml of a solution of 3% hydrogen peroxide produces 1 liter of oxygen gas (Figure 1).

 

Figure 1. Scheme of catalase splitting of hydrogen peroxide into water and oxygen gas.

 

Purposeful development of new medicines, which are solutions of hydrogen peroxide with oxygen-producing activity, began in Izhevsk on January 29, 2000, when the Federal Institute of Industrial Property (FIPS) of the Russian Federation registered a patent application for “Method of treating long-term non-healing wounds” [12, 61]. The developed method was the first invention in which a solution of 3% hydrogen peroxide heated to +37 ºC was proposed as a local oxygen-producing agent to dissolve purulent masses and turn them into oxygen foam while eliminating local hypoxia of granulation tissue at the same time (RU 2187287, 20.08.2002).

Then pharmacologists of Izhevsk under the guidance of Professor Alexander Urakov developed several new oxygen-producing hydrogen peroxide solutions and technologies of their application for the purpose of oxygen foaming of  biological objects (blood, pus, serous fluid and other viscous colloidal biological masses) due to the cleavage of hydrogen peroxide under the action of catalase into water and molecular oxygen:

- «Method for interrupting uterine hemorrhage» (RU 2288656, 10.12.06). This invention is based on a solution of 3% hydrogen peroxide heated to +42 - +45 ºC, which is administered by injection into the uterine cavity during postpartum uterine bleeding.

- «Hyper-gassed and hyper-osmotic antiseptic mixture» (RU 2331441, 20.08.2008). This invention is based on a solution of 2.7-3.3% hydrogen peroxide and 0.9-10.0% sodium chloride, which is saturated with carbon dioxide gas at an excess pressure of 0.2 atm.

- «Softening agent for thick and viscous pus» (RU 2360685, 10.07.2009).  This invention is based on a solution of 2.7 – 3.3% hydrogen peroxide and 5.0 – 10.0% sodium bicarbonate.

- «E. M. Soikher's hyperoxygenated agent for venous oxygen saturation» (RU 2538662, 10.01.2015). In fact, this invention opens a list of medical solutions of oxygen-producing antihypoxants intended for injection for the purpose of oxygenation of selected biological tissues while eliminating the formation of oxygen foam. For this purpose, a solution of 0.05-0.29% hydrogen peroxide, 0.85% sodium chloride and 0.10% sodium bicarbonate is proposed.

- «Method of maintenance of live fish during transportation and storage» (RU 2563151, 20.09.2015). This invention opens a list of hydrogen peroxide solutions in the role of oxygen-producing antihypoxants intended for injection into water in which representatives of ichthyofauna, in particular fish, swim. In this invention, to preserve the life of fish under hypoxic conditions, a solution of 6% hydrogen peroxide is proposed, which is injected into water with fish repeatedly in a single dose of 0.2 ml / kg of fish each time no later than 40 seconds after each sudden convulsive motor activity of the fish. The method ensures the timely supply of fish with a solution of hydrogen peroxide in a concentration safe for fish and in a single dose. It was found that the indicated single dose of a solution of 6% hydrogen peroxide ensures the preservation of fish life in a hermetically sealed container with water at a water temperature of +25 ° C for at least 20 minutes. It has been found that fish are able to absorb hydrogen peroxide, which is broken down into water and molecular oxygen in their body under the action of the enzyme catalase.

At the same time, in the same years, the State Fund for the Promotion of Innovations of the Russian Federation allocated Natalia Urakova a grant of 2 million rubles under the START program to conduct scientific research on the topic "Development of a drug for whitening bruises under the eyes." To carry out these scientific studies, the Institute of Thermology was opened, and the staff included the following researchers: Natalia Urakova (director), Professor Alexander Urakov, as well as assistants Anton Kasatkin and Alexey Reshetnikov. In addition to these employees, the team includes several students who are members of the Society of Pharmacologists: Leisan Chernova, Evgeny Fischer, Marat Nasyrov and Albina Gadelshina (Shchemeleva). As a result, a team of researchers at the Institute of Thermology in Izhevsk, led by Professor Alexander Urakov, developed a new group of drugs that dissolve, discolor and foam stains and blood clots due to the presence of hydrogen peroxide in the drugs. This group of drugs is called "Bruise Bleachers" [26, 31, 34, 49, 62-64]. The novelty of the developments is confirmed by patents for 16 inventions (Table 1).

