Method for the treatment of mitochondrial dysfunction in patients with diseases accompanied by chronic inflammation

Abstract

FIELD: physiotherapy.SUBSTANCE: can be used to treat mitochondrial dysfunction in patients with diseases accompanied by chronic inflammation. The method involves daily physiotherapy procedures, including: hypoxic therapy in the mode of interval hypo-hyperoxic training; hyperbaric oxygenation and ozone therapy. During interval hypoxic-hyperoxic training, the oxygen content in the hypoxic mixture ranges from 9 to 16 vol.%, and in the hyperoxic mixture – from 32 to 40 vol.%. The session lasts 45-50 minutes. Hyperbaric oxygenation is then performed in a pressure chamber at 1.3 atmospheres for 15-60 minutes. Next, ozone therapy is carried out. The duration of the stated course of treatment is 12 days.EFFECT: reducing the manifestations of mitochondrial dysfunction in patients with a wide range of diseases, and also ensuring improvement of clinical and laboratory parameters of patients.3 cl, 3 dwg, 1 tbl, 6 ex

Description

[0001] Technical field

[0002] The invention relates to medicine and concerns a non-pharmaceutical method for treating diseases through the combined use of hypo- and hyperoxytherapy, hyperbaric oxygenation, and ozone therapy. Chronic inflammation associated with mitochondrial dysfunction underlies the development of both brain diseases (neuroinflammation) and most somatic diseases (systemic inflammation). The spectrum of diseases includes neurodegenerative diseases, chronic mental illnesses, cardiovascular, endocrine and metabolic diseases, reproductive diseases, chronic latent infections and post-infectious conditions, etc.

[0003] Background of the Art Mitochondria are essential cellular organelles, whose primary functions include providing energy to the cell and maintaining oxidative balance. Mitochondrial dysfunction is accompanied by cellular energy deficiency, oxidative stress, and apoptosis, leading to functional and structural failure of the cell and organ as a whole. Mitochondrial dysfunction is divided into two main types: primary and secondary. Mitochondrial pathology is caused by a primary defect in mitochondrial function and is a genetically mediated disease associated with genetic abnormalities in mitochondrial DNA or regions of nuclear DNA responsible for encoding mitochondrial proteins. Mitochondrial pathology manifests itself with a polymorphic clinical picture, primarily involving the central nervous system, skeletal muscles, and a number of systemic manifestations.Secondary mitochondrial dysfunction is a typical pathological process that occurs in various diseases and does not have etiological or clinical specificity.

[0004] Mitochondrial dysfunction leads to disruption of energy-synthetic processes, the development of oxidative stress, and metabolic disturbances, leading to acidification of the intracellular environment and the synthesis of toxic metabolites. These factors cause damage to intracellular structures and the activation of apoptosis.

[0005] Mitochondrial dysfunction involves the synthesis of aggressive damaging factors and reduces the body's resistance to their effects. Specifically, metabolic disorders and a lack of high-energy compounds in the mitochondria lead to impaired steroidogenesis and, consequently, the development of hormonal deficiency. Reduced energy supply to the immune system, when significantly activated by chronic inflammation, leads to the development of immunodeficiency. In this situation, the body's response to stressors is inadequate, leading to a worsening of the condition even with a slight increase in stress.In the nervous system, as one of the most energy-consuming tissues, but at the same time having a rather limited antioxidant resource, mitochondrial dysfunction leads to disruption of the processes of maintaining transmembrane ion gradients, deterioration of transmembrane transport, vesicle recycling and synaptic signal transmission - the main mechanisms responsible for the correct functioning of the nervous system.

[0006] Inflammation is a factor that can initiate and maintain mitochondrial dysfunction. Inflammation leads to the secretion of cytokines that maintain oxidative stress and cause damage to mitochondrial DNA. The inflammatory process leads to a disruption of the functional activity of mitochondria, which leads to greater cell damage, the development of endothelial dysfunction, which entails the progression and generalization of chronic inflammation. In turn, damaged mitochondria can cause persistent inflammatory reactions and subsequent pathological inflammation. [Qin P, Sun Y, Li L. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review). Int J Mol Med. 2024;53(5):47.] Dysfunctional mitochondria release reactive oxygen species and molecular markers of damage, activating immune cells, including microglia in the brain, triggering the release of proinflammatory cytokines and chemokines, thereby worsening damage.Long-term exposure to reactive oxygen species (ROS) and inflammatory responses against the background of a hypoenergetic state maintain mitochondrial failure and lead to impaired mitophagy. Impaired mitochondrial dynamics can lead to the accumulation of dysfunctional mitochondria, which increases susceptibility to inflammation-induced neuronal death. [Qin P, Sun Y, Li L. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review). Int J Mol Med. 2024;53(5):47.] Under such conditions, the high energy demand of activated microglia further limits energy access to neurons, which leads to impaired cellular metabolism and massive cell death. [Cunnane S.C. et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of aging / / Nature reviews Drug discovery. - 2020. - V. 19. - No. 9. - pp. 609-633., Qin P, Sun Y, Li L. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review). Int J Mol Med. 2024;53(5):47.] As a result, a vicious circle is formed - damaged mitochondria cannot be removed, which contributes to increased oxidative stress and damage to normally functioning mitochondria.

[0007] Thus, inflammation and mitochondrial dysfunction are common and interconnected pathophysiological processes in the development and progression of chronic diseases. Moreover, both processes are systemic in nature, that is, they are inherent not only to a specific organ or system, the disruption of which is presented by the patient's clinical picture, but involve all body systems. The spectrum of nosologies includes neurodegenerative, chronic mental diseases, cardiovascular, endocrine and metabolic diseases, diseases of the reproductive system, chronic latent infections and post-infectious conditions, etc. [Patergnani S, Bouhamida E, Leo S, Pinton P, Rimessi A. Mitochondrial Oxidative Stress and "Mito-Inflammation": Actors in the Diseases. Biomedicines. 2021; 9(2):216. https: / / doi.org / 10.3390 / biomedicines9020216, Pinti MV, Fink GK, Hathaway QA, Durr AJ, Kunovac A, Hollander JM. Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis.Am J Physiol Endocrinol Metab. 2019 Feb 1;316(2):E268-E285. doi: 10.1152 / ajpendo.00314.2018., Dabravolski, S. A.; Nikiforov, N.G.; Eid, A.H.; Nedosugova, LV; Starodubova, A.V.; Popkova, TV; Bezsonov, E.E.; Orekhov, AN Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome. Int. J. Mol. Sci. 2021, 22, 3923. https: / / doi.org / 10.3390 / ijms22083923] To date, there is compelling evidence confirming that oxidative stress in the brain and chronic neuroinflammation arise as a result of the transmission of inflammatory signals to the brain after the development of chronic inflammation and oxidative stress in the periphery. [Morris, G., Berk, M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 13, 68 (2015).] Despite the remaining uncertainty regarding the extent to which mitochondrial damage is a consequence or a cause of the onset or progression of brain diseases, it is clear that mitochondrial dysfunction is an important link in pathogenesis and is inherent in most, if not all, chronic diseases at one stage or another. [Cunnane S.C. et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of aging / / Nature reviews Drug discovery. - 2020. - Vol. 19. - No. 9. - Pp. 609-633.].

