RU2766246C1 - Method for treatment and rehabilitation of patients after acute respiratory viral infections - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy, and can be used for treatment and rehabilitation of patients suffering acute respiratory viral infections. Method involves inhalations with sodium chloride mineral water using a compressor nebulizer inhaler. Water of natural source of Verkhnekamsky basin is used. One gram of the dry residue of this water is dissolved in 100 ml of sterile 0.85 % sodium chloride solution containing cerium, manganese, zinc and silver ions, so that the final concentration of cerium ions is 0.35–0.50 mcg/l, manganese 10–20 mcg/l, zinc 5–7 mcg/l and silver 0.15–0.20 mcg/l. It is administered in dose of 5 ml once day for 5 days in the period of recovery, after normalization of body temperature, after the course of antiviral and anti-inflammatory therapy.

EFFECT: use of the invention enables to reduce the symptoms of a respiratory disease, namely coughing, sputum production, nasal congestion, nasal discharge, improve night sleep and reduce fatigue due to recovery of airway epithelium by means of inhalations with saline solution containing ions of cerium, manganese, zinc and silver.

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Description

The field of technology to which the invention belongs

The invention relates to medicine, namely to the treatment and rehabilitation of patients who have had acute respiratory viral infections, including Covid-19, by inhaling the respiratory organs with a saline solution containing cerium ions and other trace elements in order to restore the epithelium of the respiratory tract.

State of the art

Most respiratory viruses infect the human body by airborne droplets and primarily penetrate the epithelial cells of the respiratory tract. Violation of the structure and function of the epithelium is accompanied by mucociliary dyskinesia, production of bronchial secretions, mucosal edema, recruitment of neutrophils and other leukocytes to the focus of inflammation, destruction of the epithelium, and the formation of hyperreactivity (spasm of smooth muscle cells) in response to nonspecific stimuli. This pathological process can be stopped by antiviral drugs, but in cases of ineffective treatment, long-term persistence of viruses in epithelial cells is observed, which can cause the formation of a chronic disease and shorten the patient's life. If acute manifestations of the disease can be stopped within a few days, then sluggish inflammation is difficult to treat with pathogenetic agents, the patient is dependent on drug therapy that eliminates the symptoms of the disease, and the ability to work decreases. The main means of rehabilitation of respiratory patients are physical exercises, breathing exercises and regular medication. Among the latter, agents that affect the production of bronchial secretions, bronchodilators, antitussives that thin sputum, inhalations of antibacterial drugs of various origins, antioxidants, and vitamins are more often used. Unfortunately, agents that stimulate the regenerative activity of the ciliated epithelium, thereby improving mucociliary clearance, have not been previously proposed.

Prerequisites for the use of inhalations of a mineral complex containing trace elements, including salts of cerium, manganese, silver and zinc, are experimental studies that have shown their antimicrobial and antiviral activity, as well as anti-inflammatory properties. Of greatest interest are the properties of salts and oxides of cerium as a means of influencing the redox potential of the cell, stimulating regenerative activity, restoring epithelial cells of the respiratory tract after an inflammatory disease [Ivanov V.K. Functional nanomaterials based on cerium dioxide and elements of the titanium subgroup: synthesis, study of the structure and size effects. - Abstract. Dis ... doc-pa chem. Sciences. M., 2011. - 48 p. Available 09/21/2020. http://www.oxide.ru/sites/default/files/thesis/IvanovVK_0.pdf.; Ivanov V.K. Nanocrystalline cerium dioxide: properties, production, application / V.K. Ivanov, A.B. Shcherbakov, A.E. Baranchikov, V.V. Kozik. - Tomsk University Publishing House Tomsk, 2013. - 284 p.]. The role of cerium in the human body has not yet been fully studied, but experimental studies show that cerium can act as a coenzyme and also affect the activity of proliferation through the structure of nucleic acids (DNA and RNA). Cerium oxide and salts have been demonstrated to have antiviral activity. One of the mechanisms of the antiviral effect of cerium is the regulation of alpha interferon production by host cells.