Table 1.

A list of invented medicines and methods of their medical use for the dissolution, discoloration and foaming of stains and blood clots, invented in Izhevsk on the basis of hydrogen peroxide.

 

CN	Title	Patent number and publication date
1	Method of express cleaning of blood stains off clothes	RU 2371532, 27.10.2009
2	Methods of diagnostics and treatment of clotted hemothorax by A.Y. Malchikov	RU 2368333, 27.09.2009
3	Bruise bleacher	RU 2539380, 20.01.2015
4	Bleaching agent	RU 2589682, 10.07.2016
5	Method for skin discoloration in bruising area	RU 2586278, 10.06.2016
6	Agent for intradermal bruise whitening	RU 2573382, 20.01.2016
7	Method for skin discoloration in bruising area	RU 2582215, 20.04.2016
8	Method for emergency bleaching and blood crust removal from skin in place оf squeezed out acne»	RU 2631593, 25.09.2017
9	Method for whitening of sore under nail	RU 2631592, 25.09.2017
10	Method for whitening of bruise under eye	RU 2639283, 20.12.2017
11	Means for intravital skin whitening near blue eyes	RU 2639485, 21.12.2017
12	Bleaching opener of dried blood for wrapping bandages adhered to a wound	RU 2653465, 08.05.2018
13	Method for blue nail treatment	RU 2641386, 17.01.2018
14	Decolorant of blood	RU 2647371, 15.03.2018
15	Bleaching cleanser of dentures	RU 2659952, 04.07.2018
16	Method of emergency bleaching of skin hematoma under eye	RU 2679334, 07.02.2019

 

After the successful completion of the bruising bleaches development phase in Izhevsk in 2019, the research team expanded to include scientists from St. Petersburg. In particular, Professor Peter Shabanov, Head of the Department of Pharmacology at the Kirov Military Medical Academy, made a significant contribution to the development of new oxygen-producing drugs. At the beginning, Peter Shabanov participated in the development of the following bleaches:

- «Method of using plaque removal solution with irrigation agent» (RU 2723138, 09.06.2020).

- «Method for screening dental cleansers on model of transparent teeth coated with dental deposit» (RU 2725131, 30.06.2020). 

- «Dandelion milky juice stains bleaching agent» (RU 2765469, 31.01.2022).

After that, Peter Shabanov became a permanent member of the team of developers of new oxygen-producing drugs created jointly on the basis of warm alkaline solutions of hydrogen peroxide [30, 31, 34-39, 51, 53, 54, 59, 62, 67, 68, 70].

Regardless of the successful development of new oxygen-producing bleachers for bruises, new oxygen-producing antihypoxants continued to be developed in Izhevsk and St. Petersburg during the same time period.

In 2016, an “Agent for increasing resistance to hypoxia” was invented (RU 2604129, 10.12.2016). This medication is a carbonated drink intended for ingestion that includes 0.3-0.5% hydrogen peroxide and oxygen gas to create an overpressure of 0.2 atm.

Also in 2016, the world's first “Lympho-subsitute for local maintaining viability of organs and tissues in hypoxia and ischemia” was invented (RU 2586292, 10.06.2016). The medicinal product is an aqueous solution intended for injection which includes 0.01-0.02% hydrogen peroxide, 0.88% sodium chloride and 0.06-0.1% glucose and bidistilled water at pH 7.4 and osmotic activity 280 mosmol/L of water. This drug solution is intended for injection into the area of ischemia and/or hypoxia for local oxygenation of selected tissue area.

In 2017, “Means for physical endurance increase” was invented (RU 2634271, 24.10.2017). It is an oral beverage that includes 3% hydrogen peroxide, 7% glucose and oxygen gas at an overpressure of 0.2 atm.

In 2018, the “Energy drink” was invented (RU 2639493, 21.12.2018). This drink is intended for enteral nutrition of children. The invented drink is in the form of a sterile solution including glucose, ethyl alcohol, 0.3-0.5% hydrogen peroxide, citric acid and prepared water for injection containing oxygen gas under overpressure of 0.2 atm.  

