[Experimental study of histamine-liberating properties of eremomycin]. / Eksperimental'noe izuchenie gistaminosvobozhdaiushchikh svoistv éremomitsina.

Eremomycin, a new glycopeptide antibiotic showed the same as ristomycin, polymyxins B and M and kanamycin histamine liberating properties. Liberation of endogenic histamine induced destructive lesions on the mucosa of the gastrointestinal tract. The most pronounced lesions were observed after intraperitoneal administration of the antibiotic. When eremomycin was administered intravenously or subcutaneously the affection of the gastrointestinal tract epithelium was less pronounced. After subplantar administration of the antibiotics pad edema in albino rats was observed. The most pronounced edema was after the use of ristomycin and the polymyxins. After the use of eremomycin and kanamycin it was at the average 2 times less pronounced. Preliminary administration of dimedrol decreased intensity of the pad edema induced by the antibiotics.

[Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin]. / Eksperimental'noe izuchenie antibakterial'noi aktivnosti, terapevticheskoi éffektivnosti i toksicheskikh svoistv kombinatsii tobramitsina s karbenitsillinom.

Tobramycin combination with carbenicillin was studied experimentally. Tobramycin is a new aminoglycoside antibiotic prepared at the Institute of New Antibiotics, the USSR Academy of Medical Sciences. It was shown that the combination had mainly synergistic action (67 per cent) on clinical strains of Pseudomonas aeruginosa which was confirmed in treatment of experimental sepsis caused by the organism. In acute experiments with albino mice there was observed summation of the general toxic action of the antibiotics used in the combination. The level and nature of the nephrotoxic action of the tobramycin combination with carbenicillin were shown in experiments with rats to be the same as those of the nephrotoxic action of tobramycin used alone. The presence of carbenicillin in the combination did not increase the inhibitory effect of tobramycin on excitement transmission in the neuromuscular synapses.

[Experimental study on chemotherapeutic efficacy, acute toxic action and nephrotoxicity of combinations of eremomycin with tobramycin]. / Eksperimental'noe izuchenie khimioterapevticheskoi éffektivnosti, ostrogo toksicheskogo deistviia i nefrotoksichnosti kombinatsii éremomitsina s tobramitsinom.

Chemotherapeutic efficacy of eremomycin in combination with tobramycin was investigated on a model of experimental sepsis of albino mice caused by Staphylococcus aureus cultures resistant to methicillin. Eremomycin is a novel original antibiotic of the glycopeptide structure isolated in the USSR and tobramycin is an aminoglycoside. Acute toxicity of the combination with a wide range of the dose fixed proportions was studied on mice and the nephrotoxic action of the antibiotics and their combinations administered intravenously for 5 days was studied on albino rats. The experiments showed that the chemotherapeutic effect of eremomycin in combination with tobramycin was of synergistic nature. Acute toxicity of the combined drugs mainly summed up and somewhat increased when the proportion of tobramycin and eremomycin was 1:2.4 or 1:3.6. Eremomycin had a dose-depended nephrotoxicity. Summing up of the nephrotoxic action of the drugs on their combined use was observed.

[Preclinical toxicological study of the new antibiotic eremomycin. Chronic toxicity and effect on intrauterine development of rats]. / Doklinicheskoe toksikologicheskoe izuchenie novogo antibiotika éremomitsina. Khronicheskaia toksichnost', vliianie na vnutriutrobnoe razvitie krys.

Toxicity of eremomycin was studied after its multiple parenteral administration to albino rats, guinea pigs and dogs in doses equivalent by the body surface to the daily doses for humans i. e. 1 and 3 g. The antibiotic was administered for 1 to 6 months. Tolerance of the antibiotic by the dogs after intravenous and intramuscular administration was satisfactory. In some animals there were observed an insignificant increase in the activity of alanine aminotransferase and a rise in the level of urea in blood serum. Pathomorphological examination of the internal organs of the albino rats and dogs showed that in high doses the antibiotic could have a damaging effect on the kidneys and epithelium of the gastrointestinal tract. The level of the damages depended on the dose of the antibiotic and duration of its use. The damages induced by eremomycin were reversible. It had no marked effect on the peripheral blood count, coagulation system and erythrocyte resistance. In the tested doses the antibiotic had no unfavourable effect on the hearing function in the experiments with guinea pigs. Studies with rats revealed that eremomycin had no teratogenic effect. A slightly pronounced embryotoxic action was observed only after using the antibiotic in doses exceeding more than 12 times the approximate therapeutic dose.