The published results of studies on the model of skin fibroblasts demonstrated the antioxidative properties of cerium oxide nanoparticles, as well as the ability to inhibit the growth of tumor cells [Von Montfort C., Alili L., Teuber-Hanselmann S., Brenneisen P. Redox-active cerium oxide nanoparticles protect human dermal fibroblasts from PQ-induced damage // Redox Biology, Volume 5, August 2015, Pages 424-429. Available on 09/22/2020. http://dx.doi.org/10.1016/j.redox.2014.11.007]. In another study, cerium in combination with silver sulfodiazine demonstrated a pronounced bactericidal effect [Lansdown A.B., Myers S.R., Clarke J.A., O'Sullivan P. A reappraisal of the role of cerium in bum wound management. Journal of Wound Care. 2003 Mar; 12(3):113-118. DOI: 10.12968/jowc.2003.12.3.26480.]. Of interest is an attempt to use salt compositions as a basis for the use of other organic, incl. synthetic substances. Thus, studies have demonstrated a pronounced antiproliferative effect of coumarins in combination with cerium, lanthanum and neodymium against lymphoma cells, which proves the effect of rare earth metals on the redox system of tumor cells [Kostova I. Synthetic and Natural Coumarins as Cytotoxic Agents // Curr. Med. Chem. - Anti-Cancer Agents, 2005, 5, 29-46.].

S.M. и др. (2018) продемонстрирован эффект микромолярного хлорида церия как эссенциального нутриента для роста растений в комбинации с другими химическими элементами [

S.M.,

L.I.,

S.,

J.A.,

Merino F.C. (2018) Cerium enhances germination and shoot growth, and alters mineral nutrient concentration in rice. PLoS ONE 13(3): e0194691. https://doi.org/10.1371/journal.pone.0194691]. Соединения церия являются также необходимыми для роста метанотропных микроорганизмов [Johannes Wostemeyer (Friedrich Schiller University Jena) https://www.researchgate.net/post/What_is_the_role_of_Cerium_and_Barium_in_the_human_body; Pol A., Barends T.R.M., Dietl A., Khadem A.F., Eygensteyn J., Jetten M.S.M., Op den Camp H.J.M. Rare earth metals are essential for metha-notrophic life in volcanic mudpots. // Environmental microbiology. 2014. V.16. Issue: 1. P. 255-264.].It is possible that cerium compounds exhibit opposite properties depending on the dose (concentration) of the biologically active compound. In the study

SM et al. (2018) demonstrated the effect of micromolar cerium chloride as an essential nutrient for plant growth in combination with other chemical elements [

SM,

li,

S.,

ja,

Merino FC (2018) Cerium enhances germination and shoot growth, and alters mineral nutrient concentration in rice. PLoS ONE 13(3): e0194691. https://doi.org/10.1371/journal.pone.0194691]. Cerium compounds are also essential for the growth of methanotropic microorganisms [Johannes Wostemeyer (Friedrich Schiller University Jena) https://www.researchgate.net/post/What_is_the_role_of_Cerium_and_Barium_in_the_human_body; Pol A., Barends TRM, Dietl A., Khadem AF, Eygensteyn J., Jetten MSM, Op den Camp HJM Rare earth metals are essential for metha-notrophic life in volcanic mudpots. // Environmental microbiology. 2014.V.16. Issue: 1. P. 255-264.].

In 2009, the US Environmental Protection Agency issued a document on the dose-dependent toxic effect of cerium compounds on the human body [Toxicological review of Cerium Oxide and Cerium Compounds (CAS No. 1306-38-3) / U.S. Environmental Protection Agency Washington, DC, 2009.-118 p. Available on 09/22/2020. www.epa.gov/iris]. As the main effect, the manifestation of which was noted in small doses, the proliferative response of the epithelium of the respiratory tract is indicated. It should be noted that the accumulation of cerium vapor in the air under industrial conditions was previously noted as an aggressive effect that causes damage to the parenchyma of the lung tissue [Flemming R. Cassee, Erna C. van Balen, Charanjeet Singh, David Green, Hans Muijser, Jason Weinstein & Kevin Dreher (2011) Exposure, Health and Ecological Effects Review of Engineered Nanoscale Cerium and Cerium Oxide Associated with its Use as a Fuel Additive, Critical Reviews in Toxicology, 41:3, 213-229, DOT 10.3109/10408444.2010.529105].

