RU2281092C2 - Agent for early pathogenetic therapy of acute radiation disease - Google Patents

Abstract

FIELD: medicine, medicinal radiobiology, pharmacy.

SUBSTANCE: invention proposes a multicomponent antioxidant complex comprising the following quenching agents of free radicals - ascorbic acid, alpha-tocopherol acetate, retinal acetate, unithiol and sodium selenite as a blocking agent of initiation of free-radical processes. By effect on viability of irradiated animals the invention exceeds the agent-prototype by 2-6 times. In distinction from the prototype, the claimed agent reduces the expression of maximal leukopenia by above two-fold, decreases the concentration of malonic dialdehyde by 1.5-2.0-fold, normalizes the intensity of free-radical oxidation in blood plasma and liver tissue and results to increasing activity of antioxidant systems. Invention can be used in treatment of acute radiation disease.

EFFECT: enhanced and valuable medicinal properties of agent.

6 tbl, 2 ex

Description

The invention relates to medicine, namely to medical radiobiology, and can be used in the treatment of acute radiation sickness.

Acute radiation sickness (ARS) is a polysyndromic pathological process that develops after a general exposure to the human body of ionizing radiation (II) in a total dose of about 1 Gy or higher. Pathogenetic mechanisms of the development of ARS are associated with the damaging effect of AI on rapidly proliferating tissues, in particular, on the hematopoietic and immune systems. Inhibition of hematopoietic and platelet-induced hematopoietic growth caused by irradiation leads to the development of pancytopenic syndrome, which is characterized by a sharp decrease in the total number, as well as the functional activity of immunocompetent cells and platelets in the peripheral blood. As a result, infectious complications and hemorrhagic manifestations arise that determine the nature of the course and outcome of the disease [1].

The current treatment guidelines for patients with ARS include the provision of aseptic regimen, the administration of antibacterial, antiviral and antifungal drugs, replacement therapy (transfusion of plasma, leukocyte and platelet mass, transplantation of allogeneic bone marrow, peripheral blood stem cells), plasmapheresis, hemosorption, etc. The organization and conduct of these therapeutic and preventive measures are possible only in a specialized hospital, equipped with nnogo complex and expensive equipment and has highly qualified medical personnel. [2]

The results of a number of studies aimed at identifying the pathogenesis of ARS suggest that one of the "triggering" mechanisms for the development of radiation damage to the body is oxidative stress - a violation of homeostasis due to overproduction of prooxidants and (or) the failure of antioxidant defense systems [3, 4].

Currently, there is convincing evidence that irradiation causes a significant increase in the content of water and fat-soluble prooxidants in tissues (including blood), primarily active oxygen metabolites (AKM), products of lipid peroxidation (LPO) and nitric oxide [3 -6]. These substances are highly reactogenic, and an uncontrolled increase in their content in the body causes cytotoxic, mutagenic and genotoxic effects. In particular, AKMs such as superoxide anion radical, singlet oxygen, hydroxyl radical, and hydrogen peroxide enhance radiation damage to the DNA structure (deletion of bases, destruction of hydrogen and phosphoester bonds, decomposition of deoxyribose, the formation of alkaline labile bonds in DNA strands, violation of DNA-protein bonds , DNA membranes, etc.) increase the number of single and double breaks in the DNA chain [3, 7, 8].

The products of oxidative degradation of lipids, primarily unsaturated fatty acids - arachidonic, linolenic, and others (hydroperoxides, epoxides, aldehydes, ketones) cause disturbances in the function and structure of biological membranes, which affects, in particular, the activity of membrane-bound enzymes and the functions of DNA-membrane complex [3, 9]. Especially pronounced gene and cytotoxic effects are exerted by such lipid peroxidation products as malondialdehyde, acrolein, crotonic dialdehyde, 2,3, -epoxy-4-hydroxynonenal, damaging the DNA structure, causing chromosomal aberrations, delayed cell division and cell death [3]. The radiomimetic properties of lipid peroxidation products served as the basis for their isolation in the group of primary lipid radiotoxins, which play a significant role in the further development of radiation damage to the cell [5].

