RU2596507C1 - Method for medical rehabilitation of mature age patients with chronic obstructive pulmonary disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pulmonology, and concerns medical rehabilitation of mature age patients with chronic obstructive pulmonary disease (COPD). That is ensured by ozone therapy by intravenous administration of 200.0 ml of ozonized physiologic saline at the rate of 8-10 ml/min. Herewith before the ozone therapy course implementation initial level of peroxidation is determined by the relation of malondialdehyde levels (MDA_ with general level of antioxidative activity (AOA). If the MDA/AOA value exceeds reference values by 50 % and more, 8 procedures of ozone therapy with the ozone concentration of 600 µg/l are performed. If the MDA/AOA value is less than 50 %, 5 procedures of ozone therapy with the ozone concentration of 2,000 µg/l are performed.

EFFECT: such differentiated approach provides reduction of oxidative stress and activation of cells protective system without exhaustion of cell resources and genome damage.

1 cl, 2 ex, 2 tbl

Description

The invention relates to medicine, in particular to pulmonology, and can be used in the rehabilitation treatment of patients with chronic obstructive pulmonary disease (COPD) of mature age (from 44 to 60 years according to the classification of the World Health Organization, 2010). The proposed method is intended for practical public health, can be feasible at the inpatient and outpatient stages of rehabilitation of patients with COPD.

The disappointing global forecast for the progressive prevalence of COPD is due to the increased duration of exposure of risk factors for the development of this pathology to the inhabitants of the planet [1]. Imbalance between lipid peroxidation and antioxidant defense (POL-AOD) systems in the body plays a paramount role in the pathogenesis of COPD and can lead to irreversible oxidative damage to biological molecules, in particular DNA cells [2]. As the most accurate integral biomarker of the level of oxidative damage to DNA, 8-hydroxy-2-deoxyguanosine (8-OHdG) is used [3], the content of which increases with COPD. Therefore, a crucial task for clinicians is the ability to control the intensity of free radical oxidative processes in this pathology in order to reduce the severity of genome destabilization [4]. A different level of peroxidation in COPD leads to the search for treatment methods that normalize the balance of the LPO-AOD system through antioxidant or prooxidant effects [5]. Activation of free-radical processes during inhibition of the AOD system, noted by a number of authors in COPD, is a classic indication for prescribing a course of antioxidant therapy [6]. However, it is necessary to take into account the presence of various options for the activation of free radical processes [7]. On the other hand, there are research results that cast doubt on the feasibility of suppressing elevated levels of lipid peroxidation, since it initiates the synthesis of the body's own defense systems, for example, by activating the enzymatic link of AOD. If the short-term use of exogenous antioxidants allows one to preserve one's own endogenous antioxidant defense of cells, then inhibition of LPO processes by their long-term use does not lead to activation of the AOD system as a result of inhibition of the synthesis of reparative systems and proteins with a protective function [8].

In this regard, the use of ozone therapy as a direct oxidative regulator of the generation of endogenous antioxidants in COPD is of considerable interest, since the main mechanism of the biological effect of ozone is mediated by the activation of lipid peroxidation, stimulation of the AOZ system of the body [9]. Adequate dosage of the free radical signal, taking into account the initial level of peroxidation in patients with COPD, will activate the cell's defense systems without depletion of cellular resources and irreversible damage to the genomic apparatus. The use of ozone therapy in patients with COPD will neutralize oxidative stress and, thereby, reduce the initial severity of destabilization of the cellular genome.

There is a method of selecting an individual dose of ozone in the treatment of patients with acute pancreatitis, which consists in experimental (in vitro) selection of the concentration of ozonized saline solution (2, 4 or 8 mg / l). The optimal dose of ozone was considered to be the one with the addition of which the minimum level of lipid peroxidation and the maximum activity of the AOZ system were recorded in the blood (RF Patent No. 2238295).

The disadvantages of the method are the following: not applicable for patients with COPD, because:

- applied ozone concentrations (4 and 8 mg / l) exceed the upper limit of the range of optimal metabolic concentrations for human red blood cells (1-3 mg / l) and do not cover a therapeutically significant range of less than 1 mg / l [10].

