A method of obtaining a radioprotector

 

(57) Abstract:

The invention relates to medicine and relates to a method of obtaining a radioprotector. The invention lies in the fact that aqueous solutions of hydroxycarboxylic acids obtained from natural raw materials in the form of humic substances is treated with ammonium molybdate. Humic substances can be obtained by processing humified material alkaline solutions under normal conditions. As humified material can be used composts, sapropel, peat from bogs and transitional mires, humus horizons of different soil types. Humic substances can be obtained from the oxidized wood lignin by treatment with oxygen-containing gas in an alkaline medium at a temperature 17020oWith the pressure of 1.9-2.5 MPa within 1-3 hours and subsequent cooling of the reaction mixture, separating the solid phase from the solution, and acidification of the latter to a pH of 2-3. Treatment with ammonium molybdate is carried out at a temperature of 405oWith possible treatment with ammonium molybdate under the action of ultrasound with radiated power of 40 W/cm2with a frequency of 22 kHz for 4-8 minutes the Invention provides a developing method for you to receive on the basis of prirodna to medicine, in particular, the radioprotectors obtained on the basis of natural raw materials.

To radioprotectors are substances that are capable for prophylactic use to have a protective effect, resulting in the preservation of life is irradiated to the living body or the weakening of the severity of radiation injury with rollover state capacity and lifetime (Century. And. Legeza, V., Vladimirov. A new classification of preventive radioprotection means. Radiation biology. Radioecology, T. 38, vol. 3, page 416, 1998).

To mitigate exposure use radioprotectors, which, as a rule, are introduced into the body before irradiation (HW Tank, Alexander P. fundamentals of radiology, M.: Izd-vo aliens. literature, 1963, page 427). The disadvantages of such substances should include the necessity of their presence in the body to radiation, certain toxicity when radioprotective dose, as well as limited time (usually 2-5 hours) in the body.

The results of liquidation of consequences of Chernobyl and other radiation situation in different countries has shown convincingly existing up to the present time, the limited database of biologically active substances with R usevich lesions. Proposed, for example, the use of a complex of vitamins and minerals (Sokolinski Century. N. and other radiation protection and radiotherapy tool "AK". Abstracts of the national conference "Scientific and practical aspects of protecting the health of people exposed to radiation in the vicinity of the Chernobyl accident", 12-14 March 1991, Minsk, page 239). Preparations of this type are available, usually in the form of substances of vegetable origin, and other biologically active compounds. The preparations on their basis are usually eposredstvenno through the body and help to speed up processes, post-radiation recovery irradiated tissues of the body. However, therapeutic effect of these drugs is poorly defined.

It is also known radioprotective agent, obtained from natural raw materials and representing ceritadewasa tuff - RIVERTWIN and hangarin (RF Patent 2028800, class a 61 K 31/00, publ. B. I. 5, 1995). RIVERTWIN and hangarin are ceritadewasa breed Chivyrkuyskogo and Changuinola fields (type of mineral clinoptilolite). They allowed as feed additives in diets of farm animals. To obtain minerals as nutritional supplements them crushed. conditions of radioactive destruction and they are recommended for use in areas contaminated and polluted by radionuclides.

The objective of the invention is to develop a method that allows to obtain on the basis of natural raw substances having the properties of radioprotectors.

The problem is solved in that a method of obtaining radioprotectors in which solutions hydroxycarboxylic acids obtained from vegetable raw materials in the form of humic substances is treated with ammonium molybdate.

Humic substances can be obtained by treating an alkaline materials under normal conditions humified material, which can be used sapropels, humus horizons of the different types of soil, compost, peat from bogs and transitional mires, etc.

Humic substances can also be obtained by oxidation of wood lignin, while wood lignin in aqueous-alkaline suspension oxidize oxygen-containing gas at a temperature of 170oC20oC and a pressure of 1.9-2.5 MPa for 1-3 hours and after cooling the reaction mixture and separating a solid phase from a solution of acidified solution produce humic acid, which after neutralization process molybdate of Ultrazvuk with radiation power 4-6 W/cm2with a frequency of 22 kHz for 6-10 minutes.