[Eremomycin in the treatment of antibiotic-associated colitis in golden hamsters]. / Lechenie éremomitsinom antibiotikoassotsiirovannogo kolita zolotistykh khomiachkov.

The efficacy of eremomycin, a new glycopeptide antibiotic, was studied on a model of antibiotic-associated colitis in golden hamsters. The colitis was induced by intraperitoneal or intragastric administration of lincomycin. In a dose of 100 mg/kg administered orally once a day for 5 days eremomycin protected the animals from the lincomycin-induced colitis: some animals survived, the others died in later periods. When the animals were infected with a pathogenetic strain of Clostridium difficile followed by exposure to lincomycin the use of eremomycin produced the similar effect.

[Characteristics of the functional state of the placental mitochondria in interrupted pregnancy]. / Osobennosti funktsional'nogo sostoianiia mitokhondrii platsenty pri nevynashivanii beremennosti.

PIP: In an attempt to evaluate early signs of placental insufficiency, the functional state of placental and chorionic mitochondria was studied in 62 pregnant women. The group included 18 women who decided to terminate pregnancy at 8-10 weeks of gestation, 13 women with normal delivery at term, 16 women who had miscarriages at 10-12 weeks of gestation, and 15 women who had miscarriages at 18-26 weeks of gestation. Functional state of mitochondria was estimated by oxygen consumption in the absence and presence of the acceptor system (hexokinase-glucose-adenosine diphosphate). Succinic and alpha-ketoglutaric acids were used as oxidation substrates. During normal pregnancy the rate of succinic acid oxidation in the absence of acceptor system (free respiration) was 12.1 and 11.8 microA 02/mg at 8-10 weeks and at term, respectively; the rate of oxygen consumption during oxidation of alpha-ketoglutarate was 7.6 and 6.2 microA 02/mg, respectively. The rate of oxygen consumption in the presence of acceptor system (coupled respiration) was 18.1 and 16.5 microA 02/mg for succinic acid and 14.4 and 11.2 microA 02/mg for alpha-ketoglutaric acid, respectively. Spontaneous miscarriage was characterized by significant decrease in the rate of oxygen consumption. Free respiration at 8-10 and 18-26 weeks was 8.6 and 63 microA 02/mg, respectively, for succinic acid and 6.8 and 5.9 microA 02/mg for alpha-ketoglutaric acid, respectively. Coupled respiration at 8-10 and 18-26 weeks was 11.2 and 5.7 for succinic acid and 9.5 and 6.5 microA 02/mg for alpha-ketoglutaric acid, respectively. These findings indicated that spontaneous miscarriage was preceded by inhibition of oxidative phosphorylation. It was suggested that functional impairment of placenta can be corrected by administration of preparations containing thiol group (cysteine).^ieng

[Experimental study of the toxic effect of combinations of tobramycin and carbenicillin]. / Issledovanie toksicheskogo deistviia kombinatsii tobramitsina s karbenitsillinom v éksperimente.

Acute toxicity of tobramycin and carbenicillin used alone and in combination was studied on albino mice. The antibiotics were combined in the following ratios: 1:15, 1:30, 1:45, 1:60, 1:75 and 1:150 (1 refers to tobramycin). The character of the toxic effect of the combinations was estimated with the Loewe graphical method and interaction indices. It was shown that interaction of tobramycin with carbenicillin in the combinations with wide ratio ranges was of an indifferent character. The toxic effect of the combinations did not reach the total toxic effect of the components used alone. It was noted that the combinations of tobramycin with carbenicillin in the ratios of 1:15, 1:30 and 1:150 were most favourable for the drug tolerance. The nephrotoxic effect of tobramycin and carbenicillin used alone and in combination was studied on albino rats. The antibiotics were administered intravenously for 5 days. It was demonstrated that the level and the character of the morphological changes in the kidneys of the rats treated with the combinations of tobramycin and carbenicillin were the same as those after the use of an analogous dose of tobramycin alone. Therefore, the nephrotoxic effect of tobramycin was not potentiated on its combined use with carbenicillin.

