[Radioprotective effectiveness of indralin in local gamma irradiation of the skin]. / Protivoluchevaia éffektivnost' indralina pri lokal'nom gamma-obluchenii kozhi.

In experiment with mice radioprotective properties of indralin were investigated on local application of the substance at the site of the hind to be exposed to gamma-60Co-rays in the doses of 16.7-39.0 Gy at rate of the dose -1.5-1.6 Gy/min. After s.c. injection (50, 100, 200 and 300 mg/kg) radioprotective efficiency of indralin in term of DRF was 1.35, 1.50, 1.35 and 1.05 for early radiation damages of the skin, -1.13, 1.62, 1.53 and 1.45 for late radiation contracture of the leg, -1.10, 1.50, 1.20 and 1.16 for radiation amputation of the foot. Under 3-fold every 2 days fractionated irradiation in total dose of 42.9 Gy radioprotective efficiency of indralin in term of DRF made 1.62 for early radiation damages of skin, -1.52 for radiation oedema of the foot, > 1.5 for radiation contracture of leg. After external cutaneous application of indralin solution on 70% DMSO solvent radioprotective efficiency of the drug in term of DRF was 1.28 and 1.37 for early and late radiation damages of skin while DRF of DMSO being equal to 1.14 and 1.22 responsively.

[The creation of original Russian beta-adrenoblockers]. / Sozdanie otechestvennykh original'nykh beta-adrenoblokatorov.

Results of search for new beta-adrenoreceptor blocking agents of different effects are summarized. Derivatives of 4-hydroxyindolyl-3-acetic acid are characterized by a prolonged beta-adrenoblocking effect, cardioselective beta-adrenoblockers were found among derivatives of N,N-bis(2-hydroxy-3-phenoxypropanol)amine, and highly effective "hybrid" beta-,a-adrenoblockers were detected among derivatives of 3(5)-phenoxymethylisoxazolines and 5-phenoxymethyl-1,2,4,-oxadiasoles. Clinical studies of one of the most promising compounds of the latter series named proxodolol showed it to be a highly effective antihypertensive, antianginal, and antiglaucoma drug. Proxodolol is permitted for clinical application. At present it is manufactured as eye drops for decreasing intraocular pressure in glaucoma; its production as a solution for injections for arresting hypertensive crises is starting.

[The role of the vasoconstrictor effect in realizing the radioprotective properties of indralin in experiments on dogs]. / Rol' vazokonstriktornogo éffekta v realizatsii protivoluchevykh svoistv indralina v opytakh na sobakakh.

In the experiments on dogs, the role of a pharmacological circulatory hypoxia in the mechanism of radioprotective effect of indraline and mexamine was studied. Angiography revealed 20-40% vasoconstriction of major arteries of legs of animals, of pelvis and abdomen caused by mexamine (10 mg/kg) and the absence of a significant effect of indraline. Disruption of a regional blood circulation in the marrow and spleen (40-50% and 70-80%, respectively) was caused by indraline to the same extent as by mexamine. For indraline, a decrease in pO2 in the marrow was about 50%. With these hemodynamic disturbances, indraline showed 80 to 100% radioprotective effect, while mexamine was inefficient. Acute hypoxic hypoxia (5-7% O2) increased a post-radiation survival rate for dogs by 40%. The radioprotective effect of indraline was blocked by tropaphen and reduced in cases of breathing with pure oxygen. Splenectomy has no effect on radioprotective properties of indraline. Thus, a hypothesis of the mechanism of a radioprotective effect of alpha-adrenomimetics was proposed.

[Mechanism of the radiation-protective effect of indralin]. / K mekhanizmu protivoluchevogo deistviia indralina.

Pharmacological test demonstrated that radioprotective activity of indralin occurs by interaction with alpha-adrenoreceptor. Radioprotective effect of indralin decreased by alpha-adrenoblocker, aminazine and theophylline. Normobaric hyperoxia during irradiation reduced radioprotective effect of indralin in doses about ED50. In experiment with mice and rats it was shown that indralin induced acute hypoxia, impaired oxygen consumption and heat production by 30-46%, spleen bloodflow to 26.3% of control level, rectal temperature by 1.5-2 degrees C (mouse). After 30-min indralin raised resistance of mice to hypoxic hypoxia that is believed due to rapid development of biochemical adaptive process in hypoxic cells.

[Monoamine oxidase inhibition by pyrrole quinoline derivatives]. / Ingibirovanie monoaminoksidazy proizvodnymi pirrolokhinolinov.