- the choice of the optimal concentration for the patient is evaluated only by the primary response of the peroxidation system (in vitro) and does not take into account the dynamics of the LPO-AOP processes in vivo.

- the method does not allow to confirm the safety and effectiveness of the recommended concentrations for course use, taking into account the dynamics of peroxidation processes and the degree of oxidative damage to the genome.

- there is a need to take a large amount of blood from the patient, the technical complexity, duration and cost of the procedure for selecting an individual concentration of ozone.

The closest in the set of essential features is a method of treating chronic bronchitis in patients with concomitant secondary immunodeficiency, including the complex use of ozone therapy and autotransfusion of photomodified blood (AUFO), in which ozone therapy is administered to a patient in remission by intravenous administration of ozonized physiological solution (OFF) in an amount of 6 procedures, every other day, when the concentration of ozone in the ozone-oxygen gas mixture is 600 μg / l, and a week after ozone therapy, the patient NTU conduct AUFOK therapy in the amount of 2 procedures with an interval of 7 days, while in the first procedure the volume of irradiated blood is 0.8 ml / kg of the patient’s weight, in the 2nd procedure - 1 ml / kg (RF Patent No. 2496527).

The disadvantages of the method are as follows:

- the duration of the course of treatment (25 days), which reduces the compliance of patients.

- lack of effectiveness of 6 ozone therapy procedures, requiring additional inclusion in the course of treatment of AUFOK-therapy.

- the technical complexity of the implementation of the AUFOK therapy methodology (exfusion, ultraviolet irradiation of blood and autohemotransfusion); the need for sterilization of the quartz cell in the apparatus, which increases the risk of infection of the patient.

- the initial level of patient peroxidation is not evaluated, allowing you to choose an effective dosage regimen for ozone therapy.

- the method does not allow to confirm the safety of the recommended concentration and course of treatment according to the severity of oxidative damage to the genome.

The task to which the invention is directed is to create an effective and safe method for the rehabilitation treatment of patients with COPD, which allows to activate the antioxidant defense of a cell without depleting its resources and irreversible damage to the genomic apparatus (Tables 1, 2).

To solve the problem according to the claimed method of rehabilitation treatment of patients with chronic obstructive pulmonary disease, including ozone therapy by intravenous administration of 200.0 ml of ozonized physiological solution with a concentration of ozone in an ozone-oxygen gas mixture of 600 μg / l, every other day, according to the invention, to patients with a stable course determine the initial level of peroxidation to select the dosage regimen and the duration of the course of ozone therapy, then a patient with a high level of peroxidation is given 8 ozone therapy procedures, a patient with a moderately elevated / normal level of peroxidation is treated with 5 ozone therapy procedures, with an ozone-oxygen gas mixture concentration of 2000 μg / l. A high level of peroxidation of patients with COPD is determined by the content of MDA / AOA above the control values by more than 50%, and a moderately elevated level of peroxidation of patients is determined by the level of MDA / AOA that exceeds the control values by less than 50% [11].

The technical result is to increase the safety and effectiveness of rehabilitation treatment of patients with COPD through the use of differentiated approaches to prescribing a dosage regimen and duration of a course of ozone therapy based on the initial level of peroxidation. The method allows to simplify the selection of the effective concentration of ozone and the duration of the course of rehabilitation treatment with the use of ozone therapy in patients with COPD by assessing the level of peroxidation before treatment; to increase the safety and effectiveness of the treatment of this pathology by selecting the concentration of medical ozone that activates the antioxidant defense of the cell without depleting its resources and irreversibly damaging the genomic apparatus. The method allows to reduce the severity of oxidative damage to DNA and lipids in patients with COPD due to the normalization of the initial imbalance of the LPO-AOP system.

The inventive method provides an effective and safe restorative treatment of patients with COPD due to the use of differentiated approaches to prescribing a dosage regimen and the duration of a course of ozone therapy based on the initial level of peroxidation. The inventive method is simple in technical execution, requires a minimum amount of funds used (medical ozonizer, sterile 0.9% sodium chloride solution, disposable systems for intravenous infusion).