Primary radiotoxins also include oxidation products of phenols (quinones and semiquinones) and DNA bases - 8-oxodioxiguanosine, hydroxy products of cytosine and uracil [3].

In recent years, nitrogen oxides — nitrogen monoxide and peroxynitrite — have a high ability to activate chain free radical reactions [3, 10, 11]. Irradiation activates NO synthetase, and this process is initiated by AKM [3].

The most pronounced radiomimetic properties are possessed by peroxynitrite, which is formed as a result of the reaction of the interaction of nitrogen monoxide with a superoxide anion radical. It has been established that peroxynitrite and its protonated form can cause chain breaks and oxidation of DNA bases, oxidation of lipids of biological membranes, and disruption of the structure of some proteins [11, 12].

The data presented convincingly indicate that oxidative stress is one of the main mechanisms for enhancing primary radiation damage in critical target structures of the cell, which are DNA and biological membranes.

It is important to note that in an intact cell, oxidative processes are under strict and extremely diverse control of antioxidant defense mechanisms, which ensure the occurrence of free radical reactions at a stationary level, necessary for normal cell activity.

The most active non-enzymatic antioxidants with the ability to suppress the processes of free radical oxidation include [3, 11-15]:

- thiol compounds (glutathione, cysteine, taurine);

- vitamins (ascorbic acid, tocopherol, beta-carotene);

- biogenic amines (serotonin, histamine, catecholamines);

- oligopeptides (carnitine, carnosine, anserine, endorphins, enkephalins);

- polyphenols, phospholipids, ubiquinone.

In addition, in the process of evolution, aerobes developed a specialized system of enzymatic antioxidants for protection against active oxygen radicals: superoxide dismutase, catalase, glutathione-dependent peroxidase and transferase, glutathione reductase, and ceruloplasmin [15].

Irradiation, as well as many other extreme factors, leads to changes in the state of the antioxidant system, the stages of mobilization, normalization and depletion are distinguished in the dynamics of this process [3]. If the resources of this protective system are exhausted, an imbalance arises between antioxidant and oxidative processes, which can lead to the occurrence of irreversible damage to the genetic apparatus and cell death [3, 15].

It was shown that irradiation causes significant violations of both the enzymatic and non-enzymatic units of antioxidant protection. The activity of catalase, superoxide dismutase, and the content of beta-carotene, tocopherol, and ubiquinone in the mitochondria of hepatocytes decreases [16, 17].

A decrease in the concentration of tissue thiols, in particular, reduced glutathione after radiation exposure at high doses, was found. Especially significant changes in the glutathione system (a decrease in the content of reduced glutathione, a decrease in the activity of glutathione reductase) were detected after irradiation in bone marrow tissue [18]. The victims of the Chernobyl accident in the latent period of ARS (4–7 days after irradiation) showed a decrease in ceruloplasmin and superoxide dismutase activity against the background of high levels of malondialdehyde and hydroperoxides in erythrocyte membranes [19].

The accumulated data indicating the activation of free radical oxidation and a decrease in the level of endogenous antioxidants in the early stages after irradiation were a pathogenetic justification for the use of antioxidants as a means of increasing the body's resistance to ionizing radiation. The most widely used vitamins C, E, bioflavonoids, thiamine and other B vitamins, carotenoids are most widely used [20-26]. There are known examples of the successful use of the antioxidant complex Vetoron (consisting of vitamins A, E, C), as well as the multivitamin preparations Amitetravit, Tetrafolevit, and others to increase the non-specific resistance of the liquidators of the consequences of the Chernobyl accident [21, 27] . Similar effects were found in a chronic experiment with dogs imitating the possible radiation environment of space flights [28]. However, the results of experimental studies with irradiation of animals in lethal doses showed that the effectiveness of vitamin preparations as anti-radiation agents is small and is manifested only in conditions of prophylactic use. So, in the works [16, 29], the radioprotective effect of the “AK” preparation, consisting of vitamins A, C, and E, was studied. It was shown that administration of the complex to mice 1 day before irradiation in doses causing the death of 70% of the animals increases their 30- daily survival up to 60%. However, the data obtained cannot serve as evidence of the presence of the complex radiation properties at higher (close to the minimum absolutely lethal) doses of radiation exposure, as well as under the conditions of medical (i.e., after irradiation) application of the formulation. This recipe is considered as a prototype.