The effect of 1-(beta-aminoethyl)-3H-pyrrole[2,3-h]quinoline (I), 3-(beta-aminoethyl)-1H-pyrrole[2,3-h]quinoline (I'), 8-amino-3H-pyrrole[2,3-h]quinoline (II), 6-amino-3H-pyrrole[2,3-h]quinoline (II') and 8-amino-1H-pyrrole[2,3-h]quinoline (III) on tyramine, serotonin and 2-phenylethylamine deaminase activities of mitochondrial monoamine oxidase from bovine brain were studied. All the compounds tested appeared to be reversibly inhibit MAO without preliminary incubation. Compounds II, II' and III specifically inhibited type A MAO; compound III exhibited the highest selectivity. The inhibition was of a mixed type. The effects of compounds I and I' were competitive and inconsistent with a classical concept on the dual activity of MAO, i. e., deamination of tyramine, a substrate common for MAO type A and MAO type B was inhibited in a greater degree than the deamination of specific substrates of MAO type A (serotonin) or type B (2-phenylethylamine). Possible reasons for the observed phenomenon are discussed.

[Radiation-modifying effect of quinoline derivatives]. / Radiomodifitsiruiushchii éffekt proizvodnykh khinolina.

In experiments with hybrid mice (CBA X C57Bl)F1 and tetrahybrids (CBWA) a study was made of the radio-modifying properties of twelve quinoline derivatives. Among them three preparations, including quipazine [1(2-quinolyl)piperazine], possessed a 50% radioprotective effect. The radioprotective effect of piperazinylcinchonine acid hydrazides was the same as that of mexamine.

[Changes in the therapeutic spectrum with respect to the pharmacological and radioprotective activity after O-alkylation of serotonin and 5(2-hydroxyethoxytryptamine)]. / Izmenenie terapevticheskoi shiroty deistviia po farmakologicheskomu i protivoluchevomu éffektu pri O-alkilirovanii serotonina i 5(2-oksiétoksitriptamina).

In experiments with mongrel mice, a study was made of the pharmacological activity of serotonin and its O-alkyl derivatives. It was estimated by the two indices, that is, the radioprotective properties and the influence on a local blood channel in the spleen, the modifying effect of the agents' toxicity being estimated as well. As an O-alkyl group of 5-alkoxytryptamines was elongated from one to three carbon atoms and the toxicity of the substances increased, their radioprotective effect decreased more readily than their effect on the local blood channel. The shortening of the range of the therapeutic action of the agents under study, with regard to the two pharmacological indices mentioned above, the alkyl group being lengthened, followed a logarithmic function which was more pronounced in relation to the radioprotective index (cos alpha 1/cos alpha 2 = 1.58).

[Radioprotective effectiveness and toxicity of 4,5-disubstituted tryptamines]. / Radiozashchitnaia éffektivnost' i toksichnost' 4,5-dizameshchennykh triptaminov.

In experiments on mice a study was made of different substituents in the 4th position of the indole ring of 5-methoxytryptamines (5-MOT) on toxicity and radioprotective efficiency of the compounds of this class. It was shown that the administration of the amino-group to a mexamine molecule increased the preparation toxicity; the nitro-group somewhat diminished the toxic properties, and the acetylamino group did not change 5-MOT toxicity. A 5-MOT derivative with a nitro group possessed the strongest radioprotective action. The radioprotective efficiency of these compounds persisted for 1-2 h.

[Blastomogenic activity of biogenic methoxyindoles]. / Blastomogennaia aktivnost' biogennykh metoksiindolov.

A considerable blastogenic activity of biogenic methoxyindoles--melatonin, 5-methoxytryptamine (5-MOT) and their common metabolite--5-methoxyindolyl-3-acetic acid (5-MIAA) was established by prolonged s.c. injection in C57BL/6 mice. However, the blastogenic effect of 5-MOT decreased by 26% when its further metabolism to 5-MIAA was blocked for some time and the synthesis of its carcinogenic metabolite was inhibited. These results showed that the blastogenic effect of 5-MOT is not direct; and it is mediated by its transformation to 5-MIAA in the body.

[Characteristics of the role of the hydroxyl group in serotonin in the pharmacological and antiradiation effect of serotonin]. / K kharakteristike roli gidroksil'noi gruppy serotonina v farmakologicheskom i protivoluchevom éffekte serotonina.

It was shown that omega-hydroxylation of O-alkyl serotonin derivatives can slightly improve the radioprotective and pharmacological properties of these substances but fails to remove completely the unfavourable action of O-alkylation of serotonin. There is a close correlation between the radioprotective effect of 5-oxyalkoxytryptamines and their action on blood supply of mouse spleen. The introduction of the alkoxy-group or the tertiary amino-group into omega-position removes the radioprotective effect of 5-alkoxytryptamines.

[Kinetics of the inhibition of mitochondrial monoamine oxidases A and B from rat liver by 1-(indolyl-3)isopropylmethylpropargylamine]. / Kinetika ingibirovaniia mitokhondrial'nykh monoaminoksidaz tipov A i B pecheni krysy 1-(indolil-3)izopropilmetilpropargilaminom.

