RU1801482C - Method of antioxidant therapy - Google Patents

Abstract

The invention relates to medicine, in particular to antioxidant therapy, and can be used to treat pathological conditions associated with impaired redox processes in the body. The goal is to increase the antioxidant effect. For this, unitiol is used in combination with ascorbic acid in a dose ratio (2.5-3.5): 1. 1 il. s fe

Description

The invention relates to medicine, in particular to antioxidant therapy in conditions accompanied by disturbances in redox processes in the body.

The use of unitiol and ascorbic acid is known both individually and in combination for antioxidant therapy.

The presence of two sulfhydryl groups in the unitol molecule, with a weakened S-H bond and a mobile hydrogen atom, gives it pronounced antioxidant properties. The drug helps to increase the level of reduced thiols, the concentration of endogenous low molecular weight thiols (glutathione regeneration), through glutathione, and also directly, promotes the regeneration of ascorbic acid (AA) (restoration of DAK); activates glutathione reductase; capable of reductive cleavage of available protein SS groups; by the principle of chelating bonds or complexation, an excess of metals with a variable valency is oxidized (copper, iron); restores oxidizing agents; shifts the redox potential towards the prevalence of reduced equivalents in non-protein thiol disulfide and ascorbate redox systems, which helps to stabilize structures; possesses hydrophilic and hydrophobic properties, which makes it possible to exhibit antioxidant activity of the drug in both the aqueous and lipid phases of the cell.

The pronounced antioxidant properties of ascorbic acid are due to the presence of a dienol group in its molecule (). In particular, ascorbic acid protects hemoglobin from oxidation and affects hemoglobin binding of oxygen, restores

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adrenaline, which oxidizes during its action, and also increases the oxygen capacity of the blood, prevents a sharp drop in the level of oxygen in tissues and organs, reduces the total oxygen consumption by the body, participates in the regulation of membrane permeability,

However, it should be emphasized that unitol and ascorbic acid, being synergists, exhibit their antioxidant properties most when used in combination.

However, the dose and ratio of mx in this combination have not been developed.

The purpose of the invention is to enhance the antioxidant effect.

For this, the drugs are administered in a dose ratio of unitol and ascorbic acid of 2.5-3.5: 1.

The choice of optimal ratios and doses of drugs was determined experimentally.

When choosing the optimal ratios of unitol and AK, their influence on the stability of lipoprotein complexes in the blood serum of practically healthy individuals was studied.

For this purpose, initial stability parameters of liprotein complexes (LPCs) were initially determined in blood serum. Then, in 10 series of studies, serum lipoproteins were incubated for 1.0 min at 37 ± 0.1 ° С in a medium containing unitol and AK in various concentration ratios: 1 series - 1: 1; 2 series - 1.5: 1; 3-2: 1; 4- - 2.5: 1; 5- to 3: 1; 6- - 3.5: 1; 7--4: 1; 8-a - 4.5: 1; 9-a - 5: 1 and 10-a 5.5: 1.

The dynamics of changes in the strength of LPC in blood serum depending on the ratios of the concentrations of antioxidant preparations in the incubation medium is graphically depicted in the drawing. .

The stability of LPC in blood serum was expressed in arbitrary units of optical density of CI, and the higher the CI value, the more pronounced destabilization of CIC.

The data obtained indicate that the presence in the incubation medium of unitol with AK in a ratio of 1: 1 to 2: 1 and 4: 1 to 5.5: 1 leads to destabilization of the LAB compared to the initial indices of the stability of the LAB before incubation with the indicated antioxidants. .Whereas. incubation of drugs in a ratio of 2.5: 1 to 3.5: 1, on the contrary, increases the strength of the LPC. Namely, with this ratio of unitol and AK, the drugs are mutually precautionary. nibble each other from oxidation. At the same time, stability of the redox homeostasis of the preparations is ensured, which eliminates the accumulation of excessive concentrations of their hydroxy derivatives. At the same time, at lower or higher ratios of antioxidants,

unbalance in the redox balance of drugs, which leads to a significant increase in the level of their hydroxy derivatives - low molecular weight disulfides and dehydroascorbic acid

0 (DAK). The latter, as is known, have a thiolivant effect, oxidize the sulfohydryl groups of the apoprotein part of the LPC, which leads to destabilization of the LPC. In addition, disulfides and DAK, the SH5 oxide of the globulin part of the hemoglobin, reduce the ability of oxygen to bind hemoglobin and reduce it ability to diffuse into tissue.