In addition to vitamins, antioxidants — thiol compounds of endogenous (glutathione) and exogenous (unitiol) origin — were studied as anti-radiation agents, but their radioprotective effect is quite moderate and appears only with prophylactic use [30–32].

Data are also known on the effect of organic selenium compounds (by incorporating the drug Selena in the standard animal diet) on the resistance to radiation exposure of outbred rats [33], but there is no information on the effectiveness of selenium in the context of its therapeutic use.

Given the foregoing, the aim of the invention was to find a means of early pathogenetic antioxidant therapy of radiation injuries, effective in conditions of exposure to the body of ionizing radiation in doses close to absolutely lethal.

This goal is achieved by creating a multicomponent antioxidant complex, including free radical quenchers - ascorbic acid, alpha - tocopherol acetate, retinol acetate, unitiol and a blocker of initiation of free radical processes - sodium selenite.

The ability to achieve the objectives of the invention is proved by the following examples.

Example 1. The experiments were performed on 105 white non-linear mice - males weighing 18-22 g. Animals were subjected to general single gamma irradiation on the IGUR-1 unit at a dose of 7.5 Gy at a dose rate of 1.25 Gy / min.

Animals of the first group served as radiation control.

The animals of the second group after 0.5, 6, 24 and 48 hours after irradiation were injected with the prototype agent (preparation "AK"), which is a three-component antioxidant complex consisting of vitamins A (7 mg / kg intragastrically), E (20 mg / kg intragastrically), C (20 mg / kg intraperitoneally).

The animals of the third group at the same time after irradiation were administered the claimed drug, which is a five-component antioxidant complex consisting of vitamins A (7 mg / kg intragastrically), E (20 mg / kg intragastrically), C (20 mg / kg intraperitoneally), unitiol (50 mg / kg intraperitoneally) and sodium selenite (0.1 mg / kg intragastrically).

The criterion for assessing the damaging effects of radiation and the therapeutic effect of the drugs was the 30-day survival rate of the irradiated animals.

The research results are presented in table 1, from which it can be seen that in mice irradiated in a minimally absolutely lethal dose, the introduction of the prototype means contributed to the survival of 20% of individuals. When using the inventive tool, in contrast to the prototype, a more pronounced anti-radiation effect is observed. With the introduction of the five-component complex, the survival rate of mice was 45%, which is 2 times higher than when using the prototype.

Table 1
The influence of the claimed means and prototype means on the survival of mice irradiated in a dose of 7.7 Gy Used remedy Number of animals Total of them survived abs. % Irradiation (control) 45 0 0 ± 2 Prototype tool thirty 6 20 ± 7 ¹ The inventive tool thirty 13 44 ± 9 ^{1.2 1} - p <0.05 compared with the irradiated control;
² - p <0.05 compared with the prototype tool.

Thus, according to the effect on the 30-day survival rate of mice irradiated in an absolutely lethal dose, the claimed agent is 2 times superior to the prototype.

Example 2

The experiments were performed on 104 nonlinear white male rats weighing 180-220 g. The animals were exposed to general single gamma irradiation on the IGUR-1 unit at a dose of 7.5 Gy at a dose rate of 1.25 Gy / min.

Animals of the first group served as radiation control.