In 2020, a team of researchers led by Prof. Aleksandr Urakov developed the “Method of extrapulmonary blood oxygenation” (Application No. 2020120367, filed 15.06.2020, published 15.12.2021). The method includes introduction into the gastrointestinal tract of the victim of 0.1-0.5 liters of a solution of 3% hydrogen peroxide heated to +36 - +42 ºC, saturated with oxygen gas under overpressure of 0.2-0.8 atm., and simultaneous tourniquet application to the proximal parts of his extremities until cessation of pulsation of peripheral arteries in them for up to 15 minutes with simultaneous cooling of the ischemic areas to +18°C.

In the same year, 2020, a patent for the invention was obtained «Aerosol for inhalations in obstructive bronchitis» (RU 2735502, 03.11.2020). Aerosol contains drinking soda, medicines and distilled water at temperature higher than 40 °C, provides microparticles sizes in range of 0.5–2 mcm by means of liquid spraying or disperse spraying with the help of ultrasonic, compression and jet inhalers and nebulisers, characterized by that the medicines used are hydrogen peroxide and lidocaine hydrochloride, wherein components are contained in following ratio (wt. %): sodium bicarbonate - 1.2; hydrogen peroxide - 0.3–0.5; lidocaine hydrochloride - 0.5; distilled water - balance, at pH 8.5, osmotic activity 280–300 mOsm/l of water and local temperature +41– +55 °C. Invention provides the urgent dissolution of thick pus, thick mucus with blood veins, improved

expectoration, respiratory relief, bronchial lumen enlarging, increased content of oxygen in bronchi without local irritant action, without amplification of obstructive bronchitis symptoms, without developing pneumonia, acidosis, alcoholic intoxication and bronchial spasm in resuscitation patients.

Then, in 2021, a patent was obtained for the invention «Aerosol for invasive mechanical ventilation in COVID-19» (RU 2742505, 08.02.2021). Spray for invasive mechanical ventilation

during COVID-19 includes, in wt.%: 2-10% sodium bicarbonate, 0.3 to 0.5% hydrogen peroxide, 0.5% lidocaine hydrochloride and the rest water for injection, with pH 8.5, osmotic activity 370-1990 mOsm/l of water and the local temperature +37- +55 °С. Use of the proposed remedy provides urgent elimination of the symptoms of obstructive bronchitis, improvement of the airway patency for respiratory gases, increase in effectiveness of pulmonary blood oxygenation during artificial ventilation of the lungs and reduction of the degree of hypoxia in intensive care patients.

Also in 2021, a team of researchers led by professor Aleksander Urakov invented a "Method of lung oxygenation in COVID-19" (Application No. 2021102618, submitted on 02.04.2021, published on 08.04.2022). Here is the formula of this invention:

“A method of lung oxygenation, including choosing the injection site between the 7th and 8th ribs in the projection area of the line located in the middle of the distance between the spine and the posterior axillary line, treating the skin in this place with an antiseptic, and performing local infiltration anesthesia with a solution of 1% lidocaine hydrochloride in this place, ultrasound-controlled injection of an injection needle into the soft tissues of the intercostal space along the upper edge of the underlying rib, piercing them and the parietal pleural membrane, attaching to the needle of the syringe, changing the pressure in the syringe, changing the pressure in the respiratory tract, introducing into the biological tissue an aqueous solution of hydrogen peroxide and sodium bicarbonate at a temperature of +37 - +42 °C in the volume that ensures the release of the resulting foam to the outside through an open passage, after that, the needle is removed, the skin in the puncture area is wiped with a damp cloth, dried and sealed, characterized in that the injection is performed into the right half of the chest when breathing and respiratory movements of the chest and diaphragm stop, the visceral pleural membrane is additionally pierced and the needle is immediately pushed an additional 3 mm deep into the right lung, injected into it a solution of 3% hydrogen peroxide and 1.8% sodium bicarbonate under the control of the upper respiratory tract, and after the appearance of foam in them and its release to the outside, intrapulmonary injection of the solution is stopped and ventilation of the lungs and respiratory movements of the chest and diaphragm are restored”.