Treatment with ammonium molybdate is carried out at a temperature of 40oC5oC.

Possible treatment with ammonium molybdate under the action of ultrasonic radiation power 40,00,5 W, the frequency of sound vibrations 22,00,5 kHz for 20-25 minutes.

Lignin, which is part of the wood, is a valuable medicinal raw materials, stocks of which are practically unlimited. Medicinal properties of lignin comprehensively reviewed in the monograph (Levanova VP Medical lignin. - Ed. N.A. Belyakov.: SP(b) - 1992, page 136). Although lignin and preparations on its basis in medicine up to the present time were regarded as sorbents, many researchers in addition to the sorption properties noted antiseptic, hypocholesterolemic, and other properties.

As wood lignin product of alkaline hydrolysis of wood, can be used chelators on the basis of lignin, such as "Polifan", "Lignosol" etc.

"Polifan" - nonspecific enterosorbent (Reg. 80/1211/3) is a brown powder without smell and taste, humidity 65%, consists mainly of lignin and contains not more than 20% residual polysacharide of raw materials are permitted to be inside the body.

Special studies have shown that the oxidation of lignin in terms of the proposed method does not generate harmful substances such as polycyclic aromatic hydrocarbons, nitrosamines and polychlorinated dicyclo-p-dioxins.

The resulting products are concentrated liquid dark brown color, containing from 0.05 to 1.00% molybdenum with a specific taste and smell.

It is well known that the process of humification (the formation of humic substances) is global and the resulting humic substances (otherwise, humic acid, which is a mixture of humic and fulvic acids) are characterized by similar spectra in the infrared region, regardless of how they are derived.

The obtained material, the authors first used as radioprotectors. Radioprotective effect of substances of a similar nature are not described in literature and authors discovered for the first time. Currently, work is underway to elucidate the structure of the compounds and their mechanism of action.

Radioprotective activity of the obtained product was evaluated for its impact on outbred mice-swimmi with other species of laboratory animals and human sensitivity to the action of the pilot radiation factors.

The following examples explain in detail the method of producing radioprotectors and their function.

EXAMPLE 1

The original aqueous alkaline suspension of lignin (mark "Polifan", reg. 80/1211/3) - non-specific enteral sorbent is oxidized by oxygen in the air.

The composition suspension

The content of Politeama - 1 kg

The content of alkali (sodium hydroxide) - 100 g

The density of the suspension 1:8

The oxidation was performed in a reactor with mechanical stirring at a temperature of 1605oC at a pressure of 2.5 MPa for 1 hour. The air flow rate was 5 l/min

The reaction mass was cooled to room temperature and the solution was separated by filtration residue. The filtrate was acidified with sulfuric acid to pH 2-3. The precipitation was separated by filtration, washed with distilled water, and then water-alcohol mixture to establish a pH of 6.0-6.5 and dried at 105oC to constant weight. The obtained humic acid was neutralized with 5% aqueous solution of ammonia at the rate of 1 g of humic acid in 80 ml of the indicated solution, thermostatically in a boiling water bath to remove excess ammonia, filtered through paper filter and added about 30. % distilled water. Received the acids and created a process developed acoustic cavitation under the action of ultrasound with radiated power of 40 W/cm2and frequency of 22 kHz for 1 min Then the solution was adjusted mark to 100 ml.

The elemental composition of the selected product in terms of organic matter, wt. %: 54% N 12% N 2%, S+O 32% (by difference). The substance decomposes without melting starting from 168oC.

The results of infrared Fourier spectra show that in the resulting product are similar in intensity of the bands 1700 cm-1and 1600 cm-1characteristic of carboxyl groups, an intense band in the region of 1200 cm-1wide on the structure of the strip with the local maxima 3400, 3200, 3100 and 2600 cm-1and strip 2926, 2815, 1460 cm-1and strip 2955 and 2870 cm-1characteristic of the methylene groups.

