[Chemical modification of an antineoplastic antibiotic bleomycetin by the C-end fragment]. / Khimicheskaia modifikatsiia protivoopukholevogo antibiotika bleomitsetina po C-kontsevomu fragmentu.

Bleomycetin, an antitumor antibiotic, was subjected to chemical modification by the C-end fragment i.e. the residue of 3-[(4-aminobutyl)amino]propylamine (spermidine++) with acylation, carbamoylation and reducing alkylation, which yielded its new semisynthetic derivatives. The use of physicochemical methods showed that the chemical modification involved the primary and secondary amino groups++ of spermidine++ and gave rise to N,N'-diacyl, N,N'-dicarbamoyl and N,N'-dialkyl bleomycetins. The biological properties of the derivatives, i.e. their cytotoxic activity, acute and pulmonary toxicities were studied. The transformation of bleomycetin by the C-end fragment lowered the antibiotic toxicity and was believed to be a promising approach to modifying its molecule.

[Production and antineoplastic activity of new asymmetric azines on the rubomycin base]. / Poluchenie i protivoopukholevaia aktivnost' novykh nesimmetrichnykh azinov na osnove rubomitsina.

New alkulidene hydrazones of rubomycin (daunorubicin) with the linear or branched chain of the carbon atoms were studied: rubomycin 13-(hexylidene-2")-hydrazone, rubomycin 13-(heptylidene-3")-hydrazone and rubomycin 13-(4"-methylpentylidene-2")-hydrazone. Alkylidene hydrazones of the formamidine derivatives were also studied: 13:cyclohexylidene hydrazone of 3'-desamino-3'-dimethylformamidine rubomycin and 13-(5"-oxypentyliden-2") hudrazone of 3'-desamino-3'-dimethylformamidine rubomycin. The latter two alkylidene hydrazones were modified twice. It was found that after a single intravenous administration to tumor-free mice the new substance had the same or lower toxicity as compared to that of rubomycin. Antitumor activity of the substances against lymphosarcoma LIO-I was studied comparatively with that of the initial rubomycin. It was shown that the molecule modification at C-13, as well as simultaneous modification at C-13 and the sugar amino group resulted in lowering of the antitumor activity in comparison to that of the starting rubomycin.

[Study of toxicity and antineoplastic activity of 14-substituted derivatives of rubomycin and carminomycin]. / Izuchenie toksichnosti i protivoopukholevoi aktivnosti 14-zameshchennykh proizvodnykh rubomitsina i karminomitsina.

Toxicity and antitumor activity of five derivatives of rubomycin and carminomycin were studied in animals. The derivatives were prepared by modification of the methyl C-14 group. These were the following: 14-chlorrubomycin, 14-chlorcarminomycin, 14-salicyloyloxyrubomycin, 14-salicyloyloxycarminomycin and 14-quinaldinoyloxyrubomycin. The chemotherapeutic study revealed that, in their activity, all the compounds were inferior to the starting antibiotics. Unlike the other derivatives, 14-chlorcarminomycin induced a significant inhibition of leukemia P-388 development (the average lifespan of the mice amounted to 165 per cent as compared to the control). However, in the magnitude of its effect, the derivative was inferior to carminomycin.

[Glycopeptide antibiotics: eremomycin, vancomycin, and teicoplanin. Comparison of several parameters of pharmacokinetics and antimicrobial activity]. / Glikopeptidnye antibiotiki: eremomitsin, vankomitsin i teikoplanin. Sravnenie nekotorykh parametrov farmakokinetiki i antimikrobnoi aktivnosti.

Pharmacokinetic parameters of eremomycin (Institute of New Antibiotics, the USSR Academy of Medical Sciences), teichoplanin (Lepetit) and vancomycin (Eli Lilly) were compared after their intravenous administration to rats in the same dose of 50 mg/kg. It was shown that the area under the concentration time curve of eremomycin was 2 times smaller than that of teichoplanin and 6 times larger than that of vancomycin. The mean retention time of eremomycin was close to that of teichoplanin and 1.6 times higher than that of vancomycin. Bioavailability of eremomycin and teichoplanin after their extravascular administration was the same and amounted to 94 per cent. Antibacterial activity of eremomycin against methicillin resistant strains of staphylococci was 4 times higher than that of teichoplanin and vancomycin.

[Eremomycin--a new antibiotic of the polycyclic glycopeptide group]. / Eremomitsin--novyi antibiotik gruppy politsiklicheskikh glikopeptidov.

