Induction of micronucleated erythrocytes by MEA, AET, WR-2721 and X-rays.

The induction of micronucleated polychromatic erythrocytes (MNPCEs) was assessed in the bone marrow of adult male Swiss mice treated with MEA (cysteamine HCl), AET (2-aminoethylisothiouronium Br.HBr), or WR-2721 (S-2-(3-aminopropylamino)ethyl phosphorothioic acid), at a dose of 200 mg/kg body weight, and/or exposed to 6 Gy X-rays. MEA, AET, or WR-2721 was given alone or 15 min prior to X-ray exposure, and the frequency of MNPCEs was determined 24 h after the aminothiol treatment and X-irradiation of mice. A genotoxic effect was shown for MEA, AET, WR-2721, and X-rays, as well as a protective effect of the aminothiols against X-ray-induced genotoxicity in the mouse erythropoietic system. The aminothiol drugs given alone, without subsequent X-irradiation, elevated the frequency of MNPCEs, and WR-2721 appeared to be less toxic than AET and MEA. After exposure of mice to X-rays, the number of MNPCEs was distinctly increased. MEA, AET, or WR-2721 administration prior to X-irradiation resulted in a reduction of the X-ray-induced elevation of the frequency of micronuclei, but a stronger radioprotective effect was obtained following WR-2721 and AET treatment than after MEA application. So, the genotoxic and radioprotective effect of the aminothiols was dependent on the compound applied.

[Decrease of toxic effects of aminothiol radiation-protective agents and increase of chemical protection action against ionizing radiation by the use of unithiol]. / Snizhenie toksicheskogo deistviia aminotiolovykh radioprotektorov i povyshenie éffekta khimicheskoi zashchity ot ioniziruiushchei radiatsii s pomoshchiu unitiola.

It has been shown that unithiol diminishes toxic action of cysteamine, AET, and disulfide of WR-1065 on mice. This permits to enhance protection of animals against X-rays by increasing of protector doses. The effect of unithiol on cysteamine action in rats was the same. Antitoxic effect of unithiol on cysteamine was shown both at i.p. and p.o. protector administration. The effect was also revealed in Chinese hamster V-79 cell culture. Combined disulfide of cysteamine and unithiol was synthetized, which ensures effective prolonged protection against ionizing radiation.

Protein level in testes, kidneys and liver after AET or MEA treatment of mice.

The adult male Swiss mice were treated intraperitoneally with AET (2-aminoethylisothiouronium Br.HBr) or MEA (cysteamine HCl), in a toxic dose of 400 mg/kg body weight. The measurements of the protein content in crude homogenates of testes, kidneys and liver were done every fourth hour throughout a 24-hour period. Treatment of mice with AET and MEA resulted in different patterns of temporal changes in the protein content in testes, kidneys and liver expressed in mg per 1 g of fresh tissue and per the whole organ weight. The extent and timing of the alterations in the protein level appeared to depend on the particular organ chosen and the thiol agent applied.

Effects of AET and MEA on the lysosomal hydrolase activities in the mouse organs.

The adult male Swiss mice were injected intraperitoneally with AET (2-aminoethylisothiouronium Br.HBr) or MEA (cysteamine HCl), in a toxic dose of 400 mg/kg body weight. The acid phosphatase (E.C. 3.1.3.2) and arylsulphatase (E. C. 3.1.6.1) activities in crude homogenates of liver and kidneys were assessed every fourth hour throughout a 24-h period. Different patterns of temporal changes in the acid phosphatase and arylsulphatase activities in liver and kidneys expressed in nkat per 1 mg of protein, 1 g of fresh tissue and per the whole organ weight, were found. The extent and timing of the alterations in the activity of each of the lysosomal hydrolases were dependent on the particular organ chosen and aminothiol compound given.

Antiradiation mixture and ionic-bond product of AET and adenyl nucleotides.

These experiments continued our line of inquiry into low-toxicity high-effectiveness radiomodifying agents obtained by binding radioprotective substances to biogenic and biologically active components or antidotes. Testes for toxicity and radioprotective effects were three preparations combining within one molecule AET and an adenyl nucleotide (AMP, ADP, or ATP). Ionic-bond formation was shown to have advantages over concomitant administration of AET and adenosine phosphoric acids as mixtures. The evidence obtained supports the rational foundation of the concept being developed by our laboratory.

Quantity of glycogen in the liver of 19-day-old foetuses after AET, 5-HT, MEA, or GSH treatment of pregnant mice on the first day of gestation.

Swiss mice were treated intraperitoneally with AET, 5-HT, MEA, or GSH, in a dose of 80 mg/kg of body weight, on the first day of gestation. On the 19th day of pregnancy, the fresh weight of liver of the foetuses, as well as glycogen content in 1 g of fresh tissue and in the whole organ were analysed. The determination of glycogen content in the foetal liver were made according to the anthrone method. As compared with controls, in the remaining groups of mice a lower fresh weight of foetal liver less glycogen per g of fresh tissue and a smaller total amount of glycogen in the whole organ were found. Among the compounds, AET appeared to be more toxic than 5-HT, MEA, and GSH.