For the selection of optimal doses, preserved blood circulating in a closed circuit with a membrane oxygenator was used. The blood of the donor was saturated with oxygen to Po - 300 mm Hg. at various exposure times. Then

5, the same was repeated against the background of unitol and AK injected into the blood at various doses and ratios. Before and during oxygenation, oxyhemoglobin (HbChz), P02 were determined, and biochemical analysis was performed of the following parameters: the content of whole blood was determined non-protein, protein and total sulfhydryl (SH) and disulfide (SS, SH) groups, and in the blood serum - the concentration of AA and the amount of its oxidized

5 forms (RP), the stability of the LPC and the level of one of the end products of LPO - malonic dialdehyde (MDA).

 The optimal dose of antioxidants administered is consistent with a unitol solution

0 based on 5.0-7.0 mg / kg of circulating blood mass. . :.

In an animal experiment, it was found that the duration of action of the preparations is up to 4 hours. However,

5, when a half dose of unitol and AK is added to the animals every 2-3 hours, it allows maintaining the antioxidant background in the body at a stable level.

Thus, the optimal ratios and doses of drugs, as well as the tactics of their administration, were experimentally determined. The obtained results confirmed the obtaining of a pronounced protective effect for blood during hyperoxia, as well as a significant 25 to 40% increase in the gas transport function of the blood when using the claimed method .

Example 1. Patient M., 63 years old. Case histories No. 2584. He was admitted to the Leningrad City Hospital N ° 17 02/14/90. in a severe condition with a diagnosis of acute cholecystitis. By urgent indications, cholecystectomy was performed. You are diagnosed with phlegmonous-calculous cholecystitis, diffuse peritonitis.

In the immediate postoperative period, the condition is extremely serious: the patient is adynamic, the skin is pale, dry, cyanosis of visible mucous membranes, a slight distal acrocyanosis are noted. Pulse - 124 beats in 1 min, rhythmic, weakly filled. AD-90/50 mm Hg Respiration is frequent, shallow, 32 in 1 min, with auscultation weakened in the lower side. R-gram increased pulmonary rice., Shock lung. The tongue is dry, coated with a yellowish coating. The abdomen is swollen, painful on palpation, intestinal motility is absent, Laboratory data: hemoglobin. 106 g / l, erythrocytes 3.2 x 12 l, white blood cells 11.6 x 109 l, hematocrit 34%, nuclear neutrophil wand 18%, segmented nuclear 73%, lymphocytes 5%, bilirubin 120.3 mmol / l .

The study of antioxidant, thiol disulfide, and ascorbate redox systems revealed a decrease in non-protein H-groups by 51.6% of the norm (with a normal content of 251.3 μmol / L), an increase in SH-rpynn by 3 times compared to the norm 316 , 2 µmol / L, the SH / SS ratio decreased to 0.64 (normal 3.96). At the same time, the protein SH / SS ratio decreased to 1.71 (at a rate of 2.63) due to a decrease in protein SH-rpynn and an increase in protein SS-rpynn. The ascorbate redox system has undergone similar changes. Thus, the level of AK decreased to 0.045 mg / l (at a rate of 0.063 mg / l) and the level of RP increased to 0.090 mg / l (at a rate of 0.066 mg / l).

. Thus, the patient noted a decrease in sulfohydryl groups and AK and the predominance of disulfide groups and oxidized forms of AK.

Against the background of unsuccessful traditional therapy, on the third day after the operation, the treatment was carried out using the proposed method. Extracorporeal membrane oxygenation was carried out along the venous-arterial circuit through the catheterized connected vein and cannulated radial artery. Blood was drawn from a vein and returned to an artery. The dialyzer DIP-02-02 was used as an oxygenator. The speed of blood perfusion through the oxygenator is 120-150 ml per minute, and the gas flow rate 02 through the oxygenator is 0.75-1.0 l / min. The duration of extracorporeal oxygenation is 4.5 hours.

10-15 minutes before the procedure, 5% unitol solution (based on 1 ml / 10 kg) and 5% AK solution (based on 0.4 ml / 10 kg body weight) were introduced. In the process of extracorporeal oxygenation, every 2 hours, 1/2 of the initially calculated dose of unitol and vitamin C was administered intravenously.