As a result of a search by patent applicants for scientific and technical sources of information, no method of rehabilitative treatment of patients with COPD using differentiated approaches to prescribing a dosage regimen and duration of a course of ozone therapy based on the initial level of peroxidation was found.

Since the set of essential features of the claimed invention is not identified from the prior art, then, according to the applicant, it meets the criteria of the invention of "novelty."

The claimed technical solution, according to the applicant, meets the criteria of the invention of "inventive step", because as a result of studies in relation to the prior art, no solutions have been identified that have features that match its distinctive features.

The claimed technical solution meets the criteria of the invention of "industrial applicability", since it can be used in health care for the specified purpose.

The inventive method is developed and tested experimentally in the clinic of the Vladivostok branch of the Federal State Budgetary Institution "Scientific Center of FPD" - NII MKVL. The results of the studies are presented in tables 1, 2.

The method is as follows.

Before a course of ozone therapy, a patient with stable chronic obstructive pulmonary disease has an initial level of antioxidant activity (AOA), the content of malondialdehyde (MDA) in the blood, and an index characterizing the level of peroxidation, MDA / AOA, is calculated. Then, depending on the initial level of peroxidation, one of two dosing regimens and the duration of the course of ozone therapy are selected, which do not lead to depletion of cellular resources and irreversible damage to the genomic apparatus. This is controlled by the values of the MDA and AOA indicators, respectively.

A patient with a high level of peroxidation undergoes 8 ozone therapy procedures, every other day, by intravenous drip of 200.0 ml of an ozonized physiological solution with an ozone-oxygen gas mixture concentration of 600 μg / l with a solution injection rate of 8-10 ml / min. The parameters of the possible rate of solution administration of 8-10 ml / min to patients of mature age were experimentally established in early studies (priority for the invention from 12/18/2014; incoming No. 082511; registration No. 2014151503).

A patient with a moderately high level of peroxidation undergoes 5 ozone therapy procedures, every other day, by intravenous drip of 200.0 ml of ozonized physiological solution with an ozone-oxygen gas mixture concentration of 2000 μg / l with a solution injection rate of 8-10 ml / min.

To obtain ozonized physiological solution, a medical ozone generator is used, approved for use by the Ministry of Health of the Russian Federation: UOTA-60-01 “Medozon” (certificate of conformity No. ROSS RU. ME34. B01135, “Medozon”, Moscow, Russia). Ozonation is carried out by bubbling 200.0 ml of a sterile 0.9% solution of sodium chloride with an ozone-oxygen mixture with a given concentration of ozone. The supply rate of medical oxygen from a gas cylinder to the ozonizer is 1 l / min, the time of saturation of physiological saline with ozone is 15 minutes.

A 0.9% sodium chloride solution was used as the most physiological infusate for ozonation.

The introduction of 200.0 ml of OGF is sufficient volume to implement the proposed method with the claimed technical result.

The parenteral route of administration of ozonized saline is the fastest in response to the patient’s blood.

The constancy of a given concentration is ensured by ozone therapy against the background of constant bubbling.

The choice of concentration of medical ozone was based on guidelines for the use of ozone therapy; the results of our in vitro studies on donated blood of patients with COPD on the selection of a safe and effective range of concentrations of medical ozone according to the severity of the genotoxic and oxidative effects.

The required number of procedures was established in our own studies based on the dynamics of lipid peroxidation and oxidative damage to the genome in vivo (after each ozone therapy procedure) (Tables 1, 2).

Multiplicity of administration of FGD every other day is better tolerated by patients than daily intravenous administration, which is established in our own studies empirically.

Treatment using ozone therapy in this way was carried out by 34 patients with stable COPD.

The diagnostic criteria for inclusion and exclusion in the study were the principles of the international classification of diseases (ICD-10), GOLD criteria (Global Strategy for the Diagnosis, Treatment and Prevention of COPD, 2011), approved by WHO and recommended for use in scientific and medical work. The severity of COPD was determined based on the recommendations of the All-Russian Scientific Society of Pulmonologists (2003) and the European Respiratory Society (EPO, 1999).