[0008] Thus, normalizing mitochondrial function will help reduce the impact of damaging factors and increase the body's energy resources. Maintaining mitochondrial function may be an effective way to support the treatment of diseases associated with mitochondrial dysfunction, inflammation, and metabolic disorders.

[0009] Mitochondrial dysfunction has multisystem manifestations with nonspecific symptoms (weakness, chronic fatigue, decreased performance, muscle hypotonia, etc.). If prolonged and accompanied by depletion of the body's resources, depending on the degree of involvement of a particular system, it can develop into a specific nosology. This primarily affects the cardiovascular and central nervous systems, which are most sensitive to oxygen deficiency. It is now known that secondary mitochondrial dysfunction underlies the development and progression of the most important socially significant diseases. Thus, the pathogenetic role of mitochondrial dysfunction has been proven in chronic diseases of the nervous system: neurodegenerative diseases, multiple sclerosis, schizophrenia, affective disorders, developmental delays, ASD, etc., also mitochondrial disorders during reperfusion changes are the main pathophysiological link in damage to nervous tissue during both acute and chronic ischemia. [1-6, Norat, P., Soldozy, S., Sokolowski, JD et al. Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation. npj Regen Med 5, 22 (2020)].

[0010] Any processes of structural and functional restoration of nervous tissue, including synapse remodeling, myelin regeneration or axonal transport, are very energy-intensive processes, so their stimulation to restore the function of damaged neurons in various psychoneurological diseases will be ineffective under conditions of a cellular hypoenergetic state, regardless of the mechanisms of action of the therapy. [Cunnane S.C. et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of aging / / Nature reviews Drug discovery. - 2020. - V. 19. - No. 9. - P. 609-633.] Thus, optimization of the brain's energy supply should be a major component of the treatment strategy. Approaches to improving mitochondrial function include influencing the mitochondrial redox state, stimulating mitochondrial biogenesis, and modulating mitochondrial dynamics. [Zong Y, Li H, Liao P, et al.Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):124. Published 2024 May 15. doi:10.1038 / s41392-024-01839-8] At the same time, strategies for combating oxidative stress and improving mitochondrial functional disorders are usually aimed at a single enzyme, transporter, metabolite, or metabolic pathway, which limits their effectiveness. The most relevant is the consideration of strategies for multimodal influence on mitochondrial function. Thus, a promising direction is the impact on mitochondrial biogenesis - the cellular mechanism of formation of new mitochondria, and mitochondrial dynamics - the process of fusion and division of mitochondria, that is, those processes that play an important role in maintaining the homeostasis of cells and tissues, and the disruption of which leads to the accumulation of damaged mitochondria. [Cunnane S.C. et al.Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of aging / / Nature reviews Drug discovery. - 2020. - V. 19. - No. 9. - P. 609-633., Qin P, Sun Y, Li L. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review). Int J Mol Med. 2024;53(5):47.] For example, compounds capable of modulating nodal regulators of the mitochondrial biogenesis network are being developed, which demonstrate the potential for pharmacological intervention to enhance mitochondrial biogenesis in conditions of mitochondrial dysfunction. [Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):124. Published 2024 May 15.].

[0011] Correction of both primary and secondary mitochondrial dysfunction by pharmacological methods is based on metabolic therapy using energotropic drugs—substances that stimulate energy metabolism and energy substrates. [7] The most commonly included drugs in pharmacological correction regimens include coenzyme Q10, L-carnitine, cytochrome C, succinic acid, and lipoic acid. Along with energotropic therapy, antioxidants, antihypoxants, vitamins and vitamin-like substances, coenzymes, and trace elements are prescribed.

[0012] Non-pharmacological methods of supporting mitochondrial function are known, based on various modes of oxidative effects on the body, the main ones being: hypoxic therapy, hyperbaric oxygenation, and ozone therapy.

[0013] Hypoxytherapy is a physiotherapeutic method of interval hypoxic training based on alternating breathing with a mixture with a reduced oxygen content and a mixture with a higher oxygen content. The method is aimed at regulating the functioning of the mitochondrial pool and increasing the energy potential of the cell. Mitochondria exposed to oxidative stress have damaged, shortened DNA and produce greater amounts of ROS, but nevertheless have a replicative advantage and accumulate in the cell faster than healthy ones, thereby leading to an increase in oxidative stress. [8] Improving the quality of the mitochondrial pool is based on the selective pathological effect of hypoxia intervals on dysfunctional mitochondria, for which periodic waves of hypo- and hyperoxia are excessively stressful and lead to critical damage to the mitochondria, triggering the natural process of their elimination - mitoptosis.[8, 9] As a result, defective mitochondria are eliminated, while normally functioning ones gain an advantage in division, increasing the accumulation of their intracellular pool. "Healthy" mitochondria, under the influence of rhythmic hypoxia, increase their adaptive capacity and are also stimulated by antioxidant mechanisms, which generally leads to the normalization of oxygen metabolism and an increase in the efficiency of energy-synthetic processes.

[0014] Furthermore, interval hypoxic training activates regulatory and adaptive systems, including the pituitary-adrenal, nervous, and endocrine systems. Exposure to hypoxia leads to the activation of both short-term and long-term adaptive mechanisms [9]. Urgent reactions are triggered by stimulation of chemoreceptors of the vascular system and the reticular formation of the brainstem by altered blood gas composition, leading to reflex changes in the respiratory and cardiovascular systems, as well as stimulation of endocrine function. At the same time, levels of thyroid hormones and insulin increase, which leads to increased intensity of oxidative processes and tissue oxygen consumption.Long-term adaptation to hypoxic exposure is associated with increased transcription of genes regulated by HIF-1 and thyroid hormones, stimulating angiogenesis, the synthesis of erythropoietin, myo- and hemoglobin, mitochondrial respiratory enzyme proteins, as well as regulators of apoptosis and cell proliferation.