0 By the end of the procedure, the patient's condition improved significantly. Dyspnea decreased to 24 breaths in 1 min, skin color improved, blood pressure increased to 115/70 mm Hg, pulse rate decreased to 108 in

5 1 min. Studies of antioxidant, thiol disulfide and ascorbate oxidizing agents. but recovery systems showed an increase in reduced non-protein and protein SH-groups (non-protein - up to 1034.2

0 µmol / L, protein - up to 7695 µmol / L) and a decrease in the increased SS-groups (non-protein-up to 380 µmol / L, protein-up to 2814 µmol / L). Meanwhile, the non-protein SH / SS ratio increased to 2.72, and the protein 5 to 2.73.

Extracorporeal membrane oxygenation was performed daily. The total number of procedures is 4. 12 days after surgery, the patient is in satisfactory condition. NII transferred to the surgical department. Recovery.

PRI me R 2. Patient K., 68 years old. The history of the disease №14718. He entered the Leningrad City Hospital №17 07/22/90. with

5 with a diagnosis of acute pancreatitis, abscess of the abdominal cavity, diffuse purulent peritonitis, On the day of admission, laparotomy was performed, drainage of the abscess and abdominal cavity. The state in the postoperative rational period is extremely difficult. Confused consciousness, gray skin, dry, visible mucous membranes, pulse 140 in 1 min, rhythmic, small filling. Heart sounds are deaf, AD-80/50 mm

5 hg In the lungs, hard breathing, 38 respiratory movements in 1 min. On a P-gram the picture of a shock lung is typical. The abdomen is swollen, there is no peristalsis. Laboratory data: moderate anemia (3.5x

0 x 10 -L), expressed leukocytosis (16.7 x 10-1) with a shift of the formula to the left until the onset of young forms of neutrophils. Bilirubin - 76 mmol / l, creatinine - 1.31 mmol / l, urea - 27.7 mmol / l. Study of thiol disulfide and

Five ascorbate redox systems revealed a sharp decrease in SH-rpynn of non-protein nature (up to 421.5 μmol / L with a norm of 1251.3 μmol / L) and an increase in SS-groups by 6 times (compared with the norm).

Non-protein ratio SH-SS decreased

up to 0.22 (with the norm of 3.96). The SH / SS protein ratio decreased to 1.58 (at a norm of 2.63), mainly due to an increase in SS-groups to 4631 µmol / L (at a rate of 3005 µmol / L). The AK content was 0.026 mg / L (at a rate of 0.063 mg / L), and the RP increased to 0.161 mg / L (at a rate of 0.66 mg / L). The AK / RP ratio decreased to 0.16 (at a rate of 0.95). Against the background of unsuccessful traditional treatment, an EMO was performed along the venous-arterial circuit, with blood taken from the subclavian vein, and returned to the radial artery. The DIP-02-02 dialyzer was used as an oxygenator. The speed of blood perfusion through the oxygenator is 120-150 ml in 1 min, the gas flow rate of Og through the oxygenator is 0.5-1.0 l in 1 min. The duration of EMO is 5 hours. 15 minutes before the EMO, a 5% solution of unitol (at the rate of 1 ml / 10 kg of body weight) and a 5% solution of AK at the rate of 0.4 ml / 10 kg were administered iv. body weight). In the EMO process, every 2 hours, 1/2 of the initially calculated dose of unitol and AK was administered intravenously.

By the end of EMO, the patient's condition improved, he regained consciousness. Normal blood pressure (110/70 mm Hg) was restored, heart rate decreased

to 110 beats per 1 min, the number of respiratory movements decreased to 26 in 1 min. Non-protein ratio. SH / SS increased to 1.16 due to an increase in SH-rpynn and a decrease in SS-rpynn (728.4 and 627.2 µmol / L, respectively). The protein ratio after completion of EMO was 2.18, mainly due to a decrease in SS-rpynn to 2986 µmol / L. The previously reduced AA content almost doubled (to 0.057 mg / L) and its oxidized forms decreased (0.089 mg / L). Daily five-time use of EMO brought the patient out of an extremely serious condition. 12 days after surgery, in a state of moderate severity, the patient was transferred from intensive care to the surgical department. Recovery.

Thus, both experimental and clinical data demonstrate a high antioxidant effect of the proposed method.

Claims (1)

SUMMARY OF THE INVENTION A method of antioxidant therapy, comprising administering unitiol in combination with ascorbic acid, characterized in that in order to enhance the antioxidant effect, the preparations are administered in a dose ratio of 2.5-3.5: 1.