However, the Federal Institute of Industrial Property of the Russian Federation refused to grant the authors a patent for this invention.

Following these invented oxygen-producing antihypoxants, Professor Alexander Urakov proposed to enhance their antihypoxic activity by saturating their solutions with oxygen gas under overpressure and injecting them into the respiratory organ by intrapulmonary, endobronchial and endotracheal injections. It was initially decided to take the pressure of carbon dioxide used in the production of carbonated drinks intended for ingestion (0.2 - 0.3 atm.) as a reference point of safe overpressure of gas in solutions. The results of experimental studies confirmed the correctness of the chosen solution and provided patents for the world's first inventions that opened the way to intrapulmonary, endobronchial and endotracheal injections:

- «Warm alkaline solution of hydrogen peroxide for intrapulmonary injection» (RU 2807851, 21.11.2023):

- «Oxygenated warm alkaline hydrogen peroxide solution for intrapulmonary injection» (RU 2831821, 16.12.2024);

- «Method of application of an alkaline solution of hydrogen peroxide to eliminate blood asphyxia» (Application No. 2024100268, filed 09.01.2024); 

- «Method of endobronchial injection of drug for emergency elimination of asphyxia» (RU 2833321, 17.01.2025).

The essence of these inventions is that as local (intrapulmonary) oxygen-producing antihypoxants, solutions of 4.5% hydrogen peroxide and 1.8% sodium bicarbonate heated to a temperature of +37 - +45 ºC, which are saturated with oxygen gas under overpressure of 0.2 - 0.3 atm, are proposed. Intrapulmonary, endobronchial or endotracheal injection of such solutions provides immediate interaction of hydrogen peroxide with sputum, mucus, pus and blood containing catalase, which immediately breaks down hydrogen peroxide into water and oxygen (Figure 2).

 

Figure 2. A warm alkaline solution of hydrogen peroxide in direct interaction with blood, mucus, pus and other tissues instantly turns colloidal fluids into oxygen foam because the hydrogen peroxide in WAHPS is instantly broken down by the action of the tissue enzyme catalase into water and oxygen gas. WAHPS: warm alkaline hydrogen peroxide solutions. Reproduced from Osipov AN, Urakova NA, Urakov AL, Shabanov PD. Warm alkaline hydrogen peroxide solution as an oxygen-releasing antihypoxic drug: potential benefits and applications. Med Gas Res. 2025 Mar 1;15(1):134-135.

 

As a result, the airways are filled with gaseous oxygen, oxygen is immediately absorbed into the blood through the lungs, which eliminates hypoxemia without cauterizing the mucous membranes of the airways [65-70]. At the same time, pus, sputum and pus inside the respiratory tract immediately turn into a soft oxygen foam, which is pushed out. In experiments in a model of asphyxia of isolated rabbit lungs with artificial sputum, it was shown that intrapulmonary injection of WAHPS in 1 second transforms artificial sputum into oxygen foam, which fills the airways and is pushed outward (Figure 3).

 

 

     Figure 3. Isolated rabbit lung before (1), after endorheal injection of 40 ml of artificial sputum (2) and 1 s  after intrapulmonary injection of 2 ml WAHPS (3). The blue arrow indicates white-colored foam. Reproduced from Urakova NA, Urakov AL, Shabanob PD. Intrapulmonary and intrabronchial oxygen-producing antihypoxants eliminate asphyxia and hypoxemia. Medical Gas Research. 2025;15(4):550-551.

Consequently, the inventors of Izhevsk and St. Petersburg have shown for the first time in the world that warm alkaline solutions of hydrogen peroxide are oxygen-producing antihypoxants, the local application of which may become in the future an alternative to oxygen gas, since oxygen can be a metabolite of hydrogen peroxide. The results of experimental studies on the antihypoxic efficacy of warm alkaline hydrogen peroxide solutions when applied topically convince that these oxygen-producing antihypoxants may take a leading place among drugs intended for inhalation, intrapulmonary, endotracheal and endobronchial injections in the future.