[Determination of the optimal proportions as regards toxicity of AET, ATP and serotonin used in combination]. / Opredelenie optimal'nogo po toksichnosti sootnosheniia AET, ATF i serotonina pri ikh kombinirovannom primenenii.

In experiments on mice, a study was made of the quantitative dependence of toxicity of AET, ATP and serotonin applied in combinations. The toxicity decreased when ATP was combined with AET and increased when ATP of AET were combined with serotonin. The toxicity of a combination of all three substances was reduced by introducing high doses of ATP.

[Use of a manganese citrate complex in the determination of liver enzyme activities in the aging process and following treatment with aminoethylisothiuronium bromide hydrobromide (AET)]. / Die Anwendung des Manganzitrat-Komplexes in Bestimmung der Enzymaktivitäten der Leber während der Alternsprozesse und nach Behandlung mit Aminoäthylisothiuronium. Br. HBr (AET).

Some oxidation enzyme as well as reductase and dehydrogenases in liver samples were estimated. With the manganese-citrate plus diethylen-p-phenylene-diamine complex method an increases reduction-capacity and succino-dehydrogenase activity was recorded in the liver samples of the 23 month old rat. No differences were found between the 6 and 12 month old rat liver samples. Following a 8-month amino-ethyl-isothiuronium. Br. HBr (AET) treatment (100 mg/kg) of mice both the reduction-capacity and the succino-dehydrogenase activity showed an elevated value in the liver samples of the experimental animals.

[General characteristics and comparative evaluation of the radioprotective properties of aryl alkyl amine adrenomimetics in experiments on mice]. / Obshchaia kharakteristika i sravnitel'naia otsenka radiozashchitnykh svoistv adrenomimetikov riada arilalkilaminov v opytakh na myshakh.

The radioprotective effect (RPE) of some arylalkylamines (AAAs) was studied in experiments on mice. Mesaton and its close analogues were injected subcutaneously 15 minutes prior to irradiation at a dose of 800 rad. The protective effect is exerted by AAAs in low doses (25--50 mumole/kg), the compounds show stable and high RPE (80--80% survival, dose reduction factor being 1.3--1.4) and low toxicity (LD50 = 4--8 mumole/kg). AAAs studied are not less effective than aminothiols. Their pharmacological spectrum--K = LD50/ED50 (200--500) is superior to that of known aminothiols and indolylalkylamines.

Radioprotective effectiveness and toxicity of ATP, AET and serotonin applied individually or simultaneously to mice. III. Radioprotective effects of pair combinations.

The work reported was done as part of an intensive investigation on toxic and radioprotective properties of three substances, ATP, AET and serotonin, administered singly or in combination to mice, with a view to identifying optimal dose ratios for cocktails. Male C57BL mice were exposed to 850 R X-rays (LD100/11) following pretreatment with drug pairs at various dose ratios. Thirty-day survival was scored. For ATP-AET, protection increased with the amount of ATP in the combination; this pair was found to be most effective at an ATP-to-AET ratio of 11:1. A similar trend was observed with ATP-Serotonin, though only up to a certain ATP level beyond which no further increase in protective effect were produced; the most favorable ratio was of 24:1. A maximum synergistic action was displayed by the AET-Serotonin pair as compared to the other two pairs; its best ratio was of 4:1. Using probit analysis, a number of PD50 (protectant dose affording 50% survival in lethal irradiation) values were estimated for the three pairs of protective agents.

[A pool hemopoietic stem cells and resistance of mice to toxic substances depending upon food rations]. / Pul krovetvornykh stvolovykh kletok i ustoichivost' myshei k toksicheskim veshchestvam v zavisnmosti ot kachestva pischevykh ratsionov

Tests set up on male-mice of the CBA/I lineage demonstrated that fat carbohydrate rations of 1:7.3 and 1:3.8 in granulated combined fodder tend to increase the number of stem cells in a statistically fashion. Among mongrel mice kept on a ration with 7 per cent of fat a combination of mexamine with AET was found to loose some of its toxicity.

Radioprotective and toxic effects of a mixture of AET and 5-methoxytryptamine in mice.

The authors studied the radioprotective efficacy and toxicity of an AET + 5-methoxytryptamine mixture and its effect on the course of respiratory exchange, using different weight ratios of the two components. The optomum was found to be 150 mg AET/kg b.w + 25 mg 5-MOT/kg b.w. This mixture gave very good protection in the supralethal exposure range and markedly prolonged its duration. The high toxicity of this mixture was abolished by the pre-administration of glutathione. Raised and longer protection was also manifested in the course of respiratory exchange, showing that an association exists between changes in energy metabolism and raised radioresistance of the organism.