The control group consisted of 15 healthy individuals comparable in age to the group of patients with COPD (average age 49.35 ± 1.61 years), with no history of an exacerbation of the chronic inflammatory process and acute inflammatory processes four weeks before the examination, no complaints at the time of inspection.

In all patients, the basic principles of treating a stable condition of COPD were applied: patient education, exclusion of risk factors; drug therapy for the prevention and control of disease symptoms (short-acting anticholinergics "on demand").

Patients with COPD, depending on the initial level of peroxidation by randomization, were divided into two groups, comparable in age and gender. In group I (n = 16), the average age of the patients was 45.50 ± 1.09 years, in group II (n = 18) - 44.62 ± 3.50 years. Patients of both groups received a course of intravenous infusion of 200.0 ml of ozonized physiological saline every other day.

Group I patients (high level of peroxidation) underwent 8 ozone therapy procedures, every other day, by intravenous drip of 200.0 ml of ozonized physiological solution with an ozone-oxygen gas mixture concentration of 600 μg / l with a solution injection rate of 8-10 ml / min .

Group II patients (a moderately elevated level of peroxidation) underwent 5 ozone therapy procedures, every other day, by intravenous drip of an ozonized physiological solution with an ozone concentration of 2000 μg / L in an ozone-oxygen gas mixture with a solution injection rate of 8-10 ml / min.

In the blood serum of patients with COPD who underwent a course of ozone therapy, 8-OHdG, the level of MDA, AOA were determined, and the MDA / AOA peroxidation index was calculated. The study was conducted before treatment (background) and after each ozone therapy procedure. The level of 8-OHdG was determined before the start of treatment (background), after the first procedure (start of treatment), the fourth procedure (middle of treatment) and the eighth procedure (end of treatment).

In patients with COPD group I (high peroxidation), an increase in MDA by 64.63% (p <0.001) with inhibition of AOA by 36.09% (p <0.01) was accompanied by an increase in MDA / AOA by 162% (p <0.001) relative to control, which indicated the absence of metabolic remission of the disease (table. 1). The use of ozone therapy was characterized by a statistically significant decrease in the initially increased peroxidation coefficient during the entire course of treatment. Normalization of MDA / AOA occurred after 3-5 procedures and after the end of procedure 8. However, despite a statistically significant decrease in the level of MDA relative to the background (p <0.001) after 3-5 procedures, its normalization did not occur. AOA index remained below the control values, not significantly changing in relation to the background. Conducting 8 procedures led to a significant decrease in the background level of MDA to control values, with an increase in the initially low level of AOA to control.

The level of oxidative DNA damage in the 1st group of patients with COPD exceeded the healthy indices by 1.99 times (p <0.001) (Table 1). Despite a significant increase in this marker at the beginning of treatment relative to the background (by 45.48%, p <0.01) and control (by 189.53%, p <0.001), by the end of treatment its decrease by 75.87% was noted ( p <0.001) and approximation to healthy indicators.

The use of 8 ozone therapy procedures, every other day, by intravenous drip of an ozonized physiological solution with an ozone concentration of 600 μg / l in patients with COPD with a high level of peroxidation can normalize it by lowering MDA with an increase in AOA and significantly reduce oxidative damage genome.

In the II group of patients with COPD (a moderately elevated level of peroxidation), a decrease in the content of MDA by 12.6% (p <0.05) and AOA by 25.56% (p <0.01) was noted with an increase in MDA / AOA by 21.71 % (p <0.05) (Table 2). The initially increased MDA / AOA ratio remained unchanged throughout the course of treatment with a statistically significant decrease of 11.61% (p <0.05) to the level of control figures after 5 treatments. Normalization of MDA / AOA after procedure 5 is due to an increase in AOA by 11.11% (p <0.05), which did not significantly change relative to the background after the first 4 procedures and steadily decreased after 6 (p <0.05), 7 ( p <0.05) and 8 (p <0.01) FGF infusions.

