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We studied the effect of an anthocyanin-containing complex from the fruits of S. aucuparia L. on doxorubicin-induced genotoxicity in bone marrow cells of C57BL/6 mice. The complex reduced the genotoxic effect doxorubicin in metaphase plates of bone marrow cells in 24, 48 h, and 10 days after the administration of the cytostatic. The mean number of single fragments and the fraction of cells with gaps and aberrant metaphases also decreased.

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Paclitaxel in a single MTD of 40 mg/kg caused chromosome aberrations and genome changes (polyploidy) in the bone marrow cells of mice early and 3 months after the injection. The quantity of early precursors of erythropoiesis in the bone marrow decreased, as did their proliferative potential irrespective of the animal gender. Injection of paclitaxel in the MTD caused the development of bone marrow hypoplasia during the early period of observation (up to 14 days) and 3 months after injection.

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Gene protective properties of synthetic antioxidant thiophane and the extract of in vitro cultivated roots of Scutellaria baicalensis were studied on the model of Dr. melanogaster larvae genetic structure damage by drugs cisplatin and cyclophosphan (cyclophosphamide). It is established that adding thiophane or Scutellaria baicalensis root extract to a nutrient medium leads to a decrease in amount of Dr. melanogaster recombinants (females bearing recessive yellow and/or singed marker mutations).

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The effect of root extract of Baikal skullcap (Scutellaria baicalensis) cultivated in vitro, on the gene structure of CBA/CaLac mice bone marrow cells damaged by anticancer drugs paclitaxel and cisplatin has been studied. It is established that the root extract exhibits gene protective property upon both single and chronic administration.

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Mutagenic properties of water soluble polysaccharides (WSPS) extracted from Acorus calamus L. have been studied. Neither a single intravenous injection nor a course intraperitoneal introduction of WSPS in a dose of 1/2 LD50 to mice of the CBA/CaLac line increases the level of cytogenetic disorders in the bone marrow cells. The investigation of WSPS by means of the somatic mosaicism test showed that the given dose of WSPS does not increase the rate of mutant spots on Drosophila wings.

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Beginning with the first hours of experiments, cisplatin evoked an increase of chromosomal aberrations in CBA/CaLac bone marrow cells. Significant increase of structural infringements of chromosomes due to chromatid breaks was revealed in metaphase plates of murine bone marrow preparations through 24 h after cisplatin intraperitoneal introduction. In late terms of research (90th day), the high level of aberrations of chromosomes was retained. The most pronounced correction of cisplatin mutagenicity was achieved using a preliminary course of thiophan introduction.

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Preclinical study of the safety of 6 preparations containing ultralow doses of antibodies to endogenous regulators showed that they are relatively safe, are well tolerated by animals in doses more than 1000-fold surpassing the therapeutic dose for humans, and produce no general toxic effect on the organism of laboratory animals.

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Experiments on CBA/CaLac mice showed that single and course administration of proproten-100 did not increase the percent of abnormal metaphases in red bone marrow cells and produced no genotoxic effects in Drosophila melanogaster wing cells in the test of somatic mosaicism.

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Intraperitoneal injection of paclitaxel (Mitotax) in a single dose of 40 mg/kg was followed by an increase in the number of mitotic granulocytic and erythroid cells, hypoplasia, and pancytopenia of the bone marrow in CBA/CaLac mice. The test preparation decreased the number of hematopoietic precursor cells for erythropoiesis and granulocytopoiesis, but increased the count of polyploid cells and incidence of structural and genomic abnormalities in bone marrow cells. These changes were reversible.

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We have carried out a preclinical toxicological investigation (acute toxicity evaluation) of Mangascan (0.5 M solution of manganese(II) - EDTA complex) and Pentamang (0.5 M solution of manganese(II) - DTPA complex), a new paramagnetic contrast agents for MRI procedures. In 14 days after single intravenous introduction of Mangascan (10.0 ml/kg) or Pentamang (5.0 ml/kg) to rats, no any toxic influence of the studied agents was detected in the general condition, bone marrow, cardiovascular and central nervous systems, and liver and kidney functions of experimental animals. No pathological changes were observed in the functional activity and morphology of the internal organs and systems. The results showed that both Mangascan and Pentamang belong to the class of low toxicity substances.

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Paclitaxel (single intravenous injection in a maximum tolerated dose of 4.6 mg/kg) to white outbred rats causes bone marrow hypoplasia, increased granulocyte and erythroid cell mitosis (metaphase-anaphase transition), and moderate pancytopenia developments in peripheral blood (hypoplastic anemia, deep, short-term neutropenia, lymphopenia and thrombocytopenia) in the first hours after injection. A considerable increase of polyploidy (4n) cells and a moderate increase in the structural changes (chromatid deletions) of chromosomes was observed on bone marrow metaphase plates in 24 h. The drug introduction causes earlier increase in the rate of thymus cells mitosis, a growth in the number of thymocytes with apoptosis signs, and a moderate decrease in the thymus and spleen weight. All changes are reversible. Long-term (90 days after injection) observation revealed decreased lymphocyte count in the peripheral blood and bone marrow and earlier thymus involution.