[Toxicity of rubomycin 13-cyclohexylidene hydrazone]. / Izuchenie toksichnosti 13-tsiklogeksilidengidrazona rubomitsina.

The systemic effect and toxicity of rubomycin 13-cyclohexylidene hydrazone (RCH) were studied in comparison to those of rubomycin on noninbred albino mice. The drugs were used intravenously in single doses or a course consisting of 5 injections. When used intravenously in a single dose RCH was 2 times less toxic than rubomycin. RCH differed from rubomycin by the character of animal death: the former induced death of the animals immediately after its intravenous administration, while with the use of the latter the animals died within the first 5-10 days after the drug injection. When used during the treatment course including 5 intravenous injections in doses of 0.45 or 0.3 of LD50, the inhibitory effects of the drugs on hemopoiesis were similar by their nature, RCH had a more pronounced cardiotoxic effect than rubomycin.

[Preclinical toxicological study of the new antibiotic eremomycin. Its acute toxicity for laboratory animals]. / Doklinicheskoe toksikologicheskoe izuchenie novogo antibiotika éremomitsina. Ostraia toksichnost' dlia laboratornykh zhivotnykh.

Eremomycin is relatively low toxic. LD50 of eremomycin on its intravenous administration to albino mice amounted to 1760 (1460-2130) mg/kg. It is 2.6, 3.5 and 6 times less toxic than ristomycin, vancomycin and teicoplanin, respectively. The rate of intravenous administration had no significant effect on eremomycin toxicity. Sensitivity of adult and preadolescent mice to eremomycin was almost the same. Eremomycin toxicity for male mice was somewhat higher than that for female mice. The use of 5 per cent glucose solution instead of distilled water as a solvent lowered 1.3-fold the toxicity of eremomycin in albino mice when it was administered intravenously. The toxic effect of eremomycin on the renal function played a significant role in the mechanism of the animal death due to the antibiotic. In experiments with guinea pigs eremomycin showed no allergenic effect. Unlike the other representatives of glycopeptide antibiotics, eremomycin had practically no local irritating effect which provided its recommendation for clinical trials not only as an intravenous but also intramuscular antibiotic.

[Effect of doxorubicin on animals in multiple intravenous administration]. / Izuchenie vliianiia doksorubitsina na organizm zhivotnykh pri mnogokratnom vnutrivennom vvedenii.

Toxicity of doxorubicin prepared with an original chemical method from rubomycin (daunomycin) was studied on albino rats and dogs. The antibiotic was administered intravenously in multiple doses. A significant loss of the body weight, a decrease in the relative weight of the spleen, thymus and ovary and an increase in the relative weight of the heart, kidneys and adrenal gland were observed in the rats after daily administration of doxorubicin in various doses 5 times. In a dose of 0.5 mg/kg doxorubicin was lethal for the dogs after 5, 7 and 10 administrations. Multiple administration of the antibiotic in doses of 0.25 and 0.125 mg/kg did not result in death of the dogs. There were areas of alopecia on the belly and joints, ulcers, body weight loss, increased urea levels in serum and diarrhea before death. The faeces contained significant admixtures of blood. Doxorubicin had an inhibitory effect on hemopoiesis of the albino rats and dogs. Before death bone marrow aplasia was recorded. After discontinuation of doxorubicin administration the inhibitory effect of the antibiotic on hemopoiesis persisted for 2-3 days. Histological examination of the organs and tissues of the animals killed at different periods after multiple intravenous administration of doxorubicin in various doses showed that doxorubicin had mainly the damaging effect on the gastrointestinal epithelium, heart muscle, epithelium of the proximal tubuli of the kidneys, lymphoid organs and testis. The damage depended on the dose of doxorubicin and duration of its use. By the character of the toxic effect and the size of the doses inducing certain effects doxorubicin made in the USSR did not differ from the analogous foreign drug.