RU2063229C1 - Agent for elimination radionuclides deposited in organism - Google Patents

Abstract

FIELD: radiology, medicine. SUBSTANCE: method involves the use of zeolite-containing tuffs as medicinal preparation for radionuclides elimination from human organism (from gastroenteric tract, mucosa or skin). EFFECT: enhanced effectiveness of agent. 2 dwg, 6 tbl

Description

 The invention relates to the field of radiation medicine and radiation hygiene and can find application in the treatment of radiation pathologies caused by the ingress of radionuclides into the body.

 Nuclear explosions, radionuclide emissions by nuclear enterprises and the widespread use of ionizing radiation sources in various industries, agriculture, medicine and scientific research have led to a global increase in the exposure of the Earth's population. Thus, anthropogenic sources of external and internal exposure were thus added to natural exposure.

The greatest potential danger is posed by such long-lived and biologically hazardous radionuclides as ¹³⁷ Cs and ⁹⁰ Ss. The challenge is to limit the intake of radionuclides in the body with food, especially ¹³⁷ Cs, given its high migration capacity.

 There are 4 known ways of exposure to radionuclides on the body: distant from radionuclides located or distributed outside the human or animal body, contact, inhalation and oral (alimentary).

 Most radionuclides are characterized by a pronounced non-uniformity (organotropy) of distribution in organs and tissues. This circumstance largely determines the features of the biological effect of incorporated radionuclides. For example, when large amounts of uniformly distributed radionuclides get into the body, a typical acute radiation syndrome develops, and when organotropic radionuclides get into the body, radiation pathology with a predominant damage to the deposition organ. In the case of prolonged exposure or when relatively small amounts of radionuclides are ingested, chronic non-specific inflammation occurs in the organs of preferential deposition with the outcome in sclerotic processes (pneumosclerosis, liver cirrhosis, nephrosclerosis or malignant tumors).

 The limitation of such outcomes is achieved by keeping external exposure as low as possible, taking into account economic and social factors, as well as by reducing internal doses due to the directed elimination of radionuclides deposited in it from the body.

 Meanwhile, the modern arsenal of drugs designed to remove deposited radionuclides from the body is very limited, despite the extreme social significance of the task (“social order”). It is especially difficult to choose the chemical means of accelerating the elimination from the body of elements of the 1st group of the periodic system, to which cesium belongs.

 Known drugs are intended primarily to prevent the resorption (absorption) of radionuclides into the blood. Such drugs are used as antidotes during emergency treatment of acute oral poisoning with radionuclides or as food additives in chronic alimentary intake of radionuclides into the body: in all cases, the drugs are intended for direct contact with radionuclides in the gastrointestinal tract.

 Enterosorbents are known as such agents: for example, adsorbar, polysimin, ferrocin, bentonite.

The complexon pentacin, a trisodium calcium salt of diethylene triaminopentaacetic acid, is known to be used to stimulate the elimination of already deposited radionuclides from the body for cases of acute and chronic poisoning with these radionuclides
However, the drug is toxic: in high doses, causes dystrophic changes in the kidneys. It has a number of contraindications: damage to the parenchyma of the kidneys, liver, coronary insufficiency, fever. Intravenous administration of the drug (slowly: streaming or drip) requires continuous monitoring of the function of the cardiovascular system.

The prototype of the claimed invention should be considered the use of synthetic zeolite (mordenite) to reduce absorption and accelerate the excretion of radioactive cesium by the body of goats and lambs that consumed hay contaminated with Chernobyl radioactive fallout. The addition of zeolite to the feed at a dose of 10 g per day unexpectedly resulted in the excretion of ¹³⁴ Cs and ¹³⁷ Cs with urine and feces in an amount 2 times greater than that absorbed at the moment with hay. Obviously, mordenite contributed not only to the binding of cesium entering feed, but also to the elimination of cesium isotopes deposited in the body.

 However, the effect / dose coefficient achieved in the prototype is not high; a similar experiment on a person eating reindeer meat infected with radioactive cesium was even less successful according to the authors themselves.