To rats of the second and third groups, 0.5, 6, 24 and 48 hours after irradiation, respectively, the prototype agent and the inventive agent were administered in the doses described in example 1.

The 30-day survival rate of irradiated animals, the dynamics of peripheral blood counts (white blood cell count), the rate of free radical oxidation (SRO), and the activity of antioxidant systems (AOS) in blood plasma and liver tissue in the first 2 days after exposure.

Material was taken for studying the state of lipid peroxidation and the antioxidant system 7, 25, and 49 hours after the radiation exposure after rat decapitation. Blood was stabilized with 4% sodium citrate in a stabilizer: blood ratio of 1: 9, centrifuged for 20 min at a speed of 3000 rpm. The plasma was then pipetted, dispensed into pre-labeled plastic microtube tubes, and stored in liquid nitrogen until testing. The liver of animals after washing with cold saline from blood for 35-50 s after decapitation was frozen in liquid nitrogen, where they were stored until the time of the study.

Liver tissue extracted from liquid nitrogen was immediately finely chopped with a blade and homogenized in a RT-2 tissue micro-grinder (Russia) with a pestle homogenizer at a speed of 3000 rpm. Homogenization was carried out in 0.1 M potassium phosphate buffer (pH 7.4) at a temperature of 0 ° C in a tissue: buffer ratio of 1: 9.

After processing the tissue from the homogenate, samples were immediately taken to determine the concentration of malondialdehyde (MDA). In this case, the time from the moment of tissue thawing to sampling did not exceed 60 s. Then, to precipitate organelles and microsomes, the remaining homogenate was centrifuged (10000 g, temperature + 2 ° С) for 0.5 h in an L8-M centrifuge (Beckman, USA). The supernatant was used to assess the intensity of the CPO and the activity of AOS.

The content of malondialdehyde, one of the secondary products of lipid peroxidation, was determined by the method of [34]. The method is based on the formation of a pink trimethine complex in the interaction of malondialdehyde with 2-thiobarbituric acid at high temperature in an acidic environment. The optical density of pink chromogen was measured on a spectrophotometer at a wavelength of 532 nm. The amount of MDA was calculated using a molar extinction coefficient of 1.56 × 10 ⁵ cm ^-1 M ^-1 . One of the most sensitive methods for detecting hydroxyl and peroxide radicals in biological substrates — the method for recording the intensity of induced biochemiluminescence [35], was used to assess the intensity of SRO and the activity of AOS.

Indicators of the morphological composition of the blood were calculated by conventional methods.

As can be seen from the data presented in table 2, the prototype tool does not have a significant effect on the lethal effect of radiation, while when using the inventive tool, the survival rate of the irradiated animals increased by 3.75 times and amounted to 45%.

table 2
The effect of the claimed means and prototype means on the survival and average life expectancy of rats irradiated at a dose of 7.5 Gy Used remedy Number of animals Total Of which survived Abs. % Irradiation (control) 32 0 12 ± 8 Prototype tool 36 6 7 ± 6 The inventive tool 36 13 44 ± 8 ^{1.2 1} - p <0.05 compared with the irradiated control;
² - p <0.05 compared with the prototype tool.

In contrast to the prototype, the use of the claimed funds was accompanied by a clear positive dynamics of post-radiation disturbances in the morphological composition of peripheral blood. As can be seen from the data presented in Table 3, radiation in both the control and the treated rats using the prototype rat caused the development of deep leukopenia from 3 to 15 days after radiation exposure (the maximum decrease by 7 days was more than 90% of initial level). At the same time, in rats that were injected with the claimed drug, the leukocyte count was significantly higher in all the studied periods than in the control and treated using the prototype.