Eremomycin is a novel antibacterial antibiotic. It was isolated at the Institute of New Antibiotics, the USSR Academy of Medical Sciences from the culture fluid of actinomycete INA-238. By its physico-chemical and biological properties the antibiotic was classified as belonging to the group of polycyclic glycopeptides. Chemical structure of eremomycin was asserted and it was shown to be a new representative of the group close by its structure to vancomycin and differing from it by the carbohydrate composition and structure of tri-phenoxytriaminotricarboxylic acid. By its anti-bacterial spectrum eremomycin was found to be close to ristomycin and vancomycin. Still, its activity was 2-10 times higher. The antibiotic was several times less toxic than vancomycin. Unlike vancomycin and ristomycin, the novel antibiotic induced no tissue necrosis after its intramuscular administration. The chemotherapeutic indices of eremomycin in treatment of staphylococcal and streptococcal sepsis in albino mice exceeded 10 times those of vancomycin. At present eremomycin is under clinical trials.

[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.

[Antitumor activity of doxorubicin in respect to solid tumors in mice]. / Protivoopukholevaia aktivnost' doksorubitsina v otnoshenii plotnykh opukholei myshei.

Antitumor activity of doxorubicin, an antibiotic prepared in the USSR was studied with respect to 4 solid tumors of mice: lymphosarcoma LIO-1, sarcoma 180, pregastric cancer OZh5 and melanoma B-16. Doxorubicin showed high antitumor activity against lymphosarcoma and sarcoma 180. However, it was somewhat lower than that of rubomycin and carminomycin. By selective antitumor activity against mouse pregastric cancer doxorubicin was superior to rubomycin and carminomycin. Estimation of antitumor activity of doxorubicin revealed its advantages in inhibition of melanoma B-16 growth, while carminomycin was superior in prolonging the animal life-span.

[Toxicity and antimicrobial properties of the new aminoglycoside antibiotic 535]. / Izuchenie toksichnosti i antimikrobnykh svoistv novogo aminoglikozidnogo antibiotika 535.

LD50 of antibiotic 535 (3'-desoxykanamycin C) on its intravenous, subcutaneous and oral administration to albino mice was 225, 1150 and at least 5000 mg/kg respectively. After a single subcutaneous administration to rabbits in a dose of 10 mg/kg antibiotic 535 was rapidly absorbed and detected in the blood and organs of the animals for 24 hours. The antibiotic was mainly excreted with the urine. Comparative investigation of the pharmacokinetics of antibiotic 535, tobramycin and kanamycin in rabbits revealed no significant differences. Antibiotic 535 showed a broad antibacterial spectrum and inhibited both grampositive and gramnegative bacteria. It was highly active against infections caused by S. aureus, E. coli and Pr. vulgaris and somewhat less active against infections caused by Ps. aeruginosa. In treatment of experimental tuberculosis of albino mice antibiotic 535 and tobramycin were inferior by their efficacy to kanamycin.

[Antitumor activity of doxorubicin in the treatment of hemocytoblastosis La and various ascites tumors in mice]. / Protivoopukholevaia aktivnost' doksorubitsina v otnoshenii gemotsitoblastoza La i nekotorykh astsitnykh opukholei myshei.

Antitumor activity of doxorubicin made in the USSR was studied on mice in respect to three transplantable tumors (lymphadenosis NK/LI, sarcoma 37 and Ehrlich's carcinoma) and hemocytoblastosis La. Doxorubicin injected intravenously 4 times was shown to be highly active against the above ascites tumors. The highest inhibitory effect of doxorubicin was observed in respect to the development of Ehrlich's carcinoma. By the selectivity of the therapeutic effect on this tumor it was superior to rubomycin and carminomycin. A high antileukemic activity of doxorubicin in respect to hemocytoblastosis La was shown. In experiments with this leukemia, intravenous injection of doxorubicin provided a higher efficacy than intraperitoneal injection. When used intravenously in the doses equivalent by their toxicity doxorubicin was inferior to rubomycin in terms of the therapeutic effect on leukemia La. However, on intraperitoneal injection of the drugs rubomycin showed no such advantage. Doxorubicin made in the USSR did not differ by its antitumor activity 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 and antitumor properties of carminomycin 13-cyclohexylidenhydrazone]. / Sintez i protivoopukholevye svoistva 13-tsiklogeksilidengidrazona karminomitsina.