[0015] Thus, interval hypoxic training leads to the activation of adaptive mechanisms at both the cellular and systemic levels, which increases the non-specific resistance of the body as a whole.

[0016] Technically, interval hypoxic therapy is performed through inhalation of a gas mixture with varying oxygen concentrations (from high to low). A device for producing hypoxic, hyperoxic, and normoxic breathing mixtures and interval complex normobaric training is used. [RU 2650205 C2] The device delivers interval air flows with varying oxygen concentrations through the body outlet and the respiratory unit into a breathing mask.

[0017] Hypoxytherapy is used in sports and wellness medicine. Various interval hypoxic therapy regimens are effectively used as therapeutic and rehabilitative methods for cardiovascular, metabolic, and neurological disorders, allergies and bronchial asthma, diabetes, and many other ailments. [10; 11] A study examining the effects of hypoxic therapy on mild cognitive dysfunction

[12] showed positive effects, including improved cognitive function, particularly short-term memory and concentration. A positive effect of the therapy on associated conditions was also noted: hypoxic training reduced blood pressure in patients, increased oxygen saturation of brain tissue, and dilated cerebral blood vessels.

[0018] Hyperbaric oxygenation (HBO) is a medical rehabilitation procedure designed to saturate body tissues with oxygen and based on breathing an oxygen-enriched mixture at elevated pressure in various modes. The hyperoxia created under these conditions not only compensates for the hypoxic state but also promotes the mobilization of the body's adaptive capabilities at various levels, including neurohumoral and metabolic effects.

[13] The effects of hyperoxia help achieve a dynamic equilibrium of oxygen-dependent biochemical processes. On the one hand, increased oxygen diffusion into tissues promotes cellular oxygen saturation, covers the cellular oxidative needs, activates oxidative phosphorylation, and replenishes energy deficiency. On the other hand, HBO leads to the activation of detoxification mechanisms, including the antioxidant system, which helps eliminate the damaging factors of oxidative stress.Thus, normalization of mitochondrial function occurs in the cell with optimization of mitochondrial respiration, bioenergetic and metabolic processes.

[0019] HBO also has an immunomodulatory effect, that is, it stimulates or suppresses the activity of the immune system depending on its initial state.

[0020] Technically, during the HBO procedure, the patient is for a certain period of time in a special chamber with a large amount of oxygen supplied to the chamber under pressure. The operating pressure of the hyperbaric chamber of various hyperbaric devices ranges from 100 to 300 kPa (1-3 atm). HBO modes with an isopressure of 1.8-2 atm and more are considered "hard"; when using such an operating pressure of the hyperbaric chamber, the development of undesirable effects (headache, heart rhythm disturbances, autonomic disorders) is most often noted; however, the clinical effect of higher pressures increases insignificantly.

[14] Hyperbaria with a lower operating pressure (up to 1.5 atm) also help to activate aerobic metabolism; their use is more appropriate, since they are universal and allow achieving a sufficiently high clinical effect without the development of any functional disorders.

[14] During the procedure, the operating pressure is automatically maintained within ±0.5 atm, and compression and decompression are provided in a smooth mode. The patient's stay in the maximum isopressure mode ranges from 40 to 60 minutes.

[0021] Hyperoxia is used in the complex treatment of various pathological conditions and chronic diseases. In particular, today the hyperbaric oxygenation method is widely used in psychoneurological diseases, including traumatic brain injury, stroke and neurodegenerative diseases. Thus, positive clinical effects have been obtained in studies concerning the use of hyperbaric oxygenation in the treatment of neurodegenerative diseases. After hyperoxic therapy, a significant improvement in cognitive function was observed in patients with Alzheimer's disease, and in patients with amyotrophic lateral sclerosis, a decrease in fatigue and an increase in muscle strength.

[15] The use of hyperbaric oxygenation in neuropsychiatric disorders has also proven effective; in particular, in children with autism spectrum disorders, improvements in language skills, cognitive function and social interaction were found during therapy.

[16] .

[0022] Ozone therapy is a therapeutic method using ozone gas, based on its disinfectant, anti-inflammatory, antioxidant, and immunomodulatory properties. Highly reactive, ozone primarily interacts with cellular membrane structures.

[0023] By selectively affecting the outer shell of pathogens, ozone inactivates them and implements its antibacterial, antifungal, and viricidal effects.

[0024] Despite the fact that ozone is a prooxidant agent, ozone therapy has a potent antioxidant effect and is indicated for the treatment of diseases associated with chronic oxidative stress. [Smith NL, Wilson AL, Gandhi J, Vatsia S, Khan SA. Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Med Gas Res. 2017 Oct 17;7(3):212-219]. Ozone promotes the oxidation of substrates and the formation of both fast-acting mediators (hydrogen peroxide) and mediators with more delayed effects (lipid oxidation products).Ozone-induced short-term moderate oxidative stress triggers an endogenous cascade of reactions that enhances the activation of transcription factors responsible for the transcription of elements of the antioxidant system, in particular, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, heat shock proteins, as well as phase II enzymes of drug biotransformation in the liver [Smith NL, Wilson AL, Gandhi J, Vatsia S, Khan SA. Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Med Gas Res. 2017 Oct 17;7(3):212-219.] Therefore, a short-term increase in the level of prooxidants increases the amount of antioxidants and can be used over a longer period of time to restore the redox balance. In addition, the production of these antioxidant enzymes affects not only the level of metabolism of mediators formed from ozone, but also the body as a whole.[Smith NL, Wilson AL, Gandhi J, Vatsia S, Khan SA. Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Med Gas Res. 2017 Oct 17;7(3):212-219.] Thus, ozone-induced oxidative stress, through regulation of redox processes, does not serve as a damaging factor, but rather mediates the effect of restoring the redox balance, which is confirmed in all preclinical and clinical studies. [Viebahn-Haensler R, León Fernández OS. Mitochondrial Dysfunction, Its Oxidative Stress-Induced Pathologies and Redox Bioregulation through Low-Dose Medical Ozone: A Systematic Review. Molecules. 2024 Jun 8;29(12):2738.].