Currently, little information has been accumulated on the clinical use of cerium salts in the treatment of various diseases. There is limited information on the positive wound-healing effect of the combined preparation Flammacerium containing a 1% solution of silver sulfodiazine and cerium nitrate [V. Ivanov https://www.researchgate.net/post/What_is_the_role_of_Cerium_and_Barium_in_the_human_body; Lansdown AB, Myers SR, Clarke JA, O'Sullivan P. A reappraisal of the role of cerium in burn wound management. Journal of Wound Care. 2003 Mar; 12(3):113-118. DOI: 10.12968/jowc.2003.12.3.26480.].

It should be assumed that similarly to the effect of cerium on plant growth, its effectiveness is manifested in combination with other necessary chemical elements. Valuable medicinal properties have been previously studied in relation to salts of manganese, silver and zinc oxide [Morozova L.V. Chemical elements in the human body. Reference materials // Edited by L.V. Morozova // Arkhangelsk: Publishing House of the Pomor State. un-ta im. M.V. Lomonosov, 2001. - 44 p.]. In particular, zinc is a part of many enzymes: carbonic anhydrase (accelerating the decomposition of bicarbonates in the blood, providing speed to the processes of respiration and gas exchange), superoxide dismutase (destroying free radicals), lactate dehydrogenase, alkaline phosphatase and other enzymes; necessary for the formation of proteins from amino acids in the human body. Zinc oxide has long been successfully used as an external agent for the treatment of inflammatory processes in the skin and mucous membranes.

The use of aerosols of saline solutions in the treatment and rehabilitation of bronchopulmonary diseases has a promising goal of influencing the electrical properties of the respiratory mucosa and electrical impedance. In our early work, it was shown that broncho-obstructive diseases are accompanied by an increase in the electrical impedance of the respiratory tract [Mishlanov V.Yu. Investigation of the function of external respiration by the method of electrical impedance spirometry: experimental and clinical parallels / V.Yu. Mishlanov, A.L. Zuev, T.L. Ustyantseva, Ya.V. Mishlanov, V.V. Savkin // Russian Physiological Journal named after I.M. Sechenov. - 2013. - T. 99. - No. 12. - C. 1425-1434.]. The reasons for the change in the electrical properties of the bronchial epithelium are the inflammatory process and the accumulation of dense bronchial secretions rich in glycated mucoproteins. A hypothesis was formulated about the possibility of changing the functional state of the epithelium and smooth muscle cells of the respiratory tract by influencing their electrical properties.