 

3.2. History of oxygen fuzes development

 

The patent for the first medical “gas fuze” designed for safe “blasting” and geyser-like removal of dense biological masses from fistulas was granted in Russia in 2008. A team of authors led by Professor Alexander Urakov invented a gassed antiseptic solution “Hyper-gassed and hyper-osmotic antiseptic mixture” (RU 2331441, 20.08.2008) [71]. This carbonated antiseptic solution consists of 2.7-3.3% hydrogen peroxide, 0.9-10.0% sodium chloride and carbon dioxide before creating an overpressure of 0.2 atm. It was shown that the direct interaction of the invented gas fuze with purulent masses, blood and mucus provides “explosion” of biological masses due to rapid release of carbon dioxide gas bubbles and oxygen gas, which is formed due to catalase cleavage of hydrogen peroxide into water and molecular oxygen, which forms a rapid process of cold boiling inside the biological mass, “exploding” it, turning it into soft foam and pushing it out of the fistula to the outside in the form of a geyser.

The first patent for medical “oxygen fuze” was granted in Russia in 2009.  Izhevsk inventors received a patent for their invented “oxygen fuze” designed for pleural cavity lavage in tuberculous empyema of the pleura: “Softening agent for thick and viscous pus” (RU 2360685, 10.07.2009).  This invention is based on a solution of 2.7 – 3.3% hydrogen peroxide and 5.0 – 10.0% sodium bicarbonate. It has been shown that this oxygen fuze provides optimal alkaline hydrolysis of lipid and protein-lipid complexes that form the basis of pus, splitting of hydrogen peroxide under the action of the enzyme catalase into water and oxygen gas, which forms the process of “cold boiling” inside the pus mass, its physical destruction by means of intra-tissue explosion-like multigas formation.

Two months later, a team of Izhevsk researchers received the 2nd patent for a medical “oxygen fuse”. This time they invented an oxygen fuse designed for urgent transformation into oxygen foam of a blood clot inside the pleural cavity: Methods of diagnostics and treatment of clotted hemothorax by A.Y.Malchikov (RU 2368333, 27.09.2009). The essence of the invention is to inject into the blood clot a solution of 1.5% hydrogen peroxide and 5% sodium hydrogen carbonate heated to 37 °C, after which the foam is removed from the pleural cavity by means of its drainage. 

Then a patent for the invention “Method and means for removal of sulphur plug” was obtained (RU 2468776, 27.06.2012). In this invention, an “oxygen fuze” was proposed for removing a large sized solid sulfur plug from the external ear canal. The fact is that as people's life expectancy increases, the proportion of elderly and senile patients in doctors' practices is also increasing, and diseases characteristic of them are more common. One of the common health problems of the elderly is hearing loss (hearing loss), which occurs due to the blockage of the external ear canal by a wax plug. Often the sulphur plug reaches a large size and becomes highly resistant, making it difficult to remove the wax plug and restore hearing [72]. To remove sulphur plugs (as well as other foreign bodies) from the external ear canal, it is recommended to use a solution of 3% hydrogen peroxide, which should be administered in a volume of a few drops to a few milliliters without heating, i.e. at room temperature [72-74]. But the effectiveness of a regular solution of 3% hydrogen peroxide remains low.

Inventors from Izhevsk and St. Petersburg have shown that a standard solution of 3-6% hydrogen peroxide can be transformed (repurposed) into an “oxygen fuze”. To do this, replace the acidic activity of the standard solution with an alkaline activity up to pH 8.4 using baking soda, and then heat the solution to a temperature of +37 - +45 °C [31, 51, 59, 61, 75]. On isolated sulfur plugs it has been shown that injection of such an oxygen fuze into a sulfur plug has a powerful destructive force.  Under laboratory conditions using isolated sulfur plugs, it has been shown that the oxygen fuzes literally explode the sulfur plug immediately, scattering sulfur plug fragments at high velocity up to 1 meter away [57]. Based on this, it was concluded that these oxygen fuzes could not be used inside the external ear canal because their explosive action could rupture the eardrum and damage the hearing aid. It was reported that researchers had invented a special warm alkaline hydrogen peroxide solution (WAHPS) with weak “explosive” activity and high safety inside the ear canal and proposed an unusual way to use it. Such a safe but effective medical “oxygen fuze” of sulfur plugs is a solution of 0.3 - 0.5% hydrogen peroxide and 1.7 - 2.3% sodium hydrogen carbonate, heated to +42 °C. In addition, a new method of its application was proposed in the form of injection of a medical “oxygen fuzer” inside the sulfur plug.