[0025] Ozone therapy has metabolic effects: it increases the rate of glycolysis, activates the citrate cycle, and stimulates ATP production. Ozone therapy leads to a significant increase in the efficiency of mitochondria in meeting the cellular need for ATP, including under conditions of increased energy demand, as well as ionic or metabolic stress. König, B., Lahodny, J. Ozone high-dose therapy (OHT) improves mitochondrial bioenergetics in peripheral blood mononuclear cells, Transl Med Commun 7, 17 (2022).

[0026] Oxidized substrates generated by ozone are systemic messengers that stimulate the innate immune system. Ozone also increases the production of several cytokines—interferon, tumor necrosis factor-α, and interleukin-2—which trigger cascades of immunological reactions that activate the immune system.

[0027] Ozone also has hemodynamic properties: inducing prostacyclin production promotes vasodilation and stimulates microcirculation and tissue reparative capacity.

[0028] Technically, ozone therapy is performed by systemic or local application of ozone. The preferred method of ozone administration for adult patients is intravenous administration in the form of an ozone-enriched saline solution.

[17] An ozone-enriched saline solution is obtained by bubbling an ozone-oxygen mixture, obtained using an ozonizer, through a sterile isotonic NaCl solution. The saline solution is ozonated immediately before administration to the patient. For pediatric patients, as well as when local application is necessary, for example, in patients with chronic inflammatory bowel disease, the recommended method of administration is rectal insufflation of a gaseous ozone-oxygen mixture using a syringe.

[0029] The wide range of properties of ozone therapy determines its widespread use in medicine for therapeutic and prophylactic purposes, primarily in infectious and inflammatory diseases, as well as in metabolic, oncological, cardiovascular and other pathologies.

[18] Indications for ozone therapy include chronic inflammatory diseases, low-grade inflammation and diseases associated with high levels of oxidative stress. Viebahn-Haensler R, León Fernández OS. Mitochondrial Dysfunction, Its Oxidative Stress-Induced Pathologies and Redox Bioregulation through Low-Dose Medical Ozone: A Systematic Review. Molecules. 2024 Jun 8;29(12):2738.

[0030] Each of the methods considered is used independently in clinical medicine.

[0031] Methods of using interval hypo-hyperoxytherapy to increase non-specific adaptive capabilities of a person and to train patients are known [RU 2289432 C1; RU 2716478 C1].

[0032] HBO is indicated for the treatment of wounds and wound infections, in gastroenterology for the treatment of ulcerative lesions and inflammatory bowel diseases, etc.

[19]

[0033] HBO is also used to improve performance levels and as part of a recovery program for athletes.

[20]

[0034] Systemic ozone therapy is used to treat multiple organ pathology [RU 2502513 C2], as well as infectious diseases, in particular herpesvirus infection [RU 2178699 C1] and Helicobacter diseases [RU 2155344 C1], as well as for the treatment of diseases in people with secondary immunodeficiency [RU 2496527 C1]. Local ozone therapy is also used to treat inflammatory diseases, such as adenoiditis [RU 2219971 C2].

[0035] Experience with the combined use of hypoxic therapy and HBO is known and is used to improve the effectiveness of the combined treatment of patients with neurocirculatory dystonia [Eliseev D.N. et al. Improving the effectiveness of the combined treatment of patients with neurocirculatory dystonia through the combined use of hyperbaric oxygenation and hypoxic therapy / / Bulletin of the National Medical and Surgical Center named after N.I. Pirogov. - 2008. - Vol. 3. - No. 1. - Pp. 92-94.]. The combined use of the described methods helps to reduce the average time for relief of subjective manifestations of the disease in patients with neurocirculatory dystonia by 3-4 days, while a significantly greater durability of the achieved positive treatment results is also noted.

[0036] A disadvantage of this method is the use of a normobaric regime. Currently, the most effective method of hypoxic therapy is interval hypoxic-hyperoxic training [RU 2289432 C1], which activates adaptive mechanisms triggered by both hypoxic and intermittent hyperoxic stimuli. HBO in the described method was performed at high working pressure, which can be accompanied by undesirable effects and individual intolerance. Another disadvantage of this method is the sequential use of hypoxic therapy and HBO, rather than their simultaneous use in a single comprehensive course with daily application of both techniques.

[0037] Experience with the combined use of hypoxytherapy and HBO in the treatment of neurocirculatory asthenia is known.

[21] The following methods were used: a course of HBO followed by a course of normobaric hypoxytherapy (the duration of each session was 20-30 minutes, during which the patient continuously breathed a hypoxic gas mixture. The oxygen content in the HBO ranged from 15 to 12%). The combined use of these methods ensured the greatest expression and durability of clinical effects (a decrease in the severity of astheno-neurotic and depressive reactions, autonomic imbalance, an increase in neuropsychic stability) compared to the isolated use of these methods.

[0038] There is experience of combined use of HBO and ozone therapy together with a comprehensive standard treatment program (diet No. 10 with restriction of animal fats; mineral water "Arkhangelskaya", No. 10; climatotherapy; physiotherapy; pharmacotherapy (disaggregants, beta-blockers, statins); balneo- and physiotherapy procedures (dry-air carbon dioxide baths, magnetic laser therapy); halotherapy) in patients with coronary heart disease after myocardial revascularization against the background of post-covid syndrome. [Kosov V.A. et al. Efficiency of sanatorium rehabilitation of patients with coronary heart disease after myocardial revascularization against the background of post-covid syndrome / / Physical and rehabilitation medicine, medical rehabilitation. - 2022. - Vol. 4. - No. 2. - P. 111-121.] When comparing a standard rehabilitation program with programs supplemented with other treatment and preventive procedures, it was found that the program supplemented with hypoxic therapy and the program supplemented with HBO are effective in the rehabilitation of patients with NYHA FC I-II, while the inclusion of both HBO and ozone therapy in the medical rehabilitation program showed a greater increase in the rehabilitation effect in severe patients.

[0039] Thus, the results of the simultaneous use of two methods in the treatment of patients, in particular hypoxytherapy and HBO [21, Eliseev DN et al. Improving the efficiency of complex treatment of patients with neurocirculatory dystonia through the combined use of hyperbaric oxygenation and hypoxytherapy / / Bulletin of the National Medical and Surgical Center named after NI Pirogov. - 2008. - Vol. 3. - No. 1. - P. 92-94.] and HBO and ozone therapy [Kosov VA et al. Efficiency of sanatorium rehabilitation of patients with ischemic heart disease after myocardial revascularization against the background of post-COVID syndrome / / Physical and rehabilitation medicine, medical rehabilitation. - 2022. - Vol. 4. - No. 2. - P. 111-121], prove the increase in the effectiveness of their combined use compared to their separate use, however, they have a number of significant disadvantages.