 In addition, as you know, synthetic zeolite is expensive, in particular, because the manufacturing process involves a complex procedure for cleaning the product from impurities, and such cleaning is not absolute.

 The objective of the invention is the search for affordable economic and technological parameters of drugs that are effective for removing from the body deposited in it radionuclides (regardless of the path and rhythm of their entry into the body).

SUMMARY OF THE INVENTION
Natural zeolite-containing tuffs of various zoning are known, among which clinoptilolite rocks are of primary importance. Domestic zeolite-containing tuffs usually contain from 30 to 90 clinoptilolite, which determines the similarity of the geochemical, adsorption, and ion-exchange properties of various varieties of zeolite-containing tuffs (For example, Table 1. Animal feeding and zeolites: guidelines for studying natural zeolites in feeding farm animals. Kemerovo , 1990, p. 5-6).

 The unique combination of sorption, catalytic, ion exchange, sieve and other properties in zeolite raw materials provides a wide range of its industrial and agricultural applications.

It is known to use zeolite-containing tuffs as food additives to reduce the levels of cesium radioisotopes in the milk of cows fed on food contaminated with Chernobyl radioactive dust. Upon contact in the gastrointestinal tract of bentonite and natural (Italian) zeolite with a radioactive feed, the content of ¹³⁷ Cs in milk decreased by 54 and 24 and the content of ¹³⁴ Cs by 52 and 25, respectively.

 However, the well-known physicochemical and biomedical properties of zeolite-containing tuffs, as well as well-known interpretations of the biological mechanisms of their action, are clearly insufficient to unequivocally expect achievement of the claimed therapeutic goal of eliminating radionuclides deposited in tissues from the body.

 The essence of the claimed invention lies in the use of natural zeolite-containing tuff for the removal of radionuclides deposited in the body (regardless of the path and rhythm of radionuclide intake into the body).

 The description is illustrated in FIGS. 1 and 2.

 FIG. 1. The effect of the agent on the removal of deposited radioactive isotopes of cesium with feces.

 FIG. 2. The effect of funds on the excretion of deposited radioactive isotopes of cesium in urine.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
Example 1. The use of zeolite-containing tuff for excretion of laboratory animals deposited radionuclides: simultaneous intake of ¹³⁴ Cs.

 Comparative enterosorption of radionuclides by zeolite-containing tuffs of various deposits. We used zeolite-bearing rock of the following deposits: Pegassky (Kemerovo region), Shivyrtuisky (Chita region), Kholinsky (Buryat Republic), Khonguruu (Republic of Sakha-Yakutia), as well as zeolite-containing rock obtained from Bulgaria.

Studies were performed on male mice C5 • BL6 weighing 18-20 grams. 6 groups were formed, 10 individuals in each. All animals received food for three days, to which ¹³⁴ Cs was added (14.1 kBq per mouse per day). During this time, animals deposited a radionuclide. Then, all mice were transferred to a standard laboratory diet, zeolite-containing tuffs in a finely ground form (particle size less than 1 mm) in an amount of 5-6 g / kg of body weight daily were added to experimental animals (group 2-6). Control mice (group 1) did not receive sorbents.

At the end of the experiment, the animals were sacrificed, the liver, kidney, heart, and the adductor thigh muscle, previously purified from the connective tissue, were isolated. Samples were weighed, the amount of ¹³⁴ Cs was determined on them using a Mini-gamma counter (LKB, Netherlands), and the radionuclide content per 1 g of organ mass was calculated. Hereinafter, the statistical processing of experimental data is performed by standard methods of variation statistics using t-student criterion.

Feeding animals natural zeolite-containing tuffs after seeding with radiocaesium causes a significant decrease in the content of deposited radionuclide in the internal organs of mice (Table 2): in the liver, kidneys, and muscles in the experimental groups
Note: in the tables, an asterisk indicates significant changes in relation to the control group. The percentage of ¹³⁴ Cs relative to the control group is indicated in parentheses.

The amount of ¹³⁴ Cs decreased by 45-70% compared with the control group. All natural tuffs exhibit a unidirectional therapeutic effect, while all of them are highly effective.