The resulting product has paramagnetism. In the product there are symmetric EPR signals with q-factor 2,0000,001, close to the value for a free electron (q=2,00) and width H=6,10,1 OE. The concentration of PMC is located at (2,50,4)1018per gram.

The organic portion of the product contains a 2.9-3.4 mg-EQ. COOH-groups in 1 g of the product and 6.0-6.4 mg-EQ. phenolic hydroxyl in 1 g of the product and the structure can be classified as polioksidony acids.

EXAMPLE 2

Lacustrine sapropel with Kali.

To 200 g of lake sapropel with a humidity of 95% was added 5.6 g sodium hydroxide and brought the total amount of the mixture to 1 liter, after which the mixture which was within 5 minutes and left for 6 hours. Upon expiration of the specified period was separated by filtration residue. The filtrate was acidified with phosphoric acid to pH 1-2. The precipitation was separated by filtration, washed with distilled water, and then water-alcohol mixture to establish a pH of 6.0-6.5 and dried at 105oC to constant weight. The obtained humic acid was neutralized with 5% aqueous solution of ammonia at the rate of 1 g of humic acid in 80 ml of the indicated solution, thermostatically in a boiling water bath to remove excess ammonia, filtered through paper filter and added about 30. % distilled water. In the resulting solution was brought to 0.2 wt. % ammonium molybdate in 1 g of humic acids and created a process developed acoustic cavitation under the action of ultrasound with radiated power of 40 W/cm2and frequency of 22 kHz for 1 minute. Then, the solution was brought mark to 100 ml.

The elemental composition of the selected product in terms of organic matter, wt. %: 60% N 6% N 2%, S+O 32% (by difference). The substance decomposes without melting WA who are present close to the intensity of the band 1700 cm-1and 1600 cm-1characteristic of carboxyl groups, an intense band in the region of 1200 cm-1wide on the structure of the strip with the local maxima 3400, 3200, 3100 and 2600 cm-1and strip 2926, 2815, 1460 cm-1and strip 2955 and 2870 cm-1characteristic of the methylene groups.

The resulting product has paramagnetism. In the product there are symmetric EPR signals with q-factor 2,0000,001, close to the value for a free electron (q=2,00) and width H=6,10,1 OE. The concentration of PMC is located at (2,50,4)1018per gram.

The organic portion of the product contains from 3.0 to 3.6 mEq. COOH-groups in 1 g of the obtained product and 6.0 to 6.5 mEq. phenolic hydroxyl in 1 g of the obtained product and the structure can be classified as polioksidony acids.

EXAMPLE 3

Was carried out similarly to example 2, with vermicompost with content of organic substances in an amount of 23% on dry substance was subjected to alkaline treatment with 0.1 M sodium hydroxide solution. 10 g of vermicompost (in terms of absolutely dry sample) was poured in 1 l of 0.1 M sodium hydroxide solution, and the mixture was which for 1 hour, after which the filtered precipitate was separated. The filtrate was acidified with sulfuric acid to R on 1 g of humic acid and heated to 40oC.

The elemental composition of the selected product in terms of organic matter, wt. %: 57% N 7% N 2%, O+S 34% (by difference).

The organic portion of the product contained a 3.2-3.8 mg-EQ. COOH-groups in 1 g and 6.2 to 6.7 mEq. phenolic hydroxyl 1,

Studies of infrared spectra, and determination of the content of COOH-groups and phenolic hydroxyl showed that the obtained humic substances on the structure can be classified as polioksidony acids.

EXAMPLE 4

Was carried out similarly to example 2, with the peat from the bog with the organic matter content of 73% on dry substance was subjected to alkaline treatment of 0.2 m solution of sodium hydroxide. 5 g of dry peat filled 0.2 M solution of caustic potash, and then left for 6 hours, followed by filtering the separated precipitate. The filtrate was acidified to pH 2-3 with phosphoric acid. Processing the selected humic acid ammonium molybdate was conducted at 45oC.