The history of the development of new drugs based on the oxygen fuzes mentioned above did not end only with them. In particular, in 2018, pharmacologists from Izhevsk received a patent for an invention that used an original oxygen fuze to painlessly and bloodlessly remove dried, bloody bandages stuck to wounds, as well as to whiten the wound and the skin around it. For this purpose, the " Bleaching opener of dried blood for wrapping bandages adhered to a wound " was invented (RU 2653465, 05/08/2018). Bleaching powder of dried blood for soaking bandages stuck to the wound contains 0.75-1% hydrogen peroxide, 1.2% sodium bicarbonate, 0.5% lidocaine hydrochloride and bidistilled water. The invented drug provides an urgent transformation of dried blood into a soft foam and a bloodless and painless removal of bloody bandages from the wound.

Consequently, the listed patents for inventions and the dates of their issuance in the Russian Federation clearly indicate that Russia is the birthplace of a new group of medicines called "oxygen fuzes".

 

3.3. History of medical oxygen generators

Oxygen-producing antihypoxants and oxygen fuzes invented in Russia were designed to be administered directly into biological objects containing the enzyme catalase. It is catalase that represents the pharmacological target for these drugs, with the help of which hydrogen peroxide is split into water and oxygen gas. In turn, the intensity of oxygen gas release determines the intensity of the cold boiling process, ranging from complete elimination of gas bubbles to their rapid formation up to “cold blast” [31, 55, 67]. Therefore, hydrogen peroxide contained in these medicines is practically not broken down into water and oxygen gas without interaction with the enzyme catalase. Therefore, the above listed drugs and methods of their medical use are not suitable for generating significant amounts of oxygen gas outside of interaction with animal and human bodies and outside of biological objects.

Nevertheless, there are still some unsolved problems in medicine with preservation of human life in conditions of absence and/or lack of oxygen gas in inhaled air, when there is no possibility to perform intrapulmonary, endotracheal and/or endobronchial injections of warm alkaline hydrogen peroxide solutions in the role of oxygen-producing antihypoxants. In particular, such problems are relevant to disaster medicine, military medicine, and pre-hospital care. The experience of emergency care in terrorist acts, man-made disasters, emergencies with fires and smoke in closed rooms has shown that victims died in the first minutes due to hypoxic brain damage due to lack of oxygen in the inhaled air. In this case, oxygen cylinders and other oxygen containers are not applicable and are contraindicated due to the risk of fire [76, 77].

To solve this problem in 2024 St. Petersburg and in Izhevsk under the leadership of Professors Peter Shabanov and Alexander Urakov, a team of researchers developed the world's first “Individual portable oxygen generator for pre-hospital care” (Application No. 2024136943, registered 09.12.2024). The essence of the invention is that as a source of oxygen use a solution of 3% hydrogen peroxide, in which iron sulfate powder is introduced in the ratio of 100 ml of solution/5 g of powder inside a polyethylene universal storage bag with a tie immediately before rendering assistance.

The technical result of this invention is the rapid filling with oxygen gas of a polyethylene universal storage bag with a tie, inhalation of oxygen from the bag regardless of the victim's movement in space together with the oxygen bag, elimination of suffocation in the victim, the feeling of fear of approaching death, lengthening the period of preservation of consciousness in the absence of electricity, breathing apparatus for individual use, cylinders with oxygen and oxygen in the ambient air at the exclusion of the development of laryngospasm. 

