ABSTRACT
Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD50 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application.
Subject(s)
Antitubercular Agents/toxicity , Heart/drug effects , Rifampin/analogs & derivatives , Serum Albumin, Human/chemistry , Stomach/drug effects , Administration, Oral , Alkaline Phosphatase/blood , Animals , Antitubercular Agents/chemistry , Bilirubin/blood , Female , Humans , Injections, Intravenous , Kidney/drug effects , Lethal Dose 50 , Liver/drug effects , Male , Mice , Rats , Rifampin/chemistry , Rifampin/toxicity , Serum Albumin, Human/administration & dosage , Solubility , Sonication , Spleen/drug effects , Toxicity Tests, Acute , Toxicity Tests, ChronicSubject(s)
Bone Marrow/drug effects , Cytostatic Agents/pharmacology , Imidazoles/pharmacology , Immunosuppressive Agents/pharmacology , Administration, Oral , Animals , Caproates , Carboplatin/pharmacology , Cisplatin/pharmacology , Cyclophosphamide/pharmacology , Cytostatic Agents/administration & dosage , Imidazoles/administration & dosage , Male , MiceABSTRACT
The relationship between the structure of new semisynthetic derivatives of doxorubicin, daunorubicin, and carminomycin and their ability to inhibit topoisomerase 1 were studied. The new derivatives inhibit the activity of topoisomerase 1 at low concentrations, induce the death of K-562 leukemia cells in culture, and produce an antitumor effect in experimental animals with P388 leukemia.
Subject(s)
Carubicin/analogs & derivatives , Carubicin/chemistry , Daunorubicin/analogs & derivatives , Daunorubicin/chemistry , Doxorubicin/analogs & derivatives , Doxorubicin/chemistry , Topoisomerase I Inhibitors , Animals , Carubicin/pharmacology , Daunorubicin/pharmacology , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Humans , K562 Cells , Leukemia P388/drug therapy , Mice , Structure-Activity RelationshipABSTRACT
We studied mutagenic, embryotoxic, and teratogenic properties of calcium ketopantoyl aminobutyrate, a preparation proposed as a new drug. Long-term oral administration of calcium ketopantoyl aminobutyrate produced no mutagenic, embryotoxic, and teratogenic effects.
Subject(s)
Aminobutyrates/toxicity , Nootropic Agents/toxicity , Pantothenic Acid/analogs & derivatives , Abnormalities, Drug-Induced , Animals , Embryo, Mammalian/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mutagenesis , Mutagenicity Tests , Mutagens/toxicity , Mutation , Pantothenic Acid/toxicity , PregnancyABSTRACT
We studied the allergic and immunotoxic effects of a new promising medicinal preparation calcium ketopantoyl aminobutyrate. Calcium ketopantoyl aminobutyrate produced no negative effects on general mechanisms of humoral and cellular immunity. This preparation did not modulate the anaphylactic reaction to bovine serum, exhibited no mitostatic and lymphotoxic properties, had no effect on the delayed-type hypersensitivity response, and did not produce active cutaneous anaphylactic reaction.
Subject(s)
Aminobutyrates/toxicity , Hypersensitivity , Immune System/drug effects , Pantothenic Acid/analogs & derivatives , Animals , Antibody Formation/drug effects , Guinea Pigs , Immunity, Cellular/drug effects , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Pantothenic Acid/toxicityABSTRACT
New polyene macrolide S44HP was purified from the culture of recombinant Streptomyces noursei strain with engineered nystatin polyketide synthase. S44HP, nystatin (NYS), and amphotericin B (Amph-B) were tested against 19 clinical fungal isolates in agar diffusion assay, which demonstrated clear differences in antifungal activities of these antibiotics. Sodium deoxycholate suspensions of all three antibiotics were subjected to acute toxicity studies in vivo upon intravenous administration in mice. NYS exhibited the lowest acute toxicity in mice in these experiments, while both Amph-B and S44HP were shown to be 4 times more toxic as judged from the LD50 values. While the acute toxicity of S44HP was higher than that of Amph-B, the data analysis revealed a significantly increased LD10 to LD50 dose interval for S44HP compared to Amph-B. The data revealed structural features of polyene macrolides, which might have an impact on both the activity and toxicity profiles of these antibiotics. These results represent the first example of preclinical evaluation of an "engineered" polyene macrolide, and can be valuable for rational design of novel antifungal drugs with improved pharmacological properties.