Table 3
The influence of the claimed means and prototype means on the content of leukocytes in the peripheral blood of rats Used remedy The content of white blood cells, n × 10 ⁹ / l before exposure after irradiation through 3 days 7 days 10 days 15 days Irradiation (control) 10.3 ± 0.5 4.2 ± 0.2 0.9 ± 0.1 1.4 ± 0.1 1.4 ± 0.1 Prototype tool 10.6 ± 0.5 4.4 ± 0.2 1.1 ± 0.1 1.6 ± 0.2 1.5 ± 0.1 The inventive tool 10.8 ± 0.4 5.3 ± 0.1 ^1.2 1.9 ± 0.1 ^1.2 2.5 ± 0.1 ^1.2 3.4 ± 0.1 ^{1.2 1} - p <0.05 compared with the irradiated control;
² - p <0.05 compared with the prototype tool.

Irradiated rats already in the early stages after radiation exposure developed typical manifestations of oxidative stress: in the blood and liver, the content of MDA increased (Table 4.), the intensity of SRO increased, and the activity of AOS decreased (Table 5, 6).

Studies have shown that the introduction of the prototype did not affect the dynamics of the accumulation of lipid peroxidation metabolite in blood plasma and liver tissue, did not reduce the post-radiation activation of free radical oxidation, and the activity of antioxidant systems remained low. Unlike the prototype, the five-component antioxidant complex contributed to a significant decrease in the concentration of MDA in blood plasma and especially in the liver tissue of irradiated animals. As can be seen from the data presented in table 4, in all the studied periods, the content of this LPO product in the liver tissue of animals treated using the inventive agent was 1.5-2.0 times lower than in the control group or treated using prototype tools.

Under the influence of the claimed agent, the intensity of SRO in the blood plasma and liver tissue was normalized already in the first day after irradiation, the activity of AOS increased (Tables 5, 6). Thus, judging by the results obtained, the antioxidant properties of the claimed drug turned out to be significantly higher in comparison with the prototype, which is apparently due to the inclusion of low molecular weight thiols (unitiol) in the complex, which restore free radicals and stabilize enzymatic antioxidants, as well as selenium compounds necessary for the stabilization of metals of variable valency and the functioning of selenium-dependent glutathione peroxidase [15].

High antioxidant activity and causes more pronounced, in comparison with the prototype, the anti-radiation properties of the claimed funds.

Thus, the studies showed that the inventive tool, which is an antioxidant complex consisting of vitamins A, C, E, unitiol and sodium selenite, has a pronounced therapeutic effect when irradiated in doses close to the minimum absolutely lethal. The anti-radiation effect of the complex is manifested by an increase in the survival of animals, accelerated recovery of leukopoiesis and a weakening of manifestations of oxidative stress.

Table 4
The effect of the claimed funds and prototype funds on the concentration of MDA in the blood plasma and liver tissue of rats irradiated at a dose of 7.5 Gy Used remedy MDA concentration: in blood plasma, µmol / l in liver tissue, nmol / g before exposure after irradiation through before exposure after irradiation through 7 h 25 h 49 h 7 h 25 h 49 h Irradiation (control) 3.28 ± 0.06 3.79 ± 0.09 ¹ 3.66 ± 0.11 ¹¹ 3.97 ± 0.09 ¹ 20.1 ± 1.2 23.8 ± 0.4 ¹ 27.8 ± 1.3 ¹ 20.2 ± 1.0 Prototype tool 3.80 ± 0.10 ¹ 3.75 ± 0.12 ¹ 3.81 ± 0.11 ¹ 23.6 ± 0.3 ¹ 24.2 ± 1.1 ¹ 20.1 ± 1.0 The inventive tool 3.46 ± 0.12 ^2.3 3.23 ± 0.13 ^2.3 2.88 ± 0.18 ^2.3 13.2 ± 0.8 ^1.2.3 13.6 ± 0.7 ^1.2.3 13.4 ± 0.4 ^{1.2.3 1} - p <0.05 compared with the level before exposure;
² - p <0.05 compared with the irradiated control;
³ - p <0.05 compared with the prototype tool