[0040] Disclosure of invention

[0041] Thus, the objective of the present invention is to reduce mitochondrial dysfunction in patients with a wide range of diseases associated with chronic inflammation, using a non-pharmaceutical method.

[0042] The technical result consists in compensation of mitochondrial dysfunction, objectively reflected by the dynamics of increase and longer-term resistance to hypoxia, as well as in ensuring improvement of clinical and laboratory parameters of patients.

[0043] The technical result is achieved due to the fact that in the method for treating mitochondrial dysfunction in patients, which includes the complex use of interval hypoxic therapy and hyperbaric oxygenation, ozone therapy is also additionally used.

[0044] Hypoxytherapy is administered in intervals, alternating inhalations of a hypoxic mixture containing 9 to 16% oxygen by volume and a hyperoxic mixture containing 32 to 40% oxygen by volume. The total duration of the procedure is 45-50 minutes. The intervals between exposures to the hypo- and hyperoxic mixtures are 3-5 minutes. During treatment, the duration of hypoxic exposure is gradually increased and the oxygen content in the hypoxic mixture is reduced.

[0045] Hyperbaric oxygenation is performed in a pressure chamber at 1.3 atmospheres with 100% oxygen for 45 minutes using an oxygen mask. Ozone therapy is administered by intravenous administration of an ozone-enriched saline solution with an ozone concentration of 85 μg / ml or by rectal insufflation with an ozone-oxygen mixture with an ozone concentration of 85 μg / ml at a rate of 3 ml of the mixture per kg of body weight.

[0046] Complex effects of interval hypoxic therapy, hyperbaric oxygenation and ozone therapy are carried out daily in sequential procedures for a course of 12 days.

[0047] The effectiveness of the impact is assessed based on the dynamics of the heart rate and saturation indicators recorded during the impact.

[0048] Brief description of drawings

[0049] The essence of the invention is explained with reference to graphic materials, where Fig. 1 shows protocols for conducting interval hypo-hyperoxic training in the first control group of patients,

[0050] - Fig. 2 shows the protocols for conducting interval hypo-hyperoxic training accompanied by hyperbaric oxygenation in the second control group of patients,

[0051] - Fig. 3 shows protocols for conducting training according to the method of the invention.

[0052] Implementation of the invention

[0053] The stated objective is achieved through the integrated use of interval hypoxic therapy, hyperbaric oxygenation, and ozone therapy. The individual use of each of these methods triggers nonspecific adaptive mechanisms. Alternating hypoxic and hyperoxic exposure (interval hypoxic therapy) promotes the normalization of mitochondrial function by eliminating defective mitochondria and renewing the mitochondrial pool while preserving and increasing the number of the most effective mitochondria. The use of hyperbaric oxygenation and ozone therapy, combined with this, ensures an adequate oxygen supply to metabolically active mitochondria and, through its prooxidant action, activates detoxification mechanisms and signaling pathways that further stimulate nonspecific resistance.

[0054] Thus, the training effect of interval hypoxic therapy is reinforced by the use of HBO and ozone therapy, ensuring a faster and higher-quality clinical response, as well as maintaining its improvement after the end of the treatment course. Consequently, the combined use of these methods provides a multimodal effect on mitochondrial function: stimulation of mitochondrial biogenesis, activation of antioxidant systems, and normalization of mitochondrial metabolism and energy production. The proposed integrated method normalizes metabolic and energy-synthetic processes at the cellular level, and, through stimulation of the neuroendocrine system, at the whole body level. The influence of the described mechanisms on typical pathobiochemical processes allows their use in various nosological groups associated with mitochondrial dysfunction.The restorative effect appears in a significantly shorter period - 3-5 times - than in known methods.

[0055] The course of treatment consists of interval hypoxia-hyperoxia therapy, hyperbaric oxygenation and ozone therapy procedures daily for 12 days.

[0056] Interval hypoxic-hyperoxygenic therapy is performed by alternating inhalations of a hypoxic (oxygen content from 9 to 16 vol.%) and hyperoxic (oxygen content from 32 to 40 vol.%) mixture in various modes under the control of somatic parameters (heart rate, saturation). The choice of mode is based on the level of hypoxia and heart rate parameters. With an increase in heart rate and a sharp decrease in saturation, the hypoxic load is reduced. The intervals of breathing with hypo- and hyperoxic mixtures are 3-5 minutes. Hypoxic exposure is carried out until either an individual minimum saturation or a maximum heart rate is achieved. Hyperoxic exposure is carried out until the initial values ​​of saturation and heart rate are achieved. The total duration of the procedure is 45-50 minutes, with the modes gradually changing to increase the duration and level of hypoxic intervals. The effectiveness of training is assessed based on the dynamics of recorded indicators - heart rate and saturation.

[0057] HBO is performed in a pressure chamber at 1.3 atmospheres with 100% oxygen at a flow rate of 10 liters per minute using a mask. The procedure lasts 45 minutes, but can last from 15 to 60 minutes depending on the patient's condition and clinical situation.

[0058] Ozone therapy is administered by intravenous administration of a saline solution enriched with ozone, with an ozone concentration of 85 μg / ml, at a rate of 200 ml per 100 ml of saline solution, for a total volume of 200-300 ml. For pediatric patients, as well as adult patients with chronic inflammatory bowel diseases, ozone-oxygen mixture with an ozone concentration of 85 μg / ml is administered via rectal insufflation at a rate of 3 ml / kg of body weight.

[0059] The effectiveness of the course of therapy is assessed by the dynamics of the development of the patient's resistance to hypoxia, by changes in training regimens with an increase in hypoxic intervals, biochemical indicators of mitochondrial function (lactate in the blood, lactate and pyruvic acid in the urine), and by the dynamics of clinical symptoms.

[0060] A detailed analysis of the effectiveness of a combined procedure compared to hypoxic therapy alone or hypoxic therapy and HBO is illustrated using a group of patients with a neuropsychiatric spectrum disorder. For patients with somatic pathology, only a clinical description and the effectiveness of the combined technique using the formula are presented.

[0061] Patients with neurodegenerative diseases were randomly divided into three groups of 10 individuals (ages 18 to 35). The first control group was treated with interval hypoxic-hyperoxic training, the second control group was treated with interval hypoxic-hyperoxic training with hyperbaric oxygenation. The third group received a combination of treatments according to the invention.