The point is that iron cations are highly effective catalysts for decomposition of hydrogen peroxide into water and molecular oxygen, and the ratio of the volume of 100 ml of a solution of 3% hydrogen peroxide and 5 g of iron sulfate powder is optimal for the corresponding chemical reaction. In this connection, mixing them with each other in the specified ratio causes immediate decomposition of all hydrogen peroxide into water and oxygen gas. The chemical reaction produces about 800 ml of molecular oxygen at normal atmospheric pressure. This volume of oxygen gas enters the respiratory system of an adult person during 8 breaths of 500 ml of normal air containing about 21% oxygen. In this case, 500 ml of air is the value of one respiratory volume of air carried out by an adult during the daytime in the state of wakefulness at rest. Therefore, a single mixing of 100 ml of a solution of 3% hydrogen peroxide and 5 g of ferrous sulfate powder provides about 800 ml of oxygen gas in the bag very quickly. This amount of oxygen is sufficient for one complete or several consecutive incomplete breaths by an adult or several complete breaths by a child.

The invented oxygen generator provides preservation of consciousness and prolongation of the period of preserved consciousness in victims for 1 - 2 minutes. In turn, this provides the victim with timely taking the right decision and the victim's exit from the smoke-filled room.

At the same time, a solution of 3% hydrogen peroxide is a popular over-the-counter preparation packed in 100 ml bottles and widely distributed in all localities not only in Russia, but also all over the world. In turn, iron sulfate powder is widely known as iron sulfate and is widely used by gardeners around the world as a means of disinsection and deratization of trees. Both the preparations are low cost and easily available to the public. Therefore, these ingredients can be used universally to create a homemade, easily portable oxygen generator for use in pre-hospital care.

Laboratory studies have shown that the application of the claimed device causes the formation of oxygen gas inside the package cavity immediately after the beginning of interaction of hydrogen peroxide solution with iron sulfate powder inside the cavity. The process of formation of oxygen gas from the solution is accompanied by the formation of foam, splashing of fine spatters and light effervescence. This process is visible to the consumer through the transparent walls of the bag, which ensures that the consumer can visualize the gassing process and its completion. At the same time as the oxygen gas is released, the process lowers its temperature, as the process of gas release is similar to evaporation and belongs to an endothermic reaction. Inhalation of cooled and moist oxygen gas has a refreshing effect in the mouth and upper respiratory tract of the victim.

 

4. Conclusion

Inventors from Izhevsk and St. Petersburg have shown for the first time in the world that warm alkaline hydrogen peroxide solutions (WAHPSs) are oxygen-producing antihypoxants. Russia was the first country in the world to invent WAHPSs for inhalation, intrapulmonary, endotracheal and endobronchial injections. In addition, Russia is also the birthplace of a new group of medicines called “oxygen fuzes”. Finally, at the end of 2024, the Russian Federation has developed the world's first individual portable oxygen generator for emergency pre-hospital care. Such an oxygen generator can be used in conditions of terrorist acts, man-made disasters, emergencies in wartime and peacetime in case of asphyxiation caused by lack of oxygen in the inhaled air, for example, due to fire and smoke in a closed room, in the absence of oxygen cylinders and breathing apparatus for individual use.

Author contributions. All authors confirm that their authorship meets the ICMJE international criteria (all authors contributed substantially to the conceptualization, research and preparation of the article, read and approved the final version before publication).

Conflict of interest. The authors declare that they have no apparent and potential conflicts of interest related to the publication of this article.

Funding source. The authors state that there was no external funding in the conduct of the study.

Об авторах

Наталья Александровна Уракова

Институт экспериментальной медицины; Ижевская государственная медицинская академия

Email: urakovanatal@mail.ru
ORCID iD: 0000-0002-4233-9550
SPIN-код: 4858-1896
Scopus Author ID: C-4969-2013

канд. мед. наук

Россия, Санкт-Петербург; Ижевск

Александр Ливиевич Ураков

Ижевская государственная медицинская академия

Автор, ответственный за переписку.
Email: alurakov@bk.ru
ORCID iD: 0000-0002-9829-9463
SPIN-код: 1613-9660

 д-р мед. наук, профессор

Россия, Ижевск, ул. Коммунаров, 281, 426034. Россия

Петр Дмитриевич Шабанов

Институт экспериментальной медицины; Военно-медицинская академия имени С.М. Кирова

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-код: 8974-7477

доктор мед. наук, профессор

Россия, 197022,Санкт-Петербург, ул. Академика Павлова, д. 12; 194044, Санкт-Петербург, ул. Академика Лебедева, 6

Список литературы