Example 2. The use of zeolite-containing tuff for excretion of laboratory animals deposited radionuclides: simultaneous intake of ¹³⁷ Cs.

 The experiment used natural zeolite-containing tuff of two deposits: Shivyrtuisky (Transbaikalia) and Khonguruu (Republic of Sakha-Yakutia) table. 1.

Studies were performed on female mice CBA • B6 F with a body weight of 18-20 grams. Before the experiment, the animals were kept on a standard diet of vivarium, then all mice were divided into three groups (control and two experimental), 20 mice each, all animals were simultaneously injected intraperitoneally with ¹³⁷ Cs at a dose of 13 kBq / g body weight.

 On the next day after the administration of the radionuclide, experimental groups of animals were added zeolite-containing tuff to the feed at the rate of 5-6 g / kg body weight (3% zeolite from the wet weight of the feed). There was no tuff in the diet of the control group. The animals were fed ad libidum, but made sure that all groups received the same amount of food. In each group, on the 3rd day, the total daily litter was collected.

Half of the mice (10 animals) from each group were killed on the 3rd day, and the remaining on the 9th day after the administration of the radionuclide. In animals, the liver, kidney, heart, and adductor muscle of the thigh were isolated, previously purified from connective tissue. The samples were weighed, the ¹³⁷ Cs content was determined in them on a Mini gamma counter (LKB, Netherlands), and the radionuclide content per 1 g of mass was calculated. The feces are similarly investigated.

 Under the influence of natural zeolite-containing tuff, the excretion of incorporated radionuclide with feces is significantly accelerated (Table 3): in the 1st experimental group (hongurin) by about 5 times, in the 2nd experimental group (shivirtuin) by 8.5 times compared to the control not getting tuff (natural elimination). It is known that incorporated and deposited radioactive cesium is mainly excreted in the urine [Harmful chemicals. Radioactive substances. L. Chemistry, 1990, p.64] Accelerated excretion of cesium with feces with a multiplicity of excretion of 5-8.5 leads to a redistribution of the excretory load from the kidneys to the gastrointestinal tract, which is often necessary for clinical indications.

As a result of more intensive elimination of the incorporated and deposited radionuclide under the influence of a zeolite-containing tuff, the radioactive contamination (and, consequently, internal radiation) of the tissues decreases faster as compared to the control: on the 3rd day, the content of ¹³⁷ Cs in the liver and kidneys was 23- 40% less, in the heart by 24 34 and in the muscles by 17-18% less than in control animals. On the 9th day in the internal organs, its content in the experimental groups was 28-53 lower than in the control.

 Using natural zeolite-containing tuff, it is possible to sharply accelerate the process of cleansing the body from radiocaesium. Calculations show that the half-life is halved.

Example 3. The use of zeolite-containing tuff shivirtuin for the excretion of radionuclides deposited in the animal: chronic intake of ¹³⁷ Cs.

The experiment was conducted under conditions as close as possible to the natural situation in which the population is currently forced to eat food contaminated with radionuclides as a result of the Chernobyl accident. The most common radionuclide is ¹³⁷ Cs [Harmful chemicals. Radioactive substances. L. Chemistry, 1990, p. 35] for which a high rate of accumulation in the body has been established [ibid., P. 64]
Laboratory rats were fed milk powder contaminated with radionuclides, which was obtained from the dairy Mr. Novozybkov (Bryansk region). Its specific activity according to the Novozybkovskaya interdistrict radiological laboratory was 8 x 10-8 Ki / kg. In the experiment there were two groups of animals control (3 individuals) and experimental (3 individuals):
1 control reproducing the situation of natural excretion of deposited radionuclides, chronically ingested by the alimentary route,
2 experimental reproducing the situation of the therapeutic effect of the medicinal substance on the dynamics of excretion of deposited radionuclides.

 All animals were added daily 2 g of milk per rat, which is 1.6 x 10-10 Ci / animal per day. The duration of feeding with such milk was 4 weeks. During this time, animals deposited a radionuclide.

