[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.

[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.

[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.

[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.

[Toxicity, pharmacokinetics and pharmacodynamics of Soviet-made doxorubicin]. / Izuchenie toksichnosti, farmakokinetiki i farmakodinamiki otechestvennogo doksorubitsina.

The LD50 of doxorubicin, prepared at the Institute of New Antibiotics of the Academy of Medical Sciences of the USSR was 4.6, 12.5, 13.5 and 570 mg/kg for single intraperitoneal, intravenous, subcutaneous and oral administrations to albino mice, respectively. When used intravenously in a single dose, it had an inhibitory effect on the blood system of albino mice and rats. The cumulative properties of doxorubicin were somewhat higher than those of rubomycin or carminomycin. At an average 30 and 96 per cent of doxorubicin were bound with the proteins of rabbit blood serum and the organ homogenates, respectively. The antibiotic levels in organs were high and persisted for prolonged periods. About 10 and 13 per cent of doxorubicin were excreted with 24 hours with urine and bile, respectively. In doses close to the therapeutic ones (1 mg/kg) doxorubicin had no significant effect on the arterial pressure and respiration of anesthetized cats. a 5--10-fold increase of the dose resulted in a marked decrease of the arterial pressure and in excitation of the respiration. The amplitude of the ECG did not change significantly. The effect of doxorubicin on the heart rate was inconclusive.

[Study of the toxicity of carminomycin 13-cyclohexylidenhydrazone]. / Izuchenie toksichnosti 13-tsiklogeksilidengidrazona karminomitsina.

The systemic effect and toxicity of carminomycin 13-cyclohexylidenhydrazone (CCH) were studied on noninbred albino mice in comparison to carminomycin. The preparation was administered intravenously and orally. It was shown that CCH was 1.3 or 2.5 times less toxic than carminomycin on its intravenous or oral administration, respectively. The cumulative properties of CCH and carminomycin on their intravenous administration were practically equal. On oral administration of CCH the level of its cumulation in mice was higher than that of carminomycin. By its nature the effect of the preparations on hemopoiesis of the mice was the same. CCH had a low cardiotoxic effect.

[Synthesis, toxicity and antitumor action of carminomycin azine (carminazine)]. / Sintez, toksichnost' i protivoopukholevoe deistvie azina karminomitsina (karminazina).

Carminomycin azine designated as carminazine was prepared by condensation of carminomycin with hydrazine hydrate. It was shown in the experiments on mice that the toxicity of carminazine was 2 and 7 times lower than that of carminomycin on its intravenous and oral administration respectively. The effect of both drugs on hemopoiesis of the mice was similar. As regards the selectivity of the antitumor effect on lymphosarcoma, strain L10-1, carminazine was inferior to carminomycin.

[Effect of Soviet bleomycin-bleomycetin on the body of animals in multiple parenteral administration]. / Vliianie otechestvennogo bleomitsina--bleomitsetina--na organizm zhivotnykh pri mnogokratnom parenteral'nom vvedenii.

Toxicity of bleomycetin was studied on 3 animal species (rats, rabbits and dogs). The antibiotic was administered intramuscularly and intravenously in various doses for a prolonged period of time. The death of the rats, rabbits and dogs treated with repeated lethal doses of bleomycetin was due to its toxic effect on the kidneys and probably lungs. The level of urea in the blood of the animals before death increased up to 300--400 mg %. Histological examination of the kidneys revealed the picture of glomerulonephritis. The lungs were highly plethoric and showed areas of alveolar collapse and consolidation consisting mainly of the collapsed alveolar epithelium. The liver was not affected by bleomycetin according to both the results of some functional tests and histological examination. tthe blood sugar level after bleomycetin administration was not altered significantly. The changes in the peripheral blood were not pronounced. An increased P wave, decreased R wave and deep S wave were seen on the ECG. Such deviitions may be due not only to the changes in the myocardium but also to the lung affection. When bleomycetiin was used repeatedly in nonlethal doses (1 mg/kg for rats, 1--2 mg/kg for rabbits and 0.25--0.5 mg/kg for dogs), the above changes were less pronounced or not manifested at all. No inhibitory effect on hemopoiesis is an important positive characteristics of bleomycetin, so that it compares very favourably with most other antitumor drugs.