[0062] Patients in all three groups were monitored long-term after treatment. Their general condition and clinical and laboratory parameters were monitored. Results from patients in the third group demonstrated stable hypoxia resistance at 2, 3, 4, and 6 weeks after treatment.

[0063] Figure 1 shows the protocols for conducting interval hypoxic and hyperoxic training over a period of 1.5 months (51 days). Training was conducted twice daily. In this case, switching from C8 to C9 to a longer training regimen took 1 day. Adaptation to the C9 training regimen until a stable saturation level was achieved and the transition to the next regimen, B1, took 37 days.

[0064] Figure 2 shows the protocols for interval hypoxic and hyperoxic training, conducted daily in conjunction with hyperbaric oxygenation. Each session was performed daily. In this combination, the hypoxic training regimen could be changed within 4-8 days. Over the course of a month of interval hypoxic training, conducted in conjunction with hyperbaric oxygenation, the training regimen was changed from C7 to B1. However, in the latter regimen, the patient remained partially resistant to hypoxia, unable to maintain a stable saturation level.

[0065] Figure 3 shows the protocols for conducting interval hypoxic-hyperoxic training over 9 days as part of the course according to the invention. The training regimen was changed every 1-2 days. During this time, the training regimen was changed from level C7 to level B4, at which the patient maintained oxygen saturation. The hypoxic training index (HTi), quantitatively reflecting the total hypoxic load, increased over 9 training sessions from 87 in the first session to 148 in the ninth, with a stable saturation level, reflecting the patient's increased tolerance to hypoxia.

[0066] From the presented hypoxic training protocols, it follows that the simultaneous use of hypoxic therapy in combination with HBO and ozone therapy allows for significantly faster and more effective development of resistance to hypoxia, compared to the use of hypoxic therapy alone or hypoxic therapy and HBO.

[0067] Table 1 shows the dynamics of laboratory parameters of mitochondrial function in patients of three groups.

[0068]

[0069] Mitochondrial function was assessed using the lactate / pyruvate ratio, which is the most sensitive and specific biomarker of mitochondrial dysfunction [Shayota BJ. Biomarkers of mitochondrial disorders. Neurotherapeutics. 2024;21(1)]. The table shows that the initially elevated lactate / pyruvate ratio in patients decreased almost twofold after the treatment course according to the invention (group 3), while with hypoxic therapy (group 1) or a combination of hypoxic therapy and HBO (group 2), the ratio decreased by 1.5 times. The decrease in the lactate / pyruvate ratio was largely due to a decrease in the level of lactic acid, that is, a decrease in the proportion of anaerobic metabolism was observed.

[0070] After a 12-day course, patients observed: positive dynamics of laboratory parameters of mitochondrial function (initially increased levels of lactate in the blood, lactate and pyruvic acid in the urine decreased by 50% or more), positive dynamics of the clinical picture (depending on the initial symptoms: improvement of motor and cognitive functions, social interaction, speech production, reduction of stereotypical movements, etc.), increased resistance to hypoxia (stable maintenance of the saturation level with increasing hypoxic load).

[0071] The presented method of treating mitochondrial dysfunction ensures stability and further increase of the achieved effect, as evidenced by the stability of maintaining the metabolic parameters of patients in the normal range over a long period of time in both physiological and pathological (stressful, painful) conditions, as well as an improvement in the general somatic condition of patients, a reduction in the symptoms of the main and concomitant diseases.

[0072] Thus, the proposed course of complex therapy is an effective way to treat mitochondrial dysfunction in patients with various pathologies, and especially with neurodegenerative diseases.

[0073] The following are clinical examples of patients from the third group of patients who were treated in accordance with the presented method (examples 1-3) and patients with somatic diseases who underwent a course of treatment according to the invention (examples 4-6).

[0074] Example 1.

[0075] A 29-year-old male. Diagnosis: Neurodegenerative disease due to mitochondrial dysfunction. Complaints of unsteadiness and instability when walking, inability to walk independently, impaired fine motor skills and handwriting coordination, impaired handwriting, mild slurred speech, tremors of the hands and feet when exerting themselves, and difficulty reading. History: At the age of 6-7, slight unsteadiness and instability when walking began to be noted, along with a "drunken gait" that slowly progressed. At school, he noted changes in his handwriting. Since the age of 18-19, he has had difficulty walking, tremors and incoordination in his hands have increased, the muscles of his calves and thighs have become thinner, and difficulty reading has developed due to oculomotor disorders. MRI of the brain: signs of atrophy of the vermis and cerebellar hemispheres. EEG is normal. ENMG: signs of severe sensorimotor axonal demyelinating neural damage. DNA testing for SCA types 1, 2, and 3 and Friedreich's ataxia is negative.

[0076] Metabolic indicators: Blood lactate 4.2 mmol / L; Organic acids in urine: lactate 52 (from here on, the measurement is in mmol / mol creatinine), pyruvic acid 67.

[0077] The patient underwent a 12-day course of daily procedures: interval hypoxic-hyperoxytherapy, hyperbaric oxygenation, and rectal ozone therapy.

[0078] Intermittent hypoxic-hyperoxytherapy:

[0079] The mode selection was based on the level of immersion in hypoxia and heart rate indicators.

[0080] Interval hypoxia-hyperoxytherapy therapy started with the "D6" mode: 3 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 3 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 5 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0081] Over the course of 12 days, due to the body’s adaptation to hypoxia, the regimes changed towards regimes with an increasingly longer duration of the hypoxia stage with a lower oxygen content in the gas mixture.

[0082] By day 12, the "C3" mode was achieved: 4 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 3 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 3 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 13%, 3 minutes of breathing a mixture with an oxygen content of 30%. The duration of the procedure is 50 minutes.

[0083] HBO was performed in a pressure chamber at 1.3 atmospheres, using 100% oxygen at a flow rate of 10 liters per minute through a mask. The procedure lasted 45 minutes and was performed daily.

[0084] Ozone therapy was administered rectally, with a single injection of 140 ml of ozone. The procedure was performed daily.

[0085] Progress was noted during therapy: increased muscle strength, improved swallowing, and improved coordination. Heart rate and oxygen saturation were monitored during training; by day 12, clinical and laboratory parameters were normal.

[0086] Example 2.