The prototype of the claimed invention is a method of inhalation therapy using various saline solutions, primarily sodium chloride solutions. As you know, inhalation therapy is one of the main methods of drug delivery in pulmonology and is used at all stages of medical care for patients with respiratory diseases (emergency care, long-term treatment, at the stages of rehabilitation), including cases of Covid-19. Aerosol therapy is included in international and Russian clinical guidelines, including Temporary guidelines for the prevention, diagnosis and treatment of a new coronavirus infection, medical rehabilitation of patients with a new coronavirus infection, GOLD 2020, GINA 2020, etc. [Temporary guidelines: prevention, diagnosis and treatment of novel coronavirus infection (Covid-19). Version 7 (06/03/2020). - 166 p. Available 09/21/2020.; Interim Guidelines: Medical Rehabilitation for Novel Coronavirus Infection (Covid-19). Version 2 (07/31/2020). - 151 p. Available 09/21/2020. https:/stopcoronavirus.rf/ai/doc/461/attach/28052020_Preg_COVID-19_vl.pdf; Global strategy for asthma management and prevention. Update 2020.-211p. Available 09/21/2020 https://ginasthma.org/; Global strategy for diagnosis, management and prevention of chronic obstructive pulmonary disease. 2020 report. - 141p. Available 09/21/2020 https://goldcopd.ors/gold-reports/]. The method of inhalation administration is used both for the relief of broncho-obstructive syndrome by administering beta-agonists or anticholinergics, and for anti-inflammatory therapy, for example, by administering inhaled glucocorticoids, and for mucolytic therapy, including the administration of saline solutions. It is known that saline solutions have a pronounced mucolytic effect and are used to change the ratio of liquid (sol) and dense (gel) phases of bronchial secretions. It is also known that with the development of inflammatory changes in the respiratory tract and damage to the epithelium, the function of Clara cells changes, which leads to the predominance of the functional activity of the submucosal bronchial glands that produce mucins, the main element of the dense phase of bronchial secretions [Dvoretsky L.I. Mucolytic and mucoregulatory drugs in the treatment of chronic bronchitis // BC. - 2005. - Volume 13, No. 15.]. At the same time, saline solutions improve the rheological properties of bronchial secretions, improve mucociliary clearance and contribute to the elimination of pathological particles, bacteria and viruses from the respiratory tract.

It is also known that the composition of saline inhalations significantly affects the clinical effects. This applies both to the chemical composition and to the concentration of inhaled saline solutions [Solopov V.N., Lunichkina I.V. Diagnosis of mucociliary insufficiency // Klin. honey. 1989. - No. 7. - S. 49-52.; Solopov V.N., Kolganova N.A. Diagnosis of disorders of mucociliary transport and principles of their correction in patients with COPD: Method, recommendations. - M., 1987.]. It is known, in addition, that a hypertonic solution of sodium chloride has a pronounced mucolytic effect and is used in the treatment of patients with cystic fibrosis (cystic fibrosis) - a disease accompanied by the most serious disorders of mucociliary transport and the development of bronchiectasis due to bacterial contamination of bronchial secretions [Cystic fibrosis (cystic fibrosis) in children . Clinical guidelines 2016. - 58 p. Available 09/22/2020. https://legaiacts.ru/doc/klinicheskie-rekomendatsii-kistoznyi-fibroz-mukovistsidoz-u-detei-utv-minzdravom/].

However, the use of hypertonic saline has a number of limitations due to the development of bronchospasm in patients with bronchial asthma. The formation of hyperreactivity of the respiratory tract is a typical manifestation of the inflammatory process of the respiratory tract and is most represented in patients with bronchial asthma [Fedoseev G.B. Mechanisms of inflammation of the bronchi and lungs and anti-inflammatory therapy / Ed. G.B. Fedoseev. St. Petersburg: Nordmed-Izdat, 1998]. Therefore, in clinical practice, inhalations of physiological sodium chloride solution or 1% baking soda solution are most often used.

Inhalations of baking soda (sodium bicarbonate) have antifungal activity and are used to prevent fungal infection in the form of mouth rinses or inhalation therapy [Danilevsky N.F., Leontiev V.K., Nesin A.F., Rakhniy Zh.I. Diseases of the oral mucosa. M .: Publishing house "Dentistry", 2001. - 273 p. Available 09/22/2020.

http://stgmu.ru/userfiles/depts/therapeutic_dentistry/Obyaleniua/Zabolevania_slizistoy_obolochki_polosti_rta.pdf.].

The history of treatment of patients with bronchial asthma demonstrates a certain effectiveness of such methods as electroaerosol therapy with bromide water of the Ust-Kachka resort [Tuev A.V., 1973], speleotherapy using sodium chloride or using sylvinite [Barannikov V.G., Krasnoshtein A.E., Papulov L.M., Tuev A.V., Chereshnev V.A. Speleotherapy in a potash mine. - Yekaterinburg: publishing house of the Ural Branch of the Russian Academy of Sciences, 1996, - 174 p.; Verikhova, L.A. Speleotherapy in Russia / L.A. Verikhova - Perm, 2000. - 240 p.; Tuev A.V., Mishlanov V.Yu. Bronchial asthma: immunity, hemostasis, treatment. - Perm: Zvezda, 2001. - 284 p.].