 At the end of the seeding, all animals were transferred to a standard laboratory diet, the contaminated milk supplement was canceled, zeolite-containing tuff (shivirtuin) was added to the food of the experimental group in an amount of 5-6 g / kg body weight. The control group of animals was kept on the same diet without adding tuff. The experiment was continued for another 4 weeks.

At the end of the experiment, the animals were slaughtered. The total content of ¹³⁴ Cs and ¹³⁷ Cs in the carcass was measured. After measurements, internal organs were removed from the animals: thymus, kidneys, spleen, lower leg bones. Then, the extracted samples of the same name from rats of the control and separate experimental groups were combined and the total content of radionuclides was starved.

 All radiological studies were performed in the radiological laboratory of Novozybkov on a single-channel gamma-ray spectrometer NK-360.

The amount of the remaining radioactive isotopes of cesium in three rats from the group that received the seed with milk (control group) ranged from 0.01 to 0.09x10 ^-8 km / kg (Table 4). In the experimental group, which received zeolite-containing tuff after seeding, the amount of radiocaesium was lower than the sensitivity threshold of the device 0.01x10 ^-8 Ci / kg.

 Similar results were obtained when measuring the radioactivity of internal organs (table. 5). The greatest decrease in the content of radionuclides was noted in the organs of immunogenesis: thymus, spleen (3.4 and 4 times, respectively), as well as bones 2.16 times and kidneys 1.4 times.

 The data presented indicate that the use of tuff as an enterosorbent helps to remove deposited radionuclides from the body.

Example 4. The use of zeolite tuff shivirtuin for the excretion of radionuclides deposited in the human body: chronic intake of ¹³⁷ Cs.

Limited clinical trials of natural zeolite-containing tuff as an enterosorbent for the removal of deposited radionuclides were carried out with the assistance of the Administration of the Bryansk Region in the Krasnogorsk region, where the soil pollution density was 70 90 Ci / km ² , in July and December 1992. Tests were conducted on volunteers with a sufficiently high level of radioactive infection of the body (more than 25,000 Bq), requiring medical monitoring of the state of health.

 Shivyrtuin was used for medical purposes (Table 1). The active principle of the sorbent is clinoptilolite, which is contained in shivirtuin in an amount of from 80 to 90%. Montmorillonite is present in the raw material in an amount of 3-5%; mordenite is not established, the needle-shaped zeolite has a carcinogenic effect. The content of radionuclides in the sorbent at the clarke level in the earth's crust. Mass fraction of toxic elements that regulate the commercial product of Priargunsky GOK (TU 10 RSFSR 359-91), in mg / kg, not more than: fluorine 1000, arsenic 4, lead 5, cadmium 0.2, mercury 0.1.

 The absorption capacity of enterosorbent in relation to cesium is 0.76-0.87 mg • equiv / g. The applied dosage form is a powder of 0.1 mm in a soft sealed package of 5.0 g.

 Shivyrtuin passed preclinical trials under the drug safety program. According to the test results, the drug is non-toxic: in determining acute toxicity, it was not possible to establish a lethal dose for enterosorbent, a study of chronic nonspecific activity showed that prolonged use of high doses of enterosorbent (30 and 75 TD) does not cause functional impairment [Toxicologist-hygienic studies of zeolites of the Shivirtuysky deposit: Report Scientific research / Rostov-on-Don Medical Institute, 1990] When determining chronic specific activity, no mutagenic, embryotoxic, immuno xic, allergenic, carcinogenic effects [Reports of the Scientific Research Institute of the Institute of Biochemistry SB RAMS, 2nd Moscow Medical Institute, 1990-1992

 Based on the research materials, the report “Assessment of the safety of the use of zeolites of the Shivyrtuyskoye deposit” and the Application for conducting large-scale clinical trials were submitted to the Pharmaceutical Committee of the Russian Federation.

 Enterosorbent was used at 5.0 g 2 times a day for 20 30 minutes before meals for 7 to 11 days. The drug was taken per os in the form of an aqueous suspension. Thus, the daily therapeutic dose of the drug for humans was approximately 0.2 g / kg.