Carminomycin 13-cyclohexylidenhydrazone (CCH) was prepared by interaction of carminomycin 13-hydrazone with cyclohexane. The antiblastomic properties of CCH were studied on mice with transplantable tumors. The preparation was administered intravenously or orally. The studies showed a high antitumor activity of CCH. When CCH was administered intravenously to mice with lymphosarcoma LIO-1, the antitumor effect selectivity of it was practically equal to that of carminomycin. When used in doses equivalent by their toxicity to those of carminomycin, CCH had practically the same inhibitory effect on sarcoma 180 as carminomycin. When used orally in doses equivalent by their toxicity to those of carminomycin, CCH was more effective than carminomycin in treatment of mice with lymphosarcoma LIO-1, sarcoma 180 and lymphadenosis NK/Ly.

[Acute toxicity of the N-acyl derivatives of carminomycin and rubomycin]. / Izuchenie ostroi toksichnosti nekotorykh N-atsil'nykh proizvodnykh karminomitsina i rubomitsina.

Synthesis of 2 new N-acyl derivatives of carminomycin and rubomycin (N-L-leucylcarminomycin and N-sarcolysylrubomycin) is described. Acute toxicity of the new and 4 known N-acyl derivatives: N-acetylcarminomycin, N,L-alanylcarminomycin, N-D-phenylalanylcarminomycin and N-D-phenylalanylrubomycin was studied on albino mice. It was shown that the N-acyl derivatives of carminomycin and rubomycin had lower acute toxicity than the initial drugs. When added to blood serum in vitro N-D-phenylalanylcarminomycin and N-D-phenylalanylrubomycin induced precipitation. The carminomycin derivatives containing the residues of L-leucine and L-alanine were less toxic than the initial antibiotic, still they had a markedly pronounced retarded toxicity.

[Synthesis of rubomycin 13-tert-butoxycarbonylhydrazone and the study of its antitumor action]. / Sintez 13-tert-butoksikrabonilgidrazona rubomitsina i izuchenie ego protivoopukholevogo deistviia.

13-Tert-butoxycarbonylhydrazone of rubomycin was prepared on interaction of rubomycin with tert-butoxycarbonylhydrazine. The new compound showed a high antitumor activity with respect to lymphosarcoma LIO-1 and Garding-Passey melanoma. The compound had no advantages over the initial rubomycin in the treatment of these tumors, was inferior to rubomycin with respect to its activity against leukemia P-388 and unlike rubomycin had practically no effect on leukemia L-1210.

[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.

[Pharmacokinetics of tobramycetin and gentamycin and the mechanism of their elimination by the kidneys]. / Farmakokinetika tobramitsetina i gentamitsina i mekhanizm vydeleniia ikh pochkami.

After subcutaneous administration of tobramycetin (tobramycin) to rabbits in single doses equivalent to the daily therapeutic doses for humans calculated for the body surface and those exceeding them by 3 times, the antibiotic was rapidly absorbed into the blood and detected within 30 and 72 hours respectively. Tobramycetin penetrated into all organs of the animals. Its highest levels were found in the kidneys and the lowest in the brain tissue. Tobramycetin was excreted with the urine in amounts equal to 80 per cent of the dose administered. No cumulation of the antibiotic was observed in the dog blood after its repeated subcutaneous administration. Comparative investigation of tobramycetin and gentamicin pharmacokinetics in rabbits after intravenous administration showed no significant differences. Both antibiotics were mainly excreted with the urine: the renal clearance averaged to 65 per cent of the total clearance, the time of a two-fold decrease in the blood levels of the antibiotics was on an average 40 minutes. Tobramycetin and gentamicin were excreted with the kidneys by means of glomerular filtration with insufficient reabsorption in the tubules.

[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, pharmacokinetics and pharmacodynamics of the Soviet bleomycin, bleomycetin, in a single administration to laboratory animals]. / Izuchenie toksichnosti, farmaokinetiki i farmakodinamiki otechestvennogo bleomitsina--bleomitsetina pri odnokratnom vvedeni laboratornym zhivotnym.

Toxicity of bleomycetin (bleomycin A2) administered intravenously, intraperitoneally, subcutaneously or intramusculary in a single dose to animals was almost identical. On its oral administration bleomycetin was 10--14 times less toxic than on its parenteral use. Rats were somewhat less sensitive to bleomycetin than mice. Bleomycetin had no significant effect on the level of the arterial pressure, respiration, ECG characteristics and elements of the vegetative nervous system in narcotized cats. After a single intravenous or subcutaneous administration to rabbits bleomycetin was detectable in the blood for 4--5 hours. The highest bleomycetin levels were registered in the skin, kidneys and lungs. Bleomycetin was mainly excreted with the urine.