Experience with using carminomycin in oncological clinical practice]

Carminomycin is an original antitumor antibiotic from the anthracycline group isolated at the Institute of New Antibiotics (USSR) in 1973. Pharmacological investigation of carminomycin revealed its satisfactory absorption from the gastrointestinal tract which proved to be a distinguishing property of the antibiotic as compared to other anthracyclines such as adriamycin and rubomycin. The clinical trials of carminomycin showed that it was mainly active against soft tissue sarcoma and breast cancer, lymphosarcoma, neuroblastoma, Wilms' tumor and Ewing's sarcoma in children, as well as acute leukemia. Various regimens for the antibiotic administration were applied: short-term, single and long-term. Suppression of hemopoiesis was considered as a limiting toxic effect. By the data available carminomycin had lower cardiotoxicity as compared with rubomycin and adriamycin. Development of oral carminomycin is believed promising.     

Antiviral action of carminomycin and some of its derivatives]

Carminomycin was shown to inhibit the development of both the DNA-containing variolovaccine virus and the RNA-containing grippe virus in chick embryos. Comparison of the effects of rubomycin, carminomycin, 14-oxy-carminomycin and carminomycin complex with bovine serum albumin in experiments with chick embryos showed that the inhibitory effect of carminomycin and its derivatives on the development of the grippe virus was much higher than that of rubomycin. The carminomycin derivatives proved to be much more active in this respect than the initial antibiotic. Carminomycin and its derivatives had a therapeutic effect on mice with experimental grippe pneumonia also on their oral use.     

Effect of the peroral use of the antitumor antibiotic, carminomycin, on the immunological reactivity of the body of animals]

Carminomycin administered orally to mice for many times in doses of 2.5 and 1.25 mg/kg induced suppression of hemagglutinine production to sheep erythrocytes and formation of immunologically competent cells in the spleen of test animals. The content of DNA and RNA in the spleen of the test animals treated with carminomycin and sheep erythrocytes was somewhat lower than that in the control mice immunized but not treated with the antibiotic. Carminomycin prolongated the life time of the skin graft by 6.5 days as compared to that of the skin homotransplant in the control animals. The oral use of carminomycin in a dose of 2.5 mg/kg induced a statistically significant decrease in the absorption capacity of the cells of the reticuloendothelial system of the animals.     

Synthesis and antitumor properties of carminomycin 13-cyclohexylidenhydrazone

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.     

Possibilities of preventing cardiotoxic complications in chemotherapy with carminomycin]

Carminomycin chemotherapy of the patients with malignant tumors is often complicated with cardiopathy which is sometimes assymptomic and registered only electrocardiographycally. Chemotherapy on the background of reparative regeneration stimulators from the series of synthetic pyrrimidine derivatives, such as methyluracyl for oral use and a soluble salt of methyluracyl for parenteral administration significantly decreased the rate of the cardiotoxic complications and promoted a decrease in their level. The use of methyluracyl and its soluble salt did not decrease the therapeutic effect of carminomycin. Methyluracyl and its soluble salt may be recommended for prophylaxis of cardiotoxic complications in chemotherapy of malignant tumors with carminomycin.     

Interaction of carminomycin with DNA according to data of laser polarized fluorescence

Anti-tumour antibiotic carminomycin interaction with chicken erythrocyte DNA is studied in aqueous-salt solutions by the laser polarized fluorescence method. Fluorescence quenches almost equally effectively during the antibiotic absorption on native (nDNA) and denatured (dDNA) DNAs, but the polarization degree of residual fluorescence differs about two times. Carminomycin binding to dDNA is characterized by one interaction type with a large density of occupancy sites - one antibiotic molecule per base pair. Carminomycin forms two types of complexes with nDNA, differing significantly with binding constants. Strong binding, intercalation, is saturated at one carminomycin molecule per 3 base pairs independently on the solution ionic strength. The weaker, external, interaction is characterized by the binding constant being by two orders of magnitude lower than that for intercalation, and the external interaction contribution is negligible.     

Distribution of 3H-carminomycin in the body of mice

Distribution of 3H-carminomycin with the specific activity of 390 mCu/g prepared by the method of isotope exchange in 3H2O was investigated on mice treated with the antibiotic administered intravenously in a dose of 2 mg/kg. It was shown that the antibiotic rapidly accumulated in the mouse tissues, mainly in the liver, kidneys, lungs and spleen. The carminomycin blood levels markedly decreased within the first 5 minutes after the drug administration and remained rather stable during the following 6 hours. The concentrations of carminomycin in the heart muscle were comparatively low. Still, at early periods they were much higher than those in the skeletal muscles. The difference disappeared by 24 hours. Carminomycin penetrated into the tissues of the brain.     