The kinetics of inhibition of the activity of monoamine oxidases A (with 5-oxytryptamine as substrate) and B (with 2-phenylethylamine as substrate) from rat liver mitochondria by a new acetyleneamine, 1-(indolyl-3)isopropylmethylpropargylamine, was studied. It was shown that the inhibition of the both forms of monoamine oxidase results in formation of an intermediate dissociating enzyme--inhibitor complex which is further converted into an irreversibly blocked enzyme. The value of the dissociation constant, Ki, of the intermediate enzyme--inhibitor complex with 2-phenylethylamine as substrate is equal to 24 . 10(6) M, that with 5-oxytryptamine--to 0.09 . 10(-6) M. The values of the rate constants, K3, for the conversion of the enzyme--inhibitor complex into an irreversibly blocked enzyme in experiments with 2-phenylethylamine and 5-oxytryptamine were rather close, i. e. 0.06 and 0.05 min-1, respectively. The results obtained indicate that the selectivity and inhibition of the activity of monoamine oxidases A and B by propargylamine derivatives is manifested at the primary step of formation of dissociating intermediate enzyme--inhibitor complexes.

[Purification and properties of the serotonin-stimulated adenylate deaminase from the mitochondrial fraction of rat liver]. / Ob ochistke i svoistvakh stimuliruemoi serotoninom adenilatdezaminazy mitokhondrial'noi fraktsii pecheni krysy

A method is described for partial purification of structurally bound adenilate desaminase from rat liver tissue mitochondria; the enzyme was stimulated by parenteral administration of serotonine. The enzymatic preparations obtained desaminated AMP, 2',3'-AMP and adenosine, but they did not effect on ATP, 2',3'-cycloAMP or 3',5'-cycloAMP. The maximal rate of desaminating of these substances by AMP-desaminase, stimulated with serotonine, exceeded approximately 1.4-fold the same values, which were obtained for the enzymatic preparations from liver tissue mitochondria of rats, administered with physiological solution. Mitochondrial serotomine-stimulated adenilate desaminase was differentiated from the other soluble adenilate desaminases by some properties; the enzyme was likely to participate also in the regulation of nucleotides balance in the organism.

[Specificity and mechanism of serotonin stimulation of adenylate deaminase activity]. / O spetsifichnosti i mekhanizme stimuliatsii serotoninom adenilatdezaminaznoi aktivnosti

Adenylate deaminating activity was stimulated in the liver mitochondria of rats in vivo not only by serotonin or synthetic indolylalkylamines, but also by phenyl- and imidazolalkyamines. Actinomycin D and cycloheximide protein biosynthesis inhibitors prevented stimulation of adenylate deaminating activity. Theophylline, phosphodiesterase inhibitor, produced a similar effect only when the extent of stimulation of adenylate deaminating activity was comparatively high.

[Effect of mexamine on the resistance of dogs to acute hypoxic hypoxia]. / Vliianie meksamina na ustoichivost' sobak k ostroi gipoksicheskoi gipoksii

As demonstrated in experiments staged on dogs mexamine hydrochloride, used in a dose of 20 mg/kg by the intraperiotoneal route 1.5 hours before the onset of acute hypoxic hypoxia increases the resistance of the organism to oxigen deficiency. Mexamine is capable of significantly intensity hypothermy in dogs during acute hypoxic hypoxia.

[Mechanism of the protective action of acetylcholine and serotonin against their cytotoxic antagonists]. / O mekhanizme zashchitnogo deistviia atsetilkholina i serotonina protiv ikh tsitotoksicheskikh antagonistov

By means of biological testing on supersensitive embryos of the sea-urchin Arbacia lixula, it has been shown that the eggs and embryos of the sea-urchin Paracentrotus lividus incubated in solutions of cytotoxic neuropharmacological drugs (cholino- and serotoninolytics), accumulate the latter. During the first (rapid) stage of binding, a level is reached which is 2-6 times higher than the external concentration; during the second stage of binding, this level gradually increases up to the values which are 8-12 times higher than the external concentration. The protecting action of exogenous acetylcholine and serotonin against the drugs studied does not inhibit their accumulation in embryonic cells. Therefore this protecting action is due to the decrease in the sensitivity of embryos to neurophysiological drugs. The protecting effect of endogenous factor produced by eggs and embryos is associated with the inhibition or abolition of the second stage of binding of cytotoxic neuropharmacological drugs.

Stimulation of adenylate deaminase activity by serotonin.

After a single intraperitoneal injection of serotonin into rats adenylate deaminase activity in the mitochondrial fraction of the liver was stimulated. The conditions under which a twofold increase in the deamination of AMP occurred, after serotonin administration,were determined. Preliminary blocking of monamine oxidase activity did not prevent this effect of serotonin.