Preparation for treating acute radiation lesions

FIELD: medicine, veterinary science.

SUBSTANCE: it is suggested to apply indometophen known previously as a radioprotector. It has been established that application of indometophen at different terms within the first 4 d after irradiation helps to increase survival rate and affect positively the flow of reparative processes in the body at no side effects.

EFFECT: higher efficiency of therapy.

2 tbl

 

The invention relates to medicine and veterinary medicine, namely to endoetheno, and can be used for the treatment of acute radiation injuries.

Endometrin (NS-1539) - domestic radioprotector long action, effective for common acute and prolonged gamma-irradiation, a single oral administration which enhances radioresistance different species of animals for up to 2 weeks [1, 2].

Indole similar synthetic nonsteroidal estrogen, endometrin refers to antiestrogens pharmacological effect which is due to inhibition of specific actions of endogenous estrogens. It is assumed that the complex antiestrogen-estradiol receptor activates the transcription of genes, which are normally either hidden or blocked by complex estradiol receptor estradiol. Estrogens stimulate protein synthesis and increase the activity of many enzymes (timidilatsintetazu, timetracking, digidrofolatreduktazy, ribonucleotides and others), which leads to activation of the synthesis of precursors of DNA, DNA, RNA and proteins and cell proliferation [3]. At the same time there is information about the inhibitory effect of antiestrogens on several enzymes of the biosynthesis of DNA and proteins [4, 5]. In this regard, it has been suggested that the genome is subject to multidirectional action of antiestrogens, and before the azan the power phase of action of antiestrogens expressed in the alternation of estrogen on the antiestrogenic effect [6].

Irradiation decreased activity of the enzymes, primarily ribonucleotides (the rate limiting enzyme in DNA synthesis), leads to inhibition of the synthesis of precursors of DNA and metabolic formation of DNA damage [7, 8], the emergence of HIV [9]. Intemationalisation ribonucleotides activity of the spleen and bone marrow of animals were recorded within 7-8 days, with a maximum increase of 2.5 times) activity 5-6 days after injection, i.e. to the moment of exposure when using it as a radioprotector [10]. The activation of the synthesis of deoxyribonucleotides needed for DNA repair, and then in a period of regeneration radiosensitive organs of mammals, and replicative synthesis provides the mechanisms of cell stability. Increasing the ability of cells to repair radiation-chemical povrezhdeniya DNA in the mechanism of radioprotective action of indometacina noted in the article [11]. According to the authors of [12] long-term increase in radioresistance in conditions of indometacina may be caused by the influence of compounds on cellular and humoral mechanisms of regulation of hematopoiesis. According to them takes place as a direct effect of indometacina on early hemopo the practical precursor cells, and mediated through the stimulation selection recodification factors elements of the hematopoietic microenvironment.

In animals and humans indometacin stimulates the synthesis of precursors of DNA, DNA, RNA and proteins, activates the synthesis of ATP, increases the potential detoxification, increases antioxidant and antiproteolytic properties of blood. Activation of metabolic processes helps improve bioenergetic and biosynthetic capacity of the cell and the resistance of the organism as a whole [6].

Described metabolic changes are reflected in the stimulating effect of indometacina and immune response in the body [13].

Thus, intemationalisation activation of metabolic processes helps to increase the reserve capacity of the organism and provides an adequate response to the irradiation, which prevents the development of failure of compensatory restoration processes in the critical period of development of radiation injury.

The aim of the invention is research and evidence of ability to apply indometacina for the treatment of acute radiation injuries.

To achieve the objectives studied therapeutic effect of indometacina with acute radiation defeat.

During the studies the authors found indometacina new property appear is seesa in therapeutic activity in acute radiation defeat.

therapeutic activity of indometacina studied in comparison with the activity of estrofem, the oral dosage form of estradiol (estradiol hemihydrate). Activity indometacina studied the survival rate and life expectancy (ALE) of dead animals within 30 days after exposure to gamma radiation137Cs installation IGUR at doses of 7.5 Grams (equal to DM91/30and of 7.25 Gy (equal to DM63/30) at dose rate of 2,04 G/min Test was carried out conforming sexually Mature mice male line (CBA×C57B)F1weighing 18-22, the Test compound was administered for therapeutic purposes intragastrically once in the form of a suspension in 0.4%aqueous solution of Tween-80 in doses of 5, 15 and 30 mg/kg in 30 min, 1, 2, 3, 4, 6 days after irradiation.

therapeutic activity of indometacina studied in comparison with the activity of estradiol hemihydrate (estrofem), which at a dose of 7 μg/mouse were injected into the stomach in the form of a suspension in 0.4%aqueous solution of Tween-80. The results of the study are presented in tables 1 and 2.