Preclinical toxicological study of the new antibiotic eremomycin. Chronic toxicity and effect on intrauterine development of rats

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.     

Effect of carminomycin on the energy metabolism of the liver in rats]

The effect of carminomycin on the liver energetic metabolism was studied experimentally on rats in dynamics after its intraperitoneal administration in a single LD50 and the therapeutic doses for a treatment course. It was found that changes in the rat liver tissues on the part of the energetic metabolism occurred irrespective of the antibiotic dose and the administration multiplicity. Mainly they were of reversible nature: the balance of consumption and resynthesis of the phosphate macroergs was impaired, the glycolytic processes increased, shifts in the activity of the enzymes of the pentose phosphate pathway of oxydation were observed. The level of the above changes was more pronounced when carminomycin was administered in LD50. The adrenal system played an important role in the mechanism of the shifts noted.     

Acute toxicity and the cumulative properties of carfecillin

Acute toxicity of oral and intraperitoneal carfecillin was studied on different species of laboratory animals, such as albino mice, rats and guinea pigs. The average lethal doses equal to 3040 (2393.7-3860.8) and 1325 (1104.2-1590) mg/kg for oral and intraperitoneal administration respectively allowed the authors to consider the antibiotic as a low toxic substance under conditions of a single administration. Higher toxicity of carfecillin as compared to carbenicillin may be due to production of free phenol on carfecillin hydrolysin in the animal organism. The different laboratory animals of both sexes had almost the same sensitivity to the antibiotic. On repeated administration of carfecillin to the albino mouse stomach (in portions of LD50) no cumulative properties of the antibiotic were observed.     

Protein-nitrogen metabolism in the liver of rats intraperitoneally administered carminomycin]

It was found in the experiments with rats that in response to carminomycin administration in a single LD50 and the therapeutic doses during the treatment course the intracellular fond of the amino acids in the liver tissue increased, the autolytic processes activated, the activity of the transamination enzymes, histidine and ammonia lyases increased. The level of the residual nitrogen increased mainly at the expense of increased ammonia production and urea levels. These changes were more pronounced when the antibiotic was administered in LD50. Independent of the administration multiplicity and the antibiotic dosage they were of reversible nature and mainly disappeared by the end of the observation.     

Pathomorphological picture of the liver in mice administered antitumor antibiotics intraperitoneally and its comparative assessment]

A single administration of carminomycin, ribomycin or olivomycin in LD50 or treatment of the experimental animals with these antibiotics for 10 days in the therapeutic doses equal to 10 per cent of the LD50 induced distrophic and necrobiotic changes in the liver. The use of bruneomycin in the equivalent doses induced sclerotic process in addition to the above doses resulted in a decrease in the colour intensity of DNA, RNA and protein as compared to the control, the content of glycogen and a marked increase in the amount of lipids in the hepatocyte cytoplasm. The most pronounced shifts were observed with the use of carminomycin, rubomycin and especially bruneomycin in single doses. With the use of olivomycin in a single dose the shifts were less pronounced. It should be noted that with the use of carminomycin and rubomycin the damages were of the same character by their intensity. The changes in the liver on the use of carminomycin, rubomycin and olivomycin in single doses or during the treatment course were reversible, while on the use of bruneomycin they preserved to the end of the experiment.     

Effect of rubomycin and carminomycin on antibody formation during the immunization of mice with various antigens

The maximum immunodepressive effect of rubomycin and carminomycin was observed when the antibiotics were administered intravenously 24 hours after the immunization. The immune response induced by the sheep erythrocytes or the lipopolysaccharide was equally inhibited by rubomycin. Carminomycin in a dose of 0.5 mg/kg (0.1 of the LD50) to a larger extent inhibited the immune response stimulated by the lipopolysaccharide. Dependence of the immunodepressive effect of the antibiotics on their dose was found when the drugs were administered intravenously or orally.     

Action of carminomycin on leukemic cell proliferation and some problems of its use in the combined therapy of leukemias

The effect of carminomycin on the mitotic cycle of the cells of the transplantable leukemia L-1210 and the therapeutic activity of other antitumor drugs, such as phopurine and cyclophosphane was studied on mice BDF1. It was found that the cells in phases S and G2 of the mitotic cycle were most sensitive to carminomycin. Transfer G1--S and phase G1 were characterized by resistance to the antibiotic effect. When carminomycin was used in combination with phopurine or cyclophosphane, clear dependence of the therapeutic efficacy on the treatment scheme was noted. Simultaneous administration of all the three drugs resulted in potentiation of the antileukemic effect. An analogous effect was observed when carminomycin was administered prior to phopurine or cyclophosphane. When the order of the drugs use was reverse, the efficacy of the combined therapy was significantly lower than the summation antileukemic effect of the drugs.     