The control of the release of the radionuclide was carried out in two ways:
the first group of 11 people on radioactivity ( ¹³⁴ Cs + ¹³⁷ Cs) excrement. The measurements were carried out by employees of the Krasnogorsk State Center for Sanitary and Epidemiological Surveillance on a single-channel gamma spectrometer NK-360. The radioactivity of urine and feces was investigated before treatment, daily during treatment (11 days) and for 6 days after treatment. The study was carried out in July-August 1992.

the second group of volunteers was 13 people for radioactive infection of the whole body. Measurements were taken before administration of enterosorbent and after 7 days of administration. The level of radioactive infection of the body was tested using ¹³⁷ Cs on a gamma spectrometer of the SICH-AMA-OZF measuring complex. These studies were performed twice: in July-August (6 people) and December 1992 (7 people).

Treatment results
1. Subjects (all local residents) chronically consume weakly radioactive food (the specific content of radionuclides in them was 0.96 ± 0.25 nCi / kg according to our data), as a result of which an equilibrium is established in the body between consumption and excretion of radionuclides . The specific content of radionuclides in excrement (natural excretion) was low: in subjects of this group it was 1.9 ± 0.42 in urine and 2.2 ± 0.52 nCi / kg in feces, which corresponds to the average settlement control.

 A day after taking the sorbent, the average radioactivity of feces sharply increased (8 times) and from 4 to 11 days exceeded the initial level by 15-35 times, and after cancellation of the sorbent remained elevated (Fig. 1). The results indicate that under the influence of zeolite-containing tuff, radionuclides deposited in the body begin to be effectively excreted. The efficiency coefficient is very high, it is 15-35, and in some cases even higher.

 Urine radioactivity increased after the start of treatment by 1.5-3.5 times, and its elevated level continued to persist for 5-6 days after the cancellation of enterosorbent (Fig. 2). An increase in the clearance of radioactive isotopes with urine with the introduction of zeolite-containing tuff per os indicates the active removal of isotopes from their depositing organs in connection with an increase in their metabolism (Fig. 2).

 2. In summer, the level of radioactive infection of the whole body of local residents was equal to 2461 ± 953 nCi before treatment, and after treatment it decreased by an average of 18.3% and amounted to 2061 ± 751 nCi (Table 6). In winter, this decrease was more pronounced, on average it amounted to 24.21% (changes are significant according to the criterion of signs). The natural excretion of a radionuclide for a person is not more than 1% of the total content per day provided that it is not supplied with food, that is, the maximum expected decrease in 7 days cannot exceed 7% (in real conditions of people living in this area, this decrease is not observed) .

 Tolerance to the drug is good, not a single person among the treated has been noted adverse reactions, there were no signs of dyspepsia. Thus, the results indicate the achievement of the stated therapeutic goals.

 A positive assessment of the results of limited clinical trials of the drug is contained in the joint Opinion of the Chief Physician of the Krasnogorsk District Hospital and the Chief Physician of the Krasnogorsk Center for Sanitary and Epidemiological Surveillance, attached to the description of the invention.

 The medical reserves of the natural zeolite-containing tuff of the Shivyrtuiskoye field amount to several million tons. Extraction and processing of raw materials is carried out on an industrial scale by the Priargunsky Mining and Chemical Combine. The technology for the production of enterosorbent is not expensive and includes only fractionation and packaging operations.

 From the presented experimental data (examples 1 and 2) it follows with obviousness that natural zeolite-containing tuff (clinoptilolite) of other deposits will also be effective for the removal of deposited radionuclides.

 All of the above confirms the compliance of the claimed invention with the criterion of "industrial applicability". TTT1 TTT2 TTT3 TTT4 TTT5

Claims (3)

 1. The use of clinoptilolite varieties of zeolite-containing rocks for excretion of deposited radionuclides from the body.  2. The use according to claim 1, characterized in that shivirtuin is used as a clinoptilolite variety of zeolite-containing rocks.  3. The use according to claim 1, characterized in that honghurin is used as a clinoptilolite variety of zeolite-containing rocks.

Images