Table 5
The effect of the claimed funds and prototype funds on the intensity of the SRO and the activity of AOS in the blood plasma of rats irradiated at a dose of 7.5 Gy Used remedy Controlled rate: SRO intensity, mV AOS activity, conv. Units before exposure after irradiation through before exposure after irradiation through 7 h 25 h 49 h 7 h 25 h 49 h Irradiation (control) 6.13 ± 0.05 6.74 ± 0.21 ¹ 6.86 ± 0.18 ¹ 6.63 ± 0.15 ¹ 7.66 ± 0.11 7.39 ± 0.20 ¹ 7.21 ± 0.18 ¹ 7.28 ± 0.15 ¹ Prototype tool 6.68 ± 0.13 ¹ 6.71 ± 0.19 ¹ 6.51 ± 0.14 ¹ 7.48 ± 0.22 7.29 ± 0.13 ¹ 7.31 ± 0.12 ¹ The inventive tool 5.36 ± 0.16 ^1.2.3 5.69 ± 0.21 ^2.3 6.29 ± 0.19 7.71 ± 0.19 7.80 ± 0.11 ^2.3 7.76 ± 0.15 ^{1.2.3 1} - p <0.05 compared with the level before exposure;
² - p <0.05 compared with the irradiated control,
³ - p <0.05 compared with the prototype tool

Table 6
The effect of the claimed funds and prototype funds on the intensity of the SRO and the activity of AOS in rat liver tissue irradiated at a dose of 7.5 Gy Used
means Controlled rate: SRO intensity, mV AOS activity, conv. Units before exposure after irradiation through before exposure after irradiation through 7 h 25 h 49 h 7 h 25 h 49 h Irradiation (control) 5.63 ± 0.12 6.92 ± 0.13 ¹ 6.86 ± 0.32 ¹ 6.67 ± 0.10 ¹ 6.99 ± 0.13 6.25 ± 0.13 ¹ 4.45 ± 0.18 ¹ 6.03 ± 0.22 ¹ Prototype tool 6.81 ± 0.18 ¹ 6.40 ± 0.21 ¹ 6.65 ± 0.17 ¹ 6.21 ± 0.14 ¹ 4.60 ± 0.22 ¹ 6.15 ± 0.21 ¹ The inventive tool 5.64 ± 0.23 ^2.3 5.15 ± 0.18 ^2.3 5.46 ± 0.22 ^2.3 6.30 ± 0.21 ¹ 6.22 ± 0.21 ^1.2.3 6.68 ± 0.22 ^{2.3 1} - p <0.05 compared with the level before exposure;
² - p <0.05 compared with the irradiated control;
³ - p <0.05 compared with the prototype tool

The inventive tool does not have undesirable side toxic effects, does not have a noticeable effect on the behavioral reactions of animals, hematopoiesis, liver and kidney function.

The claimed invention meets the criterion of "novelty", since the therapeutic efficacy of an antioxidant complex consisting of vitamins A, E, C, unitiol and sodium selenite has been proven for the first time in radiation injuries caused by irradiation in minimal absolutely lethal doses. The effectiveness of the claimed tool is twice the means of the prototype.

The claimed invention meets the criterion of "inventive step", since on the basis of available information the possibility of using the developed five-component antioxidant complex as a therapeutic agent for radiation injuries does not seem obvious.

The compliance of the claimed invention with the criterion of "suitability for use" is confirmed by the above examples and the fact that all components of the formulation are official drugs manufactured by the domestic industry [36-41].

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Claims (1)

An agent for the early pathogenetic treatment of acute radiation sickness, including retinol acetate, alpha-tocopherol acetate, ascorbic acid, characterized in that it additionally contains unitiol and sodium selenite, and the components are taken in the following amount, mg / kg: Retinol Acetate  7 Alpha tocopherol acetate  twenty Vitamin C  twenty Unitiol  fifty Sodium Selenite  0.1