However, most inhaled saline therapies have not been subjected to modern evidence-based clinical research or have been replaced by more effective modern therapies such as inhaled glucocorticoids in the treatment of asthma. Similarly, the development of the doctrine of chronic obstructive pulmonary disease allows us to formulate the concept of the use of long-acting bronchodilators. A completely different situation is developing in the field of treatment of patients with bronchiolitis, rehabilitation of patients who have had community-acquired pneumonia, SARS, a new coronavirus infection, suffering from chronic bronchitis. There are currently no evidence-based clinical guidelines for these patients (there are only interim guidelines - Interim guidelines: Prevention, diagnosis and treatment of a new coronavirus infection (Covid-19). Version 8 of 09/03/2020.).

The technical (medical) problem to be solved by the invention is the need to improve the efficiency of treatment and rehabilitation of patients after acute respiratory viral infections (including Covid-19), which is expressed in a decrease in the symptoms of a respiratory disease, namely, cough, sputum, nasal congestion , nasal discharge, improved nighttime sleep and reduced fatigue.

Disclosure of the essence of the invention

The technical result, which determines the solution of this medical problem, is to restore the epithelium of the respiratory tract using inhalation of a saline solution containing ions of cerium, manganese, zinc and silver.

A technical result is achieved in the claimed method for the treatment and rehabilitation of patients after acute respiratory viral infections by inhaling sodium chloride mineral water using a compressor nebulizer inhaler, while using water from a natural source of the Verkhnekamsk pool, one gram of the dry residue of which is diluted in 100 ml of sterile 0 85% sodium chloride solution containing ions of cerium, manganese, zinc and silver so that the final concentration of cerium ions is 0.35-0.50 µg/l, manganese 10-20 µg/l, zinc 5-7 µg/l and silver 0.15-0.20 mcg/l, using 5 ml 1 time per day for 5 days during convalescence, after normalization of body temperature, completion of courses of antiviral and anti-inflammatory therapy.

The technical result is also achieved by treating and rehabilitating patients after coronavirus infection of the respiratory system Covid-19.

Implementation of the invention

For the preparation of saline, a natural mineral spring of the Verkhnekamsk basin is used. Water is taken from the source in the month of June, approximately 1 month after the snow cover has melted. Water from the source is filtered and subjected to evaporation in an electric furnace. Dry residue, weighing 1 gr. Placed in a sterile laboratory glassware (flask) and diluted with a sterile physiological (0.85%) solution of sodium chloride with a volume of 100 ml. The mass spectrometry method (chromato-mass spectrometer "Khromatek - Crystal 5000") determines the concentration of ions of cerium, manganese, zinc and silver. Then, having made a simple proportion, the solution is diluted with physiological sodium chloride solution so that the final concentration of cerium is 0.35-0.50 μg / l, manganese 10-20 μg / l, zinc 5-7 μg / l and silver 0, 15-0.20 µg/l. Subsequently, the saline solution is filtered through fine filters, then through an antibacterial filter (eg Primo® Liquid Filter, EuroClone, Italy, pore size 0.45 µm) and autoclaved.

The method of using a saline solution in the form of inhalations of 5 ml once a day for 5 days using a compressor inhaler and a nebulizer during the period of normalization of body temperature after antiviral and anti-inflammatory therapy.

The invention is illustrated by the following examples.