Comparison of the action of carminomycin and rubomycin on the dynamics of the primary and secondary immune responses

The effect of rubomycin and carminomycin on the dynamics of the primary and secondary immune response and formation of the immunologic memory to sheep red cells in mice was studied. Differences in the character of the antibiotics effect indicative of the higher selective action of carminomycin on multiplying cells, precursors of the antibody-forming plasmids, were found. Theoretically interesting discrepancies in the effect of the antibiotics on the content of the antibodies in the serum and the antibody-producing cells in the spleen were shown. It was demonstrated that carminomycin had no effect on formation of the immunologic memory inspite of a noticeable decrease in the total number of the spleen nuclear cells and the number of the antibody-forming cells at the moment of immunization under the effect of the antibiotic.     

Results of an experimental study of the pharmacokinetics of polymyxin B sulfate]

Pharmacokinetics of polymyxin B sulfate of Soviet production was studied in various species of animals with the use of different administration routes and dosage. After a single intramuscular administration of the drug to dogs in doses of 1.1 and 2.2 mg/kg the antibiotic was detected within 5 hours at the maximum level during the 1st hour. A two-fold increase of the dose was accompanied by 1.5 times increase in the antibiotic level. Repeated administrations of polymyxin B sulfate in a dose of 4.5 mg/kg did not result in an increase in the blood level as compared to a single use of the drug. When polymyxin B sulfate was administered intravenously, the concentration peak was observed in 15 minutes independent of the dosage. Later the antibiotic level decreased. The maximum level of the drug in the mice was observed 1 hour after its intramuscular administration in a dose of 8 mg/kg, the highest levels being registered in the kidney tissues and urine.     

Toxicity and pharmacological properties of carminomycin complex components]

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.     

Erythromycin penetration into the cerebrospinal fluid of patients]

Permeability of erythromycin through the barrier of blood-cerebrospinal fluid in neurosurgical patients after its oral administration in a dose of 300-500 mg and intravenous administration in a dose of 200 mg was studied. The erythromycin was determined after the antibiotic single administration at intervals of 40 minutes to 6 hours. A total of 31 observations were performed. Low penetration of erythromycin into the cerebrospinal fluid of the patients was shown. The administration route (oral or intravenous) practically had no effect on the antibiotic penetration level into the subarachnoidal spaces. The highest liquor levels were observed within the period of 3 to 6 hours after the drug administration. The maximum index of penetration from the blood into the cerebrospinal fluid was about 10 per cent. The erythromycin penetration increased in cases with inflammatory changes in the meninges.     

Effect of 1,25(OH)2D3 on the relative contributions of skeletal 45Ca and intestinal 40Ca to blood calcium in normal and thyroparathyroidectomized dogs

The effects of gradually increasing doses of 1,25(OH)2D3 on plasma calcium and 45Ca radioactivity were studied in young dogs that had been extensively prelabelled with 45Ca. The effects of orally and intravenously administered 1,25(OH)2D3 were evaluated in normal and thyroparathyroidectomized dogs fed a normal diet. In normal dogs when 1,25(OH)2D3 increased the plasma calcium within the normal range (2.9-3.1 mmol/L) there was no significant increase in plasma 45Ca. In thyroparathyroidectomized dogs, oral or intravenous 1,25(OH)2D3 increased the low blood calcium to a normal level (1.8-2.9 mmol/L) without significantly increasing plasma 45Ca. In normal and thyroparathyroidectomized dogs, any 1,25(OH)2D3-induced increase in plasma calcium above the normal range was associated with a significant increase in 45Ca, indicating mobilization of bone calcium. Intravenous administration of 1,25(OH)2D3 in the normal or thyroparathyroidectomized dogs had a much larger effect than oral doses in mobilizing bone 45Ca when inducing a similar level of hypercalcemia. The major physiological effect of 1,25(OH)2D3 in the low or normal range of plasma calcium is on intestinal absorption of calcium without a significant effect on mobilizing bone calcium. The pharmacological effect of 1,25(OH)2D3 in vivo is to mobilize bone calcium as well as dietary calcium into blood.     

Mechanism of the myeloinhibitory effect of carminomycin]

The proliferative activity and level of aberrant mitoses in the cells of the bone marrow were studied experimentally on 223 noninbred mice treated with carminomycin administered intraperitoneally in single (LD50) and repeated doses. When the antibiotic was used in a single dose the values of the mitotic activity of the bone marrow elements did not correspond to the severity of depression and thir quantitative composition, which was explained by an impairement of the mitosis quality and possible interkinetic destruction of a significant part of both erythroid and immature myeloid cells capable of division at early stages after the exposure. At the same time the level of the bone marrow devastation under conditions of the treatment with repeated doses was mainly determined by inhibition of the erythronormoblast proliferative activity.