Subject(s)
Antifungal Agents/pharmacology , Nystatin/analogs & derivatives , Nystatin/pharmacology , Amphotericin B/pharmacology , Amphotericin B/toxicity , Animals , Antifungal Agents/isolation & purification , Antifungal Agents/toxicity , Colony Count, Microbial , Genetic Engineering , Lethal Dose 50 , Male , Mice , Microbial Sensitivity Tests , Nystatin/isolation & purification , Nystatin/toxicity , Polyketide Synthases/genetics , Streptomyces/genetics , Streptomyces/metabolism , Toxicity Tests, AcuteABSTRACT
We studied the effect of combination treatment with T-activin and vitamin E on acute toxicity and antitumor activity of cyclophosphamide in mice. Combined administration of these preparations 1.37-fold increased the maximum permissible dose of cyclophosphamide without affecting its LD(50)and delayed mouse death from cyclophosphamide toxicity. Most mice died only 3 days after combination treatment with the test preparations and cyclophosphamide in doses of LD(16)-LD(84). The second peak of death from hematologic toxicity of cyclophosphamide was absent under these conditions. T-activin and vitamin E did not abolish the antitumor effect of cyclophosphamide on mice with subcutaneously implanted P-388 lympholeukemia. Tumor growth was suppressed by 100%.
Subject(s)
Antineoplastic Agents, Alkylating/toxicity , Cyclophosphamide/toxicity , Peptides/pharmacology , Thymus Extracts/pharmacology , Vitamin E/pharmacology , Animals , Antineoplastic Agents, Alkylating/therapeutic use , Cyclophosphamide/therapeutic use , Drug Therapy, Combination , Leukemia P388/drug therapy , Mice , Mice, Inbred Strains , Peptides/therapeutic use , Thymus Extracts/therapeutic use , Vitamin E/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Olipifat is an antineoplastic drug containing pyrophosphate and a product of special lignin processing. Donor C57Bl/6J mice with syngeneic B16 melanoma received a single 5-day course of olipifat. Effect of olipifat on antitumor resistance was evaluated by local neutralization test [3]. In animals with rapid melanoma growth, splenic cells from intact donors stimulated tumor growth. Olipifat abolished this growth-stimulating effect of splenocytes. In animals with slow melanoma growth, splenocytes had no effect on the growth of melanoma or Lewis lung cancer. In this case, splenocytes from olipifat-treated donors completely arrested the growth of melanoma B16 and decelerated the growth of Lewis lung carcinoma.
Subject(s)
Antineoplastic Agents/therapeutic use , Lignin/analogs & derivatives , Lignin/therapeutic use , Animals , Carcinoma, Lewis Lung , Lymph Nodes/drug effects , Lymphatic Metastasis , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Spleen/drug effects , Thymus Gland/drug effects , Time FactorsABSTRACT
It was demonstrated in in vivo and in vitro experiments that interleukin-2, obtained by cultivation of donor lymphocytes and purified by gel filtration, induces the production of mouse and human killer lymphocytes possessing high cytolytic activity against tumor cells. Interleukin-2 does not cause irreversible changes of the physiological and morphologic indices of vital activity in mice.
Subject(s)
Antineoplastic Agents , Interleukin-2/therapeutic use , Animals , Cytotoxicity Tests, Immunologic/methods , Drug Screening Assays, Antitumor , Female , Humans , Interleukin-2/isolation & purification , Interleukin-2/pharmacology , Interleukin-2/toxicity , Killer Cells, Lymphokine-Activated/drug effects , Killer Cells, Lymphokine-Activated/immunology , Leukemia P388/drug therapy , Leukemia P388/immunology , Lymphocytes/drug effects , Lymphocytes/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Time Factors , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/immunologyABSTRACT
An indole alkaloid isolated from Catharanthus roseus in the Soviet Union and named amotin differs in terpenoid moiety structure of the indole part of the molecule from the foreign preparation vinblastine and its Soviet analog rosevine. In experimental study amotin has exhibited a high antileukemic activity which was more expressed than that of vinblastine. Tolerant doses of amotin cause moderate reversible morphological alterations in hematopoietic organs, gastrointestinal mucosa, liver, kidney, adrenals, testes, ovaries.