The elemental composition of the selected product in the calculation of the organic matter, wt. %: 51% N 12% N 2% O+S 35% (by difference).

The organic portion of the product contains 3,4-4,0 mg-EQ. COOH-groups in 1 g and 6.3-6.9 mg-EQ. phenolic hydroxyl 1,

Isledon humic substances on the structure can be classified as polioksidony acids.

EXAMPLE 5

Was carried out similarly to example 2, with 500 ml of lake sapropel with a humidity of 90% and a dry matter content of 31% was added 500 ml of distilled water, 5.6 g sodium hydroxide (0.1 M), 6 g of urea (0.1 M) and 37 g of the trylon B (0.1 M). After stirring for 1 hour under normal conditions the precipitate was separated by filtration. The filtrate was acidified with sulfuric acid to pH 1-2.

In the solution of humic acids contributed 0.17 wt. % ammonium molybdate in 1 g of humic acid and heated to 40oC.

The elemental composition of the selected product in terms of organic matter, wt. %: 52% N 16% N 2% O+S 30% (by difference).

The organic portion of the product contains of 3.0-3.4 mEq. COOH-groups in 1 g and 6.0-6.4 mg-EQ. phenolic hydroxyl 1,

Studies of infrared spectra, and determination of the content of COOH-groups and phenolic hydroxyl showed that the obtained humic substances on the structure can be classified as polioksidony acids.

EXAMPLE 6

Was carried out similarly to example 2, to 100 g of the humus horizon of soil (a horizon And from ordinary Chernozem) with the content of total carbon 7% was added 500 ml of distilled water, and then 1.12 g sodium hydroxide (0.02 M),x conditions 6 hours and the precipitate was separated by filtration. The filtrate was acidified with sulfuric acid to pH 1-2.

In the solution of humic acids contributed to 0.2 wt. % ammonium molybdate in 1 g of humic acid and heated to 40oC.

The elemental composition of the selected product in terms of organic matter, wt. %: 56% N 8% N 3% O+S 33% (by difference).

The organic portion of the product contains 3,4-4,0 mg-EQ. COOH-groups in 1 g and from 6.4 to 7.0 mEq. phenolic hydroxyl 1,

Studies of infrared spectra, and determination of the content of COOH-groups and phenolic hydroxyl showed that the obtained humic substances on the structure can be classified as polioksidony acids.

EXAMPLE 7

Radioprotective efficiency obtained by the proposed method substances were tested on outbred mice-males weighing 18-20 g

The irradiation was carried out at the facility RUM-17 under the following conditions: voltage of 180 kV. The current is 15 mA, the filter of 0.5 mm si+1,0 mm Al, focal length 70 cm, dose rate 0,355 G/min, the direction of irradiation: the back-chest. Absorbed doses to the animals of different groups were 2,4,6,8,10,15 and 20 Gr.

For irradiation, the mice were placed on 10 specimens in plastic canisters. As a control efficiency of radiation is ukljuceno anode tube at the same time, that and irradiated. Animal experimental and control groups were irradiated at the same time, and then were kept in the same conditions as non-irradiated control.

Monitoring was performed using individual dosimeter ID-11 and the subsequent evaluation of the readings on the machine TH-32.

The substance obtained in example 1, in the form of a 1% solution in saline in a volume of 0.2 ml was administered to the experimental animals intramuscularly in a dose of 100 mg/kg (2 mg per individual). The drug was administered 1 time per day 5, 4, 3 and 2 days before radiation exposure. The total dose of the drug for 4 days amounted to 400 mg/kg (8 mg per individual).

To identify radiomodification efficiency of the studied drugs used group of mice that on the same pattern as that of the animals of the experimental groups were injected with saline, after which mice were subjected to radiation treatment, as described above. Mouse another group was subjected to false irradiation without the introduction of any drugs and was seen as a biological control.

Observing animals experimental and control groups was performed within one month before irradiation and 30 days after radiation exposure.

the s General relatively uniform irradiation of mice in bone marrow and intestinal dose range.