[0087] A 25-year-old man. Diagnosis: Neurodegenerative disease due to mitochondrial dysfunction. History: Born at 40 weeks, rapid labor, single umbilical cord entanglement, acute fetal hypoxia. BMI 4600 g, height 53 cm, Apgar 4-7. His condition was severe from birth, and he was fed through a tube. He was discharged in a stable condition on the 13th day. Subsequent development was normal for his age. At the age of 13, a shuffling gait appeared. From the age of 17, oculomotor disorders appeared. Then, the disease gradually progressed: weakness in the legs appeared, followed by the need to use a wheelchair. He has not walked since the age of 23. Also, intolerance to bright light appeared, frequent headaches. Back and neck pain.

[0088] Excessive salivation, difficulty swallowing. Urinary and bowel control has gradually developed. Panic attacks are common.

[0089] Metabolic indicators: Blood lactate 5.3 mmol / L; Organic acids in urine: lactate 89, pyruvic acid 45.

[0090] The patient underwent a 12-day course of daily procedures: interval hypoxic-hyperoxytherapy, hyperbaric oxygenation, and rectal ozone therapy.

[0091] Intermittent hypoxic-hyperoxytherapy:

[0092] The mode selection was based on the level of immersion in hypoxia and heart rate indicators.

[0093] Interval hypoxia-hyperoxytherapy therapy started with the "D6" mode: 3 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 3 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 5 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0094] Over the course of 12 days, due to the body’s adaptation to hypoxia, the regimes changed towards regimes with an increasingly longer duration of the hypoxia stage with a lower oxygen content in the gas mixture.

[0095] On day 12, the "C4" mode was achieved: 4 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 4 minutes of breathing a mixture with an oxygen content of 14%, 3 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 13%, 3 minutes of breathing a mixture with an oxygen content of 30%. The duration of the procedure is 48 minutes.

[0096] HBO was performed in a pressure chamber at 1.3 atmospheres, using 100% oxygen at a flow rate of 10 liters per minute through a mask. The procedure lasted 45 minutes and was performed daily.

[0097] Ozone therapy was administered rectally, with a single injection of 140 ml of ozone. The procedure was performed daily.

[0098] During therapy, progress was noted: increased muscle strength, improved swallowing, decreased oculomotor disorders, heart rate and saturation indicators were normal.

[0099] Example 3.

[0100] A 23-year-old male. Diagnosis: Neurodegenerative disease due to mitochondrial dysfunction. Medical history: Full-term delivery, Apgar score 8 / 9. Weight 3760 g. Hypotonia and muscle weakness have been present since birth. Early motor development was delayed. Psychospeech development is close to normal. Muscle fatigue and exhaustion were noted at school. Since the age of 15, muscle disorders have worsened: increased muscle weakness, decreased endurance, and he began to stumble when walking. By the age of 23, he walked with support and could not climb stairs independently. He eats without choking, and his voice is not nasal. On examination: muscle strength in the legs is 3.5 points symmetrically, in the arms 4 points symmetrically. Tendon reflexes are reduced symmetrically on both sides. There are no sensory abnormalities. Brain MRI: no structural abnormalities. ENMG: signs of primary muscle damage. DNA diagnostics for SCA types 1, 2, and 3, and Friedreich's ataxia are negative.

[0101] Metabolic parameters: Blood lactate 4.2 mmol / L; Organic acids in urine: lactate 52, pyruvic acid 67.

[0102] The patient underwent a 12-day course of daily procedures: interval hypoxic-hyperoxytherapy, hyperbaric oxygenation, and rectal ozone therapy.

[0103] Intermittent hypoxic-hyperoxytherapy:

[0104] The mode selection was based on the level of immersion in hypoxia and heart rate indicators.

[0105] Interval hypoxia-hyperoxytherapy therapy started with the "D6" mode: 3 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 3 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 5 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0106] Over the course of 12 days, due to the body’s adaptation to hypoxia, the regimes changed towards regimes with an increasingly longer duration of the hypoxia stage with a lower oxygen content in the gas mixture.

[0107] On day 12, the "C6" mode was achieved: 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0108] HBO was performed in a pressure chamber at 1.3 atmospheres, using 100% oxygen at a flow rate of 10 liters per minute through a mask. The procedure lasted 45 minutes and was performed daily.

[0109] Ozone therapy was administered rectally, with a single injection of 140 ml of ozone. The procedure was performed daily.

[0110] Progress was noted during therapy: muscle strength in the legs increased to 4 points, and in the arms to 4.5 points. Endurance increased. The patient began climbing stairs with support. Heart rate and oxygen saturation are normal.

[0111] Example 4.

[0112] Female, 61 years old. Diagnosis: Stage 3 hypertension. Type 2 diabetes mellitus. Diabetic polyneuropathy. Receives antihypertensive and hypoglycemic therapy.

[0113] Metabolic parameters: Blood lactate 5.0 mmol / L; Organic acids in urine: lactate 63, pyruvic acid 70.

[0114] The patient underwent a 12-day course of daily procedures: interval hypoxic-hyperoxytherapy, hyperbaric oxygenation, and rectal ozone therapy.

[0115] Intermittent hypoxic-hyperoxytherapy:

[0116] The mode selection was based on the level of immersion in hypoxia and heart rate indicators.

[0117] Interval hypoxia-hyperoxytherapy therapy started with the "D6" mode: 3 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 3 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 5 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0118] Over the course of 12 days, due to the body’s adaptation to hypoxia, the regimes changed towards regimes with an increasingly longer duration of the hypoxia stage with a lower oxygen content in the gas mixture.

[0119] On day 12, the "C5" mode was achieved: 4 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 4 minutes of breathing a mixture with an oxygen content of 13%, 3 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 13%, 3 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 13%, 3 minutes of breathing a mixture with an oxygen content of 30%. The duration of the procedure is 49 minutes.

[0120] HBO was performed in a pressure chamber at 1.3 atmospheres, using 100% oxygen at a flow rate of 10 liters per minute through a mask. The procedure lasted 45 minutes and was performed daily.

[0121] Ozone therapy was administered rectally, with a single injection of 160 ml of ozone. The procedure was performed daily.

[0122] During therapy, progress was noted: decreased numbness in the lower extremities, increased sensitivity in the distal parts of the extremities, in dynamics one month after the course - a reduction in the dosage of hypoglycemic drugs with a stable glycemia level.

[0123] Example 5.

[0124] Boy, 10 years old. Diagnosis: Genetically determined cardiomyopathy (mutation in the TNNT2 gene), restrictive phenotype. CHF stage 2A. FC II according to NYHA. Pulmonary hypertension. Cardiac liver fibrosis (F4 on the METAVIR scale).