Example 1: general conditions for treatment and rehabilitation

The method is carried out as follows. 1 gram of the dry residue of salts obtained by evaporation of Verkhnekamsk spring mineral water under sterile conditions is diluted in 100 ml of a sterile sodium chloride solution. In the prepared solution, the concentrations of ions of cerium, manganese, zinc and silver are determined by mass spectrometry. Then, having made a simple proportion, the solution is diluted with physiological sodium chloride solution so that the final concentration of cerium is 0.35-0.50 μg / l, manganese 10-20 μg / l, zinc 5-7 μg / l and silver 0, 15-0.20 µg/l. The saline solution is filtered through an antibacterial fine filter (filter pore size 0.45 µm) and autoclaved. Inhalations of 5 ml of saline solution are prescribed to patients with acute respiratory viral infections, including cases of a new coronavirus infection (Covid-19), after normalization of body temperature and completion of a course of antiviral therapy once a day for 5 days. The symptoms of a respiratory disease are monitored - the intensity of cough, the amount of sputum, the severity of nasal congestion, nasal discharge, the quality of night sleep and the reduction in fatigue are assessed.

Example 2

A 53-year-old man complained of cough, fever, pain in the muscles of the back, knee joints, general weakness, impaired ability to work, moderate dyspnea. These symptoms have occurred within the last 2 days. The maximum rise in temperature in the evening was 38.9 C. It was found that cough appears in the morning and afternoon, accompanied by the release of a small (up to 20 ml per day) amount of sputum; shortness of breath in the form of a need for frequent breathing, difficulty in breathing occurs in the daytime. Muscle and joint pains correspond to the time of the rise in temperature, decrease after taking paracetamol. Objectively revealed a moderate violation of nasal breathing on both sides. Moderate hyperemia of the posterior pharyngeal wall. Auscultatory breathing is carried out symmetrically, hard (the duration of the inhalation phase is equal to the duration of the exhalation phase). In the study of the joints of deformation, defiguration, violations of the range of motion were not revealed. The back muscles are moderately painful on palpation.

The patient was prescribed oseltamivir at a dose of 75 mg per day for 5 days. After 5 days, the body temperature almost returned to normal, muscle and joint pain disappeared, shortness of breath and general weakness decreased. Cough persists with the release of 20-30 ml of mucous sputum per day. Hard breathing persists in the lungs, single dry rales in different departments, changing the timbre after coughing. Ability to work is limited due to cough, persistent general weakness, feelings of shortness of breath. Assigned to inhalation of saline solution, according to the proposed method 1 time per day for 5 days using a home compressor inhaler.

After 5 days, the patient's condition improved, the cough significantly decreased, accompanied by the discharge of liquid sputum in minimal quantities, does not limit the daily life of the patient. The sensation of shortness of breath has ceased. Functionality has been restored. Example 3

In order to test the proposed method of interactive diagnostics, 15 people were examined, including 8 practically healthy individuals and 7 patients with acute respiratory viral disease. All study participants, after signing informed consent, received daily saline inhalations, according to the proposed method. Severe adverse effects of treatment have not been established. In practically healthy individuals, in 3 cases, liquid mucous sputum was discharged in a volume of not more than 1-2 ml per day, with virtually no cough. In patients with acute respiratory viral infections, inhalations were prescribed after a course of antiviral therapy on the 5th-7th day of the disease. In all cases, a decrease in cough, the amount of sputum secreted was revealed. In 4 patients with complaints of non-severe dyspnea (mMRC 1), the disappearance of this symptom, the disappearance of general weakness, and restoration of working capacity were noted.

Claims (2)

1. A method for the treatment and rehabilitation of patients after acute respiratory viral infections by inhalation of sodium chloride mineral water using a compressor nebulizer inhaler, characterized in that water from a natural source of the Verkhnekamsk pool is used, one gram of the dry residue of which is diluted in 100 ml of a sterile 0.85% solution sodium chloride containing ions of cerium, manganese, zinc and silver, so that the final concentration of cerium ions is 0.35-0.50 µg/l, manganese 10-20 µg/l, zinc 5-7 µg/l and silver 0 ,15-0.20 mcg / l, using 5 ml 1 time per day for 5 days during the convalescence period, after normalization of body temperature, completion of courses of antiviral and anti-inflammatory therapy. 2. The method according to claim 1, where the treatment and rehabilitation of patients after coronavirus infection of the respiratory system Covid-19 is carried out.