10
Table 1

The effectiveness of indometacina when introduced at different times after acute exposure of mice at a dose of 7.5 G
GroupDose, mg/kgTime after training dayThe number of animal is Survival, %Mean life span, days
Control--69912,3±0,5
13,2÷11,4
Indometacin3013030*13,0±0,8
14,6÷11,4
Indometacin1512941*13,4±0,9
15,3÷11,5
Indometacin3033027*12,7±0,4
14.4V÷11,8
Indometacin1532935*13,1±0,6
14.4V÷11,8
Indometacin3030 min1013,8±1,8
17,8÷9,8
Indometacin1530 min1030*13,6±2,3
19,0÷8,2
Indometacin304102016,3±1,7
20,3÷12,3
Indometacin151017,0±1,0
41019,2÷14,8
Estrofem7 µg/mouse3151316,0±1,0
18,0÷14,0
(*) the difference is significant compared with the control group by criterion χ2

The introduction of indometacina at doses of 15 and 30 mg/kg after 1 and 3 days after exposure to radial and contributed to the increased survival of mice on average, 30%and 20%, respectively. The trend to improved survival can be seen in the groups irradiated animals, which endometrin was administered after 30 min and 4 days in the same doses of 15 and 30 mg/kg Single oral administration of estradiol hemihydrate (estrofem) three days after radiation exposure has not resulted in significant increases in survival of animals. Given that the maximum radioprotective effect of indometacina occurs when the radiation dose that make up LD70-80further study of therapeutic effect of the compound was carried out at a lower (of 7.25 Gy) dose mice.

Endometrin at a dose of 30 mg/kg significantly increased the survival of mice compared with the control group on average 40-45% after single oral administration in a period of 30 min to 3 days after exposure. The use of indometacina at a dose of 15 mg/kg contributed to the improved survival even greater percentage of mice relative to the control group. Lower (5 mg/kg) dose of indometacina and later (6 days) time after radiation therapy were ineffective. However, it should be noted that the use of indometacina at a dose of 5 mg/kg after 1 and 3 days after irradiation slightly better life expectancy of the dead mice.

The survival rate of mice after a single oral what about the application of radioprotective doses (30 and 15 mg/kg) indometacina was comparable with the efficiency of estrofem, oral dosage form of estradiol. Estrofem unlike indometacina animals were injected repeatedly, starting with 3 days a day up to 21 days after exposure to radiation.

The experimental results suggest that the use of indometacina at different times within the first 4 days after exposure, can have a positive effect on the course of reparative processes in the body.

Currently, practical medicine has no therapeutic agents with similar indometacinum efficiency, recorded after a single oral administration in the first four days after irradiation, without any side effects.

Literature

1. Borovkov M.V., Chupina LN. // Radiobiol. Congress. Kiev, 20-25 September 1993: abstracts of the reports. Part 1. Pushchino, 1993. P.137-138.

2. Borovkov M.V., Shlyakova YEAR, Chernov, G. A., N. N. Suvorov. // Third Congress on radiation research. Moscow, 14-17 October 1997: abstracts of the reports. T.II. M., 1997. Pp.163-164.

3. Sergeev PV, Mineeva E.N. Antiestrogens: molecular mechanisms of action // Chemical-Pharmacol. Journe. 1990. 24. No. 5. P.4.

4. Martin L. Estrogens in the environment / Ed. McLachlan J.A. New York, 1980.

5. Martin L. Non steroidal antiestrogens / Ed. Satherland R.L. Sydney, 1981. P.143.

6. Chernov GA, Sharygin V.L., Pulatova, M.K., Scarf VG, Borovkov M.V., Shlyakova YEAR, Khristianovich, Mitrokhin SCI, N. Todorov. Mol the molecular mechanisms of action of radioprotector of indometacina. Biochemical and bioenergetic aspects. Izvestiya. ser. biological. 1996, No. 3, s-291.

7. Pulatova M.K., Sharygin V.L., Filatov D.E., Todorov I.N. // Highlights of Modern Biochemistry / Eds A.Kotyk, I.Scoda, V.Paces, V.Kostka. Zeist: VSP Int. Sciense Publishers, 1989. P.215-229.

8. Pulatova, M.K., Sharygin V.L., Filatov DA etc. // Dokl. THE USSR ACADEMY OF SCIENCES. 1988. T. No. 1. S-237.

9. Ulmann Century, L.J. Gudas, Clift S.M., D.W. Martin Jr. // Proc. Natl. Acad. Sci. USA. 1979. V.76. P.1074-1077.

10. Pulatova, M.K., Sharygin V.L., Shlyakova YEAR of the Reaction system for the synthesis of deoxyribonucleotides for exposure and modification of radioprotectors. Radiation biology. Radioecology. 2003, t, No.1, p.29-43.

11. Mazurek VK, V.F. Mikhailov, Osenkov L.N., Borovkov M.V., Chernov GA, Raev NF Effect of potential radioprotective tools - connection of NA-1539 - on reparative DNA synthesis induced damaging effect of chemical mutagen N-nitroso-N-metalmachine and radiation. Radiation biology. Radioecology. 1995, t.35, No. 4, s-535.

12. Lebedev V.G., frost B.B., Vorotnikov T.V., Cheap SHE Studying mechanisms of radioprotective action of indometacina on hematopoietic precursor cells in long-term cultures of bone marrow of mice. Radiation biology. Radioecology. 1999, t, No. 5, s-533.

13. Mikhailov P.P., Maltsev V., Shlyakova YEAR and other Effects of radioprotector of indometacina on the immunological reactivity of the organism. Radiat. biology. Radioecology. T. No. 4, S-431.

The use of indometacina as a therapeutic agent in acute radiation damage.



 

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