The results obtained are presented in tables 1-4. Table 1 presents data on the dynamics of the death of mice after irradiation with different doses. Table 2 shows the effect of the drug on the dynamics of the death of mice after irradiation with different doses. Table 3 presents the rates of death and survival rate of mice after irradiation with different doses. Table 4 shows the indicators radioprotective efficacy of the drug under irradiation of mice with different doses.

As evaluation criteria radiomodification efficacy used the following indicators.

Percentage mortality (% mortality) was calculated by dividing the absolute number of dead animals on their total number in the study group, followed by multiplication by 100.

The survival rate of animals (% survival) - the remaining share percent from death.

Life expectancy (ALE) of dead animals was calculated by adding the number of days in the life of every dead animals after irradiation, and then dividing this figure by the number of dead animals in the study group. Indicator ALE expressed in days.

The percentage protection preparer CLASS="ptx2">

Index of survival (And survival) was calculated as the ratio of the survival rate of mice in the experimental group to the same value of the control group.

The protection factor (To protect) was calculated as the ratio of the difference between the percentage of death of mice in the control (% loss of control) and experimental (% death experience) groups to the percentage loss in control (% loss of control):

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The change factor dose (PID) was calculated as the ratio of doses that cause the same biological effect (in particular, DM50/30or SD50/5) when the application of the proposed tool and without it:

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From table 2 it is seen that the death of animals, not subjected to pharmaceutical protection, was determined from the dose of 2 Gy, and the dose of 8 Gy surviving after irradiation animals were not. When defining indicators of lethal doses revealed that SD16/303.50 G, SD50/30- 5,33 G, SD84/30- 7,15 Gr. The average life expectancy of dead animals after irradiation in bone marrow dose range was in the range from 16 (4G) to 9 days (8G). After irradiation in Escherichia range of doses (10, 15, 20 Gy) was observed 100% mortality, and the animals lived an average of 3.17 days.

Cieniem indicators mortality. When its prophylactic use SD16/30was 4,71 Gr, SD50/30- 6,56 Gr, SD84/30- to 8.41 Gr. Feed offered funds under irradiation of mice in the minimum lethal dose amounted to 1.28, at sub-lethal dose of 1.26, with absolutely minimal lethal doses of 1.25, i.e., when irradiated mice in bone marrow dose range from 2 to 8 Gy) feed with increasing absorbed dose remained practically unchanged.

Prophylactic use of the drug has led to an increase in life expectancy of the deceased animal after irradiation at a dose of 10 Gy at 1.6 times and almost 1.5 times extends the life of animals after irradiation at a dose of 15 Gy. TV

1. A method of obtaining a substance having the properties of radioprotector, from natural raw materials, characterized in that it is obtained from natural raw materials humic substances and process them with ammonium molybdate.

2. The method according to p. 1, characterized in that the treatment with ammonium molybdate is carried out at a temperature of 405oC.

3. The method according to p. 1, characterized in that the treatment with ammonium molybdate is performed under the action of ultrasound with a radiated power of 40 W/cm2with a frequency of 22 kHz for 4-8 minutes

4. The method according to p. the ora under normal conditions.

5. The method according to p. 4, characterized in that the humified material is treated with an alkaline solution in the presence of urea and complexone.

6. The method according to p. 4 or 5, characterized in that as humified material used peat from upland or transitional bogs, or sapropel, or compost, or humus horizons of different soil types.

7. The method according to p. 1, characterized in that the use of humic substances derived from oxidized wood lignin.

8. The method according to p. 7, characterized in that before oxidation of wood lignin spend processing the reaction mass under the action of ultrasound with power radiation 4-6 W/cm2with a frequency of 22 kHz for 6-10 minutes

9. The method according to p. 7 or 8, characterized in that humic substances produced by oxidation of wood lignin in alkaline oxygen-containing gas at a temperature 17020oWith the pressure of 1.9-2.5 MPa within 1-3 hours and subsequent cooling of the reaction mixture, separation of the solid phase from the solution, and acidification of the latter to a pH of 2-3.

 

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