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Single and course administration of ultralow doses of antibodies gamma-interferon did not increase the incidence of cytogenetic abnormalities in bone marrow cells from BALB/c mice and produced no genotoxic effect on Drosophila melanogaster wing cells in the test of somatic mosaicism.

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Single and repeated administration of ultralow doses of antibodies to erythropoietin did not increase the count of aberrant metaphases in bone marrow cells of BALB/c mice and were not genotoxic for Drosophila melanogaster wing cells in the test of somatic mosaicism.

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The safety of bayacon, a new drug based on Baikal aconite intended for the treatment of inflammation-proliferative dermatitis (psoriasis), was studied on a preclinical level. With respect to a single introduction in rats and mice, the drug is classified as a low-toxicity substance. However, a 3-month oral administration of bayacon (0.25, 0.5, and 2.5 mg/kg) in rats showed a number of dose-dependent functional and morphological changes. A dose of 2.5 mg/kg induced weak hyporegenerative anemia, neutrophile leukocytosis, and dystrophic changes in the stomach mucosa, heart, liver, and kidneys. All these symptoms disappeared within two weeks after abolition of the drug. Oral administration of bayacon (0.1 and 0.5 mg/kg) in rabbits produced no pathological morphofunctional changes in the organs and tissues studied. In rats, bayacon 2.5, 0.5, and 0.25 mg/kg doses of bayacon led to dose-dependent changes in some characteristics of the reproduction system. The drug did not influence the expression of allergic reactions and showed no immunotoxicity and mutagenicity manifestations.

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A new D-glucuronic acid (DGA) preparation was studied for toxicological safety on a preclinical level. The results obtained upon a single acute DGA administration in rats, mice, and rabbis showed that the drug exhibits moderate toxicity. A one-month treatment of rats (at a single daily dose of 50, 250, and 500 mg/kg, i.p.) and dogs (50 mg/kg, i.v.) induced neither functional nor morphological changes in hemopoietic and lymphoid organs, kidney, heart, as well as in the digestive, nervous, hemostatic, and fibrinolytic systems. The intraperitoneal administration of DGA produced a pronounced local irritation effects. The liver of both rats and dogs treated with DGA showed dose-dependent adipose degeneration, which decreased upon the drug abolition. The administration of DGA in 50, 100, and 250 mg/kg doses led to dose-dependent changes in some characteristics of the reproductive system in rats. DGA did not modify the extent of allergic reactions and showed no immunotoxicant and mutagen properties.

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Carboplatin injected intravenously in a maximum permissible dose to Wistar rats inhibited erythro- and granulocytopoiesis in the bone marrow, caused hyporegenerative anemia, leukopenia, and thrombocytopenia in the peripheral blood, led to hypoplasia of the thymus and spleen, and produced moderate apoptosis-inducing effects. These effects were observed within the first month after treatment. In mice carboplatin induced chromatid aberrations in the bone marrow and increased the count of erythrocytes with micronuclei. Moderate hypoplasia of erythro- and granulocytopoiesis and accelerated involution of the thymus were observed 3 and 6 months after cytostatic treatment. Our results indicate that carboplatin possesses higher myelotoxic activity compared to cisplatin.

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A new drug preparation ecorsin based on the dry aspen bark extract was studied for toxicological safety on a preclinical stage. The drug exhibited no toxicity upon a single administration to rats and mice (both male and female). The intragastric administration of ecorsin for 3 months to rats (at a daily dose of 50, 250, and 500 mg/kg) and rabbits (25 and 50 mg/kg) led to neither functional not morphological changes in hemopoietic and lymphoid organs, liver, kidney, heart, digestive system, and CNS. The long-term administration resulted in a partial atrophic modification of convoluted seminiferous tubules in impuberal male rats, while not affecting the testes of aged animals. The administration of ecorsin at 50, 250, and 500 mg/kg led to dose-dependent changes in some characteristics of the reproductive capacity in rats. Ecorsin did not modify the extent of allergic reactions and produced no immunotoxicant and mutagen effects.

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Epirubicin (pharmorubicin, India), an antitumor antibiotic of the anthracycline group, was studied in regard to its effect on peripheral blood, bone marrow and lymphoid organs (the thymus and spleen) of CBA mice after its intraperitoneal administration in a single dose equal to the MIC (7.8 mg/kg) and in a course dose (1/5 of the MIC 5 times a day). The cytogenetic impairments induced by the cytostatic were estimated on metaphase plates with the bone marrow specimens and by counting the peripheral blood erythrocytes with micronuclei (the micronuclear test). It was shown that epirubicin induced cytogenetic disturbances in the hemopoietic cells within the first 72 hours. The antibiotic had a marked reversible effect on the erythroid population and lymphoid tissues and a moderate toxic action on the granulocyte population. The antibiotic did not affect thrombocytopoiesis. The single administrations had a more pronounced and prolonged myelotoxic and lymphotropic effect.

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