Preclinical studied of general toxic properties of preparations containing ultralow doses of antibodies to endogenous regulators.

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.

[Myelotoxicity of paclitaxel (mitotax)].

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.

Carcinogenic effect of an antitumor drug etoposide in laboratory animals.

Intravenous injection of antitumor drug etoposide in the maximum tolerated dose was followed by the development of breast cancer in 38.1% female Wistar rats and 6.7% female outbred mice.

Pharmacological correction of etoposide ovariotoxicity.

The possibility of reducing the ovariotoxicity of antitumor drug etoposide with buserelin, a hypothalamic regulator of pituitary function, was studied in female Wistar rats. Quantitative analysis of ovarian structural and functional elements on serial sections through the entire organ showed that 3 months after combined treatment with etoposide and buserelin, the morphological picture of the ovarian glands did not differ from that in intact animals of the same age, while etoposide monotherapy led to earlier development of atrophic processes. Six months after treatment, the number of bi- and multilayer follicles was significantly higher in rats receiving combined therapy compared to animals treated with etoposide alone.

Evaluation of the progeny of rats treated with topoisomerase II inhibitor vepesid.

Progeny of Wistar rats treated with vepesid 1, 3, and 6 months before mating is characterized by common pathological changes. These changes were more pronounced and more diverse in animals descending from females receiving the cytostatic compared to the progeny of treated males. The severity of toxic effects depended on the period between mating and vepesid treatment. Cytostatic treatment 3 months before mating was associated with minimum toxicity for the progeny.

Morphological and functional state of rat ovaries in the early and late periods after injection of vepesid.

Morphological and functional state of the ovaries in female Wistar rats was assessed in the early and late periods after administration of antitumor drug vepesid in a single maximum tolerated dose. In the early period, the drug pronouncedly decreased the number of primordial follicles, bi- and multilayer follicles, and the total number of generative elements. The number of graafian vesicles and corpora lutea did not decrease. In the late period, exhaustion of the reserved potencies of gonads was more pronounced than in the control. Morphological alterations in the ovaries were accompanied by inhibition of the functional state of the female reproductive system in the period corresponding to the action on mature and primordial follicles. This inhibition manifested in increased postimplantation mortality.

Effect of vepeside on the function of reproductive system in rats.

Experiments on adult rats showed that a single intravenous injection of antitumor drug vepeside in a MTD (maximum tolerable dose) reduced the reproductive status during periods corresponding to exposure of mature sex cells, spermatocytes, and spermatogonia in male rats and exposure of oocytes in ovulating, mature, and primordial follicles in female rats. Reduction of the male and female reproductive function manifested in increased antenatal mortality of the progeny. The toxic effects of the drug on mature male sex cells caused temporary partial infertility.

Stress-inducing effect of hypoxia of different origin and its correction with Inula Helenium L. tincture.

In order to evaluate the severity of stress, the effects of single and repeated exposure to hypoxia of different origin (hemic, tissue, and circulatory) on the classical parameters of the Selye triad, cytological characteristics of lymphoid organs, and karyometric parameters (nucleus diameters) were studied in all adrenal zones, and analysis of correlations was carried out. The corrective effect of Inula helenium L. tincture manifested in prolongation of the life-span and normalization of somatic and morphological parameters.

[Delayed response of the red blood system (erythron) to carboplatin administration during pregnancy]. / Reaktsi sistemy krasnoi krovi (éritrona) v otdalennye sroki posle vozdeistviia karboplatina u beremennykh krys.

Pregnant rats exhibited regenerative anemia development 3 months upon a single intravenous injection of carboplatin in a maximum tolerated dose; the effect increased by the end of pregnancy. The character of changes in parameters of the peripheral and central erythron parts (increased level of erythrocyte hemolysis, decrease in the amount of erythrocytes, increase in the number of reticulocytes, development of erythropoietic hyperplasia in bone marrow and spleen) was indicative of the hemolytic type of anemia.

[Myelotoxicity of high-molecular-weight poly(ethylene oxide)]. / O mielotoksichnosti vysokomolekuliarnogo poliétilenoksida.

The effects of administration of the parent substance of high-molecular-weight poly(ethylene oxide) (HMWPEO) with a molecular mass of 3-6 x 10(6) D and the related drug polyetox (representing a water-soluble lyophilized form of HMWPEO suitable for intravenous injection) on the characteristics of peripheral blood and bone marrow were studied in rats. HMWPEO was injected intravenously and intraperitoneally in a single toxic dose. Polyetox was injected intraperitoneally in a therapeutic dose and in 3- and 10-fold doses over a period of 30 days. Single i.v. and i.p. injections of HMWPEO in the maximum tolerable dose leads to a dose-dependent reversible hemolytic anemia of medium degree, neutrophilic leukocytosis, lymphopenia, and thrombocytopenia. The chronic i.p. adminstration of polyetox in a 10-fold therapeutic dose caused red blood cell lysis and led to the development of reversible regenerative anemia.

Status of the progeny of rats treated with platinum-containing cytostatics.

Wistar rat pups from rats treated with first- and second-generation platinum-containing cytostatics (platidiam, carboplatin) 1, 3, and 6 months before mating with intact partners had similar disorders. The severity of these disorders depended in many cases on the chemical structure of the drug and sex of the parent treated with the cytostatic. The severity of toxic effects in the progeny of intact females mated with cytostatic-treated males decreased with prolongation of the period elapsing between the treatment and mating. Carboplatin produced a more potent toxic effect on the reproductive function of rats compared to platidiam.

[Effect of human recombinant granulocyte colony-stimulating factor on mouse hematopoietic and lymphoid organs]. / Vliianie rekombinantnogo granulotsitarnogo koloniestimuliruiushchego faktora cheloveka na krovetvornye i limfoidnye organy myshei.

Experiments on intact CBA/CALac mice demonstrated that single (1.25 mg/kg) and repeated (0.125 and 1.25 mg/kg, 30 days) injections of recombinant human granulocyte colony stimulation factor lead to reversible dose-dependent granulocyte lineage hyperplasia in bone marrow, regenerative neutrophilic leukocytosis, and thrombocytosis in peripheric blood and to splenic granulo-, erythro-, and thrombocytopoiesis more expressed in males.

[Preclinical toxicological study of ecorsin]. / Doklinicheskoe toksikologicheskoe izuchenie ékorsina.

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.

[Morphological estimation of apoptosis in preclinical studies of new drugs]. / Sposob morfologicheskoi otsenki apoptoza dlia klinicheskogo izucheniia novykh lekarstvennykh sredstv.

A method for morphological estimation of the thymus cell loss during apoptosis proposed, which can be used as a screening test in the stage of preclinical characterization of new biologically active compounds. Efficacy of the proposed method is demonstrated by evaluating the degree of apoptosis-inducing effect of some antitumor preparations.

[The mechanisms of the hepatotoxic action of the antitumor preparation vepesid]. / Mekhanizmy gepatotoksicheskogo deistviia protivoopukholevogo preparata vepezida.

It was shown in experiments on rats that intravenous infusion of the antitumor drug vepesid in a maximum tolerated dose causes stimulation of free-radical oxidation and changes in the fractional composition of lipids and phospholipids in the hepatic tissue. Changes in the activity of aminotransferases and alkaline phosphatase in the blood were recorded.