RADIOPROTECTORS — substances of preferential synthetic origin which administration before radiation on Wednesday with biological objects or in an organism of animals and the person reduces the striking action of ionizing radiation.
The basic possibility of pharmakokhimichesky antiactinic protection (see) mammals was shown in 1949 by Patt (H. M of Patt) et al. who established a possibility of prevention of death of a part of mice by means of the cysteine (see) entered by it in several minutes before x-ray radiation in a lethal dose. A little later 3. Buck established significantly a bigger radio protective effect of decarboxylized derivative cysteine — Cysteaminum — and its disulfide — Cystaminum (see). Introduction of these connections before radiation of animals prevented death of 100% of mice at 100% of death of the control animals subjected to radiation in the same dose, but without introduction of radioprotectors.
Rubles are intended generally for individual protection of an organism from. external radiation in force majeure (emergency, military conditions) and for preferential protection of normal fabrics at radiation therapy of malignant tumors. From many studied means the most effective R. belonging to two big classes — to sulfur-containing connections and indolylalkylamines are selected. Also aminoalkylthiophosphates, aminoalkilizotiuroniyevy derivatives, sulfur-containing amino acids, peptides (glutathione) and their corresponding disulfides belong to sulfur-containing radioprotectors. From other sulfur-containing connections as R. dithiocarbamates and derivatives of a tiazolidin are studied.
Only those aminothiols in which the hydrocarbon chain separating an amino group from SH group consists of 2 or 3 carbon atoms have radio protective activity. SH груипа in these connections shall. to be free or to be released in the course of their metabolism in an organism. Sulfur-containing R.' part enter only parenterally, others are effective also at appointment inside. The maximum concentration in blood in the first case comes in 5 — 15 min., and in the second — in 30 — 60 min. In an organism these R. are distributed unevenly; e.g., the maintenance of Cystaminum in a thyroid gland, kidneys, marrow, adrenal glands and a spleen exceeds their contents in heart and in skeletal muscles. In large numbers sulfur-containing R. come to a liver where there is their inactivation. From an organism they are allocated with urine partially in not changed look, and generally in the form of decomposition products: taurine, hypotaurine., Cystaminum disulphoxide, aminoaldehyde and sulfate. The products of metabolism an aminoetilizotiuroniya which are allocated from an organism are 2-guanidoetansulfonovy to - that, 8-acetyl-2-mercaptoethylguanidine and sulfates.
Cysteaminum, Cystaminum, Propaminum beta mercaptopropylamine), derivatives 2-aminoalkylthiophosphoric to - you and its sodium salt (tsistafos) and a pro-saw analog 2 aminopropyl aminoethylthiophosphoric to - that are of the greatest practical interest (gammafos). To a gammafos the special attention, as is drawn to perspective R. at radiation therapy of tumors. In researches on animals with the intertwined tumors, it was shown what in certain time slices between administration of drug and radiation gammafos selectively weakens defeat of normal fabrics, without influencing antineoplastic action of ionizing radiation. It gives the chance to increase an exposure dose of a tumor, without exceeding a limit of tolerance of the healthy fabrics surrounding it. In a number of the countries since 1980 a wedge, tests of a gammafos are begun.
Homologs and derivatives of a triptamin (fig.) belong to indolilakilamina. The most effective R. from a class an indole silt alkyl of amines — serotonin (see) and Mexaminum (see), and also their derivatives are natural compounds — biogenic amines (see). All of them are received also in the synthetic way. From other biogenic amines studied as R., the arylalkylamines called often by pyrocatechins as their major representatives — adrenaline and noradrenaline and also beta feniletilamin, tyramine, ephedrine, a histamine and acetylcholine are of the greatest interest. The majority of indolylalkylamines is effective at parenteral administration. Meksamiya can appoint inside; in this case it is also quickly soaked up, reaching the maximum concentration in blood in 20 — 30 min. As well as sulfur-containing R., indolylalkylamines in an organism are distributed unevenly. The greatest concentration of Mexaminum at intake is noted in kidneys, a liver and a spleen. Within the first days he is brought with urine partially in not changed look, and within two next days — in the form of a key product of his metabolism (5-metoksi-3-indolyacetic to - you).
In an explanation of mechanisms of action of R. there is no uniform point of view. E. F. Romantsev develops representation about complex biochemical, the mechanism of action of R., special value in Krom belongs to temporary inhibition of replikativny processes and stimulation of DNA repair. There is an opinion on existence of the general mechanism of antiactinic protection. So, e.g., according to Yu. B. Kudryashov and E. N. Goncharenko's hypothesis, the radio protective effect of any R. in an organism is implemented due to synthesis and release of a complex of the biogenic amines having antiactinic properties and decrease in maintenance of products of peroxide oxidation of lipids — endogenous radio sensitizers. The hypothesis biochemical, the shock which is arising under the influence of R. in a cell and temporarily raising a threshold of the striking action of ionizing radiation expresses. According to E. Ya. Grayevsky, as the uniform material substrate determining the level of natural radiation resistance and its variation by R. endogenous SH groups are. Attempts to connect the molecular mechanism of protective action of R. with post-radiation DNA repair are made. Dependence of action of R. on a condition of the genetic device controlling systems of DNA repair is shown.
The antiactinic effect of R. in an organism is implemented by two ways. Crucial importance for manifestation of a protective effect of sulfur-containing R. has achievement of threshold concentration of R. in cells of critical bodies (the hemopoietic system and intestines) at general irradiation or in cells of any other protected fabrics at local radiative effects. The preferential mechanism of radio protective action of indolylalkylamines in an organism consists in creation of a fabric hypoxia owing to a temporary spasm of blood vessels.
Due to the different mechanisms of protective action of R. and quantitative distinctions in degree of protection separate R. of critical systems it is reasonable to apply the mixes P. belonging to different classes to strengthening of a radio protective effect.
A quantitative index of efficiency of R. is the so-called factor of change of a dose (FCD) which is defined by the relation of ravnoeffektivny doses: in numerator of a dose of radiation at R.'s use, in a denominator — doses of radiation without use of River. At separate R.'s use size FID fluctuates in the range of 1,5 — 2,0 whereas during the use of the FID multi-component mixtures P. reaches 3 — 4.
Antiactinic protection of an organism can be reached by use of the general hypoxia caused by inhalation of the gas mixtures which are grown poor by oxygen. This method received the name of hypoxyradiotheraphy and is studied for preferential protection of normal fabrics at radiation therapy of malignant tumors.
Despite a large number of pilot studies, R. did not find broad practical application yet. It is connected by hl. obr. in the side effects arising at R.'s use in radio protective doses. Overcoming these difficulties lies on the way of the combined use of R. possessing the different mechanism of protective action. At the same time, as shown in experiments on different types of animals, simultaneous introduction of three and more R. or their use together with gas hypoxemic mixtures allows to reach a considerable radio protective effect at falloff or lack of undesirable toxic manifestations. Besides, on the example of a gammafos and its analogs perspectives of synthesis of the new more effective and deprived of side effect on a human body R. are visible to selective protection of normal fabrics at radiation therapy of tumors.
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V. S. Shashkov, S. P. Yarmonenko.