[Toxicity of tobramycin in single and multiple administrations to laboratory animals]. / Izuchenie toksichnosti tobramitsina pri odnokratnom i mnogokratnom vvedenii laboratornym zhivotnym.

The LD50 of tobramycin sulphate administered intravenously, intraperitoneally, subcutaneously and orally to albino mice was 77 (73--82), 262 (234--294), 560 (500--627) and greater than 10500 mg/kg respectively. With an increase in the rate of intravenous administration tobramycin toxicity increased. When tobramycin sulphate was administered subcutaneously daily in multiple doses equivalent to the daily therapeutic doses from humans (calculated for the body surface) and in the doses 2--3 times higher than the above therapeutic ones, the function of the kidneys, liver and the Preier's reflex did not significantly change. When the doses were 8--10 times higher than the therapeutic ones, an increase in the urea level in the blood serum, disappearance and a decrease in the Preier's reflex were observed. The impairment of the kidney function was accompanied by degenerative changes in the convoluted tubules of the kidneys, ischemia of the renal glomeruli and appearance of protein secretion in their capsule cavities. The picture of the peripheral blood did not suffer significant changes. The studies on the acute and chronic toxicity of tobramycin sulphate prepared at the Institute of New Antibiotics showed that the drug did not differ from the import tobramycin samples.

[Effect of the multiple peroral administration of carminomycin on the body of animals]. / Vliianie karminomitsina na organizm zhivotnykh pri mnogokratnom peroral'nom vvedenii.

Toxicity of carminomycin used orally for many times was mainly evident from suppression of blood formation, the level of the suppression being dependent on the antibiotic dose. Carminomycin had a low suppressing effect on the white blood in rats. At low doses even moderate leucocytosis was observed. The indices of the functional state of the liver, kidneys, sugar blood levels, content of glycogen and fat in the liver, relative mass of the rat organs after repeated oral administrations of karminomycin to the animals remained mainly unchanged. A change in wave T on the ECG of the dogs treated with high doses of the antibiotic was registered. Histological examination of the organs and tissues of the animals killed after repeated oral administrations of carminomycin revealed pathological changes only in the spleen and thin intestine. Such changes were not more pronounced than those after repeated intravenous administration of the equivalent doses of the antibiotic (by the effect on the blood formation). This allowed the author to recommend the oral administration route for carminomycin trials in clinics.

[Acute toxicity of carminomycin administered perorally to laboratory animals]. / Izuchenie ostroi toksichnosti karminomitsina pri peroral'nom vvedenii laboratornym zhivotnym.

Rather high species sensitivity to carminomycin was found in the experiment with albino mice, rats, guinea pigs, rabbits and dogs. The highest difference in the antibiotic toxicity for various species of the laboratory animals was shown on oral administration of the drug which was due to the differences in the antibiotic absorption from the gastro-intestinal tract. On single oral administration to the dogs in toxic or lethal doses the antibiotic suppressed the blood formation up to aplasia of the bone marrow. The equitoxic doses of carminomycin on its single oral and intravenous administration differed approximately by 3 times. Carminomycin had no effect on the smooth muscles of the isolated rabbit ear vessels and cat intestine in situ. The antibiotic had an irritating effect on the rabbit eye mucosa. Carminomycin had no skin-irritating effect.

[Comparative study of the cardiotoxicity of the anthracycline antibiotics, rubomycin, carminomycin and dihydrocarminomycin, in experiments on white mice]. / Sravnitel'noe izuchenie kardiotoksichnosti antratsiklinovykh antibiotikov rubmoitasina, karminomitsina i digidrokarminomitsina v opytakh na belykh myshakh.

The experiments on albino mice treated with rubomycin, carminomycin or dihydrocarminomycin on its 5-fold intravenous administration in doses equal to similar portions of LD50 of the respective antibiotic on its use in a single dose showed that all the 3 antibiotics induced changes in the myocardium close by their character. The heart affections were evident from swelling of separate muscle fibers, degeneration of the myofibrils, homogenization, vacuolization and resorption of the sarcoplasma, pathological changes in the nuclei, atrophy of some muscle fibers. Rubomycin had the highest cardiotoxic effect. Then followed dihydrocarminomycin and carminomycin. All the antibiotics studied in the experiments with mice had mainly an inhibitory effect on the lymphoid hemopoiesis. The effect of carminomycin was the highest. The animal death during the injections and immediately after administrations of the antibiotics must be due to their suppressing effect on hemopoiesis. The deaths at more remoted periods must be due to the cardiotoxic effect of the antibiotics.