[0125] Metabolic parameters: Blood lactate 6.1 mmol / L; Organic acids in urine: lactate 48, pyruvic acid 53.

[0126] Brain natriuretic propeptide (NT-proBNP) 7033 pg / ml.

[0127] The patient underwent a 12-day course of daily procedures: interval hypoxic-hyperoxytherapy, hyperbaric oxygenation, and rectal ozone therapy.

[0128] Intermittent hypoxic-hyperoxytherapy:

[0129] The mode selection was based on the level of immersion in hypoxia and heart rate indicators.

[0130] Interval hypoxia-hyperoxytherapy therapy started with the "D6" mode: 3 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 3 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 5 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0131] Over the course of 12 days, due to the body’s adaptation to hypoxia, the regimes changed towards regimes with an increasingly longer duration of the hypoxia stage with a lower oxygen content in the gas mixture.

[0132] On day 12, the "C4" mode was achieved: 4 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 14%, 4 minutes of breathing a mixture with an oxygen content of 30%, 4 minutes of breathing a mixture with an oxygen content of 14%, 3 minutes of breathing a mixture with an oxygen content of 30%, 4 minutes of breathing a mixture with an oxygen content of 14%, 3 minutes of breathing a mixture with an oxygen content of 30%, 5 minutes of breathing a mixture with an oxygen content of 13%, 3 minutes of breathing a mixture with an oxygen content of 30%. The duration of the procedure is 48 minutes.

[0133] HBO was performed in a pressure chamber at 1.3 atmospheres, using 100% oxygen at a flow rate of 10 liters per minute through a mask. The procedure lasted 45 minutes and was performed daily.

[0134] Ozone therapy was administered rectally, with a single injection of 100 ml of ozone. The procedure was performed daily.

[0135] During therapy, progress was noted: decreased shortness of breath, increased tolerance to physical activity.

[0136] Considering the hereditary nature of the disease and the severity of the condition, the patient repeated the courses of procedures, 3 courses were completed over the course of a year. In the third course of therapy according to the invention, the patient achieved the "B1" training mode: 5 minutes of breathing with a mixture containing 12% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 11% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 11% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 6 minutes of breathing with a mixture containing 11% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 10% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 10% oxygen, 3 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 50 minutes.

[0137] During repeated courses, a slight decrease in the right heart chambers is observed in dynamics, better collapse of the inferior vena cava, according to repeated liver fibroelastography - F3 on the METAVIR scale.

[0138] Example 6.

[0139] Female, 35 years old. Diagnosis: Post-Covid-19 status. Asthenic-depressive syndrome. History: In 2020, she suffered from a severe coronavirus infection. After a month of recovery, she began complaining of depressive mood and low stress tolerance. She also experienced a marked decrease in performance, memory, and concentration. She also experienced rapid physical and mental fatigue. She also experienced sleep disturbances with difficulty falling asleep and frequent nighttime awakenings.

[0140] Metabolic parameters: Blood lactate 3.7 mmol / L; Organic acids in urine: lactate 53, pyruvic acid 74.

[0141] The patient underwent a 12-day course of daily procedures: interval hypoxic-hyperoxytherapy, hyperbaric oxygenation, intravenous ozone therapy.

[0142] Intermittent hypoxic-hyperoxytherapy:

[0143] The mode selection was based on the level of immersion in hypoxia and heart rate indicators.

[0144] Interval hypoxia-hyperoxytherapy therapy started with the "D6" mode: 3 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 14% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 3 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 4 minutes of breathing with a mixture containing 13% oxygen, 5 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen, 5 minutes of breathing with a mixture containing 13% oxygen, 4 minutes of breathing with a mixture containing 30% oxygen. The duration of the procedure is 48 minutes.

[0145] Over the course of 12 days, due to the body’s adaptation to hypoxia, the regimes changed towards regimes with an increasingly longer duration of the hypoxia stage with a lower oxygen content in the gas mixture.

[0146] On day 12, the "C8" mode was achieved: 4 minutes of breathing with a mixture of 13% oxygen, 4 minutes of breathing with a mixture of 30% oxygen, 4 minutes of breathing with a mixture of 13% oxygen, 3 minutes of breathing with a mixture of 30% oxygen, 5 minutes of breathing with a mixture of 13% oxygen, 3 minutes of breathing with a mixture of 30% oxygen, 4 minutes of breathing with a mixture of 12% oxygen, 3 minutes of breathing with a mixture of 30% oxygen, 5 minutes of breathing with a mixture of 12% oxygen, 3 minutes of breathing with a mixture of 30% oxygen, 4 minutes of breathing with a mixture of 11% oxygen, 3 minutes of breathing with a mixture of 30% oxygen. The duration of the procedure is 46 minutes.

[0147] HBO was performed in a pressure chamber at 1.3 atmospheres, using 100% oxygen at a flow rate of 10 liters per minute through a mask. The procedure lasted 45 minutes and was performed daily.

[0148] Ozone therapy was administered via intravenous infusion of 200 ml of ozone-oxygen mixture. The procedure was performed daily.

[0149] Progress was noted during therapy: normalization of sleep, increased performance, increased tolerance to physical and mental stress, stressful situations, decreased mood and decreased cognitive functions were leveled out.

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Claims

1. A method for the treatment of mitochondrial dysfunction in patients with diseases accompanied by chronic inflammation, characterized by the fact that conduct interval hypo-hyperoxic training in the form of alternating inhalations of a hypoxic mixture with an oxygen content of 9 to 16 vol.% and a hyperoxic mixture with an oxygen content of 32 to 40 vol.% for a total duration of 45-50 minutes in individual modes, taking into account changes in heart rate and saturation indicators, hyperbaric oxygenation in a pressure chamber under a pressure of 1.3 atmospheres with 100% oxygen for 15-60 minutes using a mask and ozone therapy, In this case, treatment is carried out daily for 12 days and the hypoxic inhalation regimens are gradually changed towards increasing the duration of intervals and decreasing the oxygen content.

2. The method according to paragraph 1, characterized in that ozone therapy is carried out by intravenous administration of a physiological solution enriched with ozone, with an ozone concentration of 85 μg / ml at a rate of 200 ml of ozone per 100 ml of physiological solution in a total volume of 200-300 ml.

3. The method according to paragraph 1, characterized in that ozone therapy is administered to pediatric patients and adult patients with chronic inflammatory bowel diseases by rectal insufflation with an ozone-oxygen mixture with an ozone concentration of 85 μg / ml at a rate of 3 ml of mixture / kg of body weight.

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