The level of oxidative DNA damage in the II group of patients with COPD exceeded healthy ones by 2.1 times (p <0.001) (Table 2). After the first procedure, there was a significant increase in this marker relative to the background (by 105.00%, p <0.001) and control (by 334.93%, p <0.001). However, during the course of ozone therapy, the value of this indicator steadily decreased. By the end of treatment, a decrease in the initial level of oxidative damage to the genome by 26.26% (p <0.01) was noted, however, it remained above the control by 56.43% (p <0.001).

The use of a shorter course of ozone therapy (5 procedures), every other day, by intravenous drip of an ozonized physiological solution with a concentration of ozone in an ozone-oxygen gas mixture of 2000 μg / l in patients with COPD with a moderately elevated level of peroxidation can normalize the balance of POL-AOS by increasing total AOA and reduce oxidative damage to the genome.

The use of ozone therapy in patients with COPD can neutralize oxidative stress through the stimulation of AOA mediated by LPO activation and, thereby, reduce the initial severity of destabilization of the cellular genome. The use of differentiated approaches to prescribing different dosage regimens of ozone therapy according to the initial level of peroxidation provides a preventive correction of the development of the genotoxic effect by choosing the concentrations of medical ozone that do not exceed the antioxidant status of the cells.

Example 1. Patient A., 46 years old, suffers from COPD for 6 years with an exacerbation of the disease 1-2 times a year. Prior to ozone therapy, the patient has an elevated MDA level (4.62 μmol / L). An increase in MDA by 87.80% (p <0.001) with inhibition of AOA by 24.81% (p <0.01) was accompanied by an increase in the coefficient of MDA / AOA by 132.3% (p <0.001) relative to the control (high level of peroxidation) . The level of 8-OHdG exceeded the control values by 2.9 times (p <0.001). The patient underwent 8 ozone therapy procedures, every other day, by intravenous drip of 200.0 ml of ozonized physiological solution with a concentration of ozone in an ozone-oxygen gas mixture of 600 μg / l with a solution injection rate of 8-10 ml / min. After a course of ozone therapy, the MDA (2.83 mmol / L) and AOA (1.22 mmol / L) values approached the control values, a 1.7-fold decrease in the marker of oxidative damage to DNA (p <0.001) and its approximation to healthy . The patient well tolerated a course of ozone therapy, considering it useful. Schedules annual recurrence.

Example 2. Patient L., 42 years old, has been suffering from COPD with exacerbations up to 2 times a year for 5 years. Prior to ozone therapy, the patient had a lowered MDA level (2.08 μmol / L) with AOA suppression by 32.3% (p <0.01). An increase in the ratio of MDA / AOA by 16.16% (p <0.01) relative to the control (moderately increased level of peroxidation) was revealed. The level of 8-OHdG exceeded the control values by 2 times (p <0.001). Five ozone therapy procedures were carried out, every other day, by intravenous drip of 200.0 ml of ozonized physiological solution with a concentration of ozone in an ozone-oxygen gas mixture of 2000 μg / l with a solution injection rate of 8-10 ml / min. After the course of treatment, the studied parameters of the biochemical analysis of blood returned to the range of normal values. Adverse reactions during the course of ozone therapy have not been established. The patient notes a marked improvement in overall health and the creation of a positive attitude towards the disease. Insists on repeating the course of ozone therapy in a year.

LITERATURE

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Claims (1)

A method of restorative treatment of patients with chronic obstructive pulmonary disease (COPD), including ozone therapy, by intravenous administration of 200.0 ml of ozonized physiological solution with a solution injection rate of 8-10 ml / min, characterized in that patients with a stable course of COPD before the course of ozone therapy are determined the initial level of peroxidation according to the ratio of the levels of malondialdehyde (MDA) with a general antioxidant status (AOA) and with a value of MDA / AOA exceeding control parameters by 50% or more, is higher com peroxidation level, carry out 8 ozone therapy procedures with an ozone concentration in the ozone-oxygen gas mixture of 600 μg / l, and with a MDA / AOA level exceeding the control indicators by less than 50%, a moderately elevated level of peroxidation, carry out 5 ozone therapy procedures with the concentration of ozone in the ozone-oxygen gas mixture of 2000 μg / l.