[Comparative study of the cardiotoxicity of the anthracycline antibiotics, carminomycin and adriamycin, in white mice]. / Sravnitel'noe izuchenie kardiotoksichnosti antratsiklinovykh antibiotikov karminomitsina i adriamitsina na belykh myshakh

The cardiotoxic effect of karminomycin and adriamycin administered intravenously for 5 times in equitoxic doses constituting equal portions of LD50 of the respective antibiotic on its single intravenous administration was studied on albino mice. Histological examination of the heart showed that almost identical damages of the myocardium occured after administration of karminomycin and adriamycin in doses of 0.45 of LD50 (1.5 mg/kg) and 0.3 of LD50 (6.3 mg/kg) respectively. The character of the damages due to the antibiotics was close, the most significant changes were observed when the animals were sacrificed 1 month after the last administration of the drug. The histological method is of value in estimation of the cardiotoxic effect of the drugs, using mice as the model suitable for the investigation. Adriamycin had more pronounced cumulative properties as compared to karminomycin: suppression of the weight gain in the mice and their death rate were higher with the use of adriamycin.

[Toxicity and pharmacological properties of carminomycin complex components]. / Toksichnost' i farmkologicheskie svoistva komponentov karminomitsinovogo kompleksa

Acute toxicity of the components of the carminomycin complex after intravenous administration to albino mice increased as follows. I less than II less than III. Component II induced a decrease in all the indices of the bone marrow and peripheral blood of the animals. It was most pronounced in dogs. The dogs died after administration of component II in the lethal doses as a result of the bone marrow aplasia. The indices of the functional state of the liver and kidneys in the animals after administration of components I and II changed slightly. Component III administered repeatedly to rabbits even in low doses induced significant impairments in the function of the liver and kidneys. Component II differed from component I by more pronounced cardiotoxicity. On the basis of the experimental data and the results published earlier component I is recommended for clinical trials as the least toxic one.

[Action of antibiotic 1719 from a group of diazo compounds on hematopoiesis in laboratory animals and its pharmacokinetics]. / Deistvie antibiotika 1719 iz gruppy diazosoedinenii na krovetvorenie laboratornykh zhivotnykh i ego farmakokinetika

Antibiotic 1719 administered intravenously to rats in a single dose of 6.0 mg/kg induced a transitory decrease in the number of myelocariocytes on the 2nd-5th day of its use mainly at the account of decreased numbers of lymphoid elements. Simultaneously momentory leucopenia (granulocytopenia) and more stable lymphopenia were observed. When the antibiotic was administered intravenously to dogs in a dose of 0.9 mg/kg 4 times and in a dose of 0.4 mg/kg 40 times, an insignificant decrease in the number of myelocarlocytes was noted. Leucopenia, lymphopenia and thrombocytopenia in the peripheral blood almost completely disappeared after discontinuation of the preparation administration. Leucocytosis (granulocytosis), lymphopenia and thrombocytopenia were registered in the dogs and rabbits treated with the antibiotic in doses of 1.5 and 3.0 mg/kg 3 and 11 times respectively. When the antibiotic was added to the rabbit blood serum in concentrations of 0.5-5 gamma/ml, 70 to 80 per cent of the preparation bound with the blood proteins. After a single intravenous administration of antibiotic 1719 to rabbits in doses of 10 and 15 mg/kg, it was detected in the blood only for 5 to 15 minutes after the administration in concentrations not exceeding 0.3 and 0.5 gamma/ml. The antibiotic penetrated into all organs in small amounts and persisted there for 1.5 to 3 hours after the administration. The antibiotic was excreted with the bile in amounts of 0.3-0.5 per cent of the dose administered for 1 to 2 hours after a single administration. The antibiotic was excreted with the urine for 3-4 hours after the administration in amounts of 3.5 per cent after a single administration and 60-72 per cent after multiple administrations.