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.

SP-D-dependent regulation of NO metabolism in lipopolysaccharide-stimulated peritoneal macrophages.

This work was designed to study the role of surfactant protein D in the regulation of NO synthesis by "non-alveolar" microphages. We evaluated whether the effects of surfactant protein D depend on the phenotype of macrophages. In the absence of surfactant protein D, the LPS-induced iNOS response was shown to decrease in macrophages of native and proinflammatory phenotypes by 30%, and in macrophages of the antiinflammatory phenotype (by 63%). Under the influence of lipopolysaccharide in high doses (500 ng/ml), NO(2)*- production by mouse macrophages without surfactant protein D was reduced in native cells (by 25%), but increased in proinflammatory (by 40%) and antiinflammatory phenotypes (by 12% compared to mouse macrophages with surfactant protein D). Our results suggest that surfactant protein D is involved in the immune response in the whole organism, but not only in the lungs. The effect of surfactant protein D depends on the phenotype of macrophages.

[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.

[Myelotoxity of the nuclear enzyme inhibitors irinotecan and etoposide].

Irinotecan (campto) and etoposide cause the loss cells due to apoptosis, the early development of hypoplasia in bone marrow and lymphoid organs, and pancytopenia in peripheral blood upon single intravenous injection in maximum tolerated doses to white outbred rats. Etoposide causes more severe apoptosis and myelotoxicity than irinotecan. The changes are reversible within one to three months. On longer terms (from three to six months) after irinotecan and etoposide injection, there were a moderate decrease in the red blood cells and hematocrit, an increase of the MCV and MCHC indices, and premature thymus involution.

[Preclinical toxicological study of the new enterosorbent noolit].

The safety of the new enterosorbent noolit has been evaluated within the framework of its preclinical characterization. Single introduction of noolit to rats and mice (females and males) in maximum doses for intragastric administration (5.0 - 20.0 g/kg) does not lead to the loss of experimental animals. Single administration of large doses (5 - 40 times the effective dose) can reduce the growth of the total body weight and lead to the development of nonlethal pathological changes of hemopoietic organs, which is manifested by a weak regenerative anemia (5% of cases); neutrophile, eosinophile, and basophile leukocytosis (3% of cases); and a decrease in the glucose level in blood serum. In chronic experiments on rabbits, the administration of noolit for 3 months in a dose of 0.5 and 2.0 g/kg (2 and 8 times that recommended for humans) did not reveal any toxic action on the functional and morphological state of the main systems and organs (blood, liver, kidneys, lungs, heart, gastrointestinal tract, sex organs, etc.).

Effect of ultralow doses of antibodies to erythropoietin on antenatal and postnatal development of the offspring.

We studied the effects of ultralow doses of antibodies to erythropoietin on antenatal and postnatal development of rat offspring. Daily administration of the preparation on days 1-6, 6-16, and 16-19 of pregnancy did not increase embryonic mortality and was not associated with congenital malformations, fetal growth retardation, high incidence of pathological changes in fetal organs, and delayed ossification (compared to control and intact animals). For evaluation of their embryotoxic effect manifested in the postnatal period ultralow doses of antibodies to erythropoietin were administered throughout pregnancy. The offspring of treated and intact rats did not differ in physical development, appearance of sensory and locomotor reflexes, locomotor, exploratory, and emotional behavior, and learning and adaptive capacities.

[Pyruvate dehydrogenase activation in the skeletal muscles of the chick embryo during electrostimulation]. / Aktivatsiia piruvatdegidrogenazy v skeletnykh myshtsakh kurinogo zarodysheva pri élektrostimuliatsii.

The pyruvate dehydrogenase activity in the skeletal muscle during chicken embryo-genesis and early postnatal life amounts to 550 +/- 50 mU per g tissue, on the average; electrostimulation (1 Hz) induced a two-fold increase in its activity starting from the 15th day of incubation.

[Effect of quinine and quinidine on the status of hematopoietic and lymphoid organs]. / Vliianie khinina i khinidina na sostoianie krovetvronykh i limfoidnykh organov.

The effect of quinine and quinidine introduction in subtoxic doses on the characteristics of the hemopoietic and lymphoid organs was studied in BALB/c mice. The treatment led to reversible anemia and neutrophile leukocytosis in peripheral blood. There was a tendency to the early decrease in neutrophiles the late decrease in lymphocytes in the bone marrow. The quinine-induced decrease in erythrocytes was accompanied by reticulosis, lowered erythrocyte osmoresistance, and intensified spleen erythropoiesis; quinidine induced reticulocytopenia and a decrease in the bone narrow erythroblasts. The use of both compounds was accompanied by a decrease in thymus weight and increase in the thymocyte loss in the early period, followed by the spleen weight increase in the long term.

[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.

[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 toxicologic study of a Baikal aconite tincture (bayacon)]. / Doklinicheskoe toksikologicheskoe izuchenie nastoiki akonita baikal'skogo (Baiakona).

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.

[Status of the pool of hematopoietic stem cells in the peripheral blood in patients with lung cancer before and during polychemotherapy]. / Sostoianie pula krovetvornykh kletok-predshestvennikov perifericheskoi krovi u bol'nykh rakom legkogo do i v usloviiakh provedeniia polikhimioterapii.

The pool of hematopoietic cells-precursors from the peripheral blood of patients with lung cancer stage III-IV was characterized by reduced number of circulating cells-precursors of granulomonocyto-(CFU-GM) and erythropoiesis (CFU-E). In the course of antitumor chemotherapy the counts of CFU-GM and CFU-E diminished 2 and 4-fold, respectively. The prednisolone functional test determined that depletion of CFU-GM and CFU-E pools in the peripheral blood was preceded with lowered pool reserve for hematopoietic precursors.

[Influence of mast cells on the regulatory mechanisms of hemopoietic bone marrow in inflammation]. / Vliianie tuchnykh kletok na kostnomozgovye mekhanizmy reguliatsii gemopoéza pri vospalenii.

Acute infectious peritonitis simulated in mice was used to show that previous osmotic deterioration of the abdominal mast cell population significantly influenced the function of hemopoiesis-inducing microenvironment (HIM). The earlier production of the colony-stimulating and erythropoietic activities by the non-adhesive myelokaryocytes and the decreased production of these activities by the adhesive cells have been established. The results obtained evidence that mast cells modulate HIM mediating their influence on hemopoiesis under natural conditions of inflammation.

[Blood system responses in inflammation and mechanisms of their development]. / Reaktsii sistemy krovi pri vospalenii i mekhanizmy ikh razvitiia.

A model of acute infectious peritonitis in mice demonstrated that the inflammation is attended by marked biphasic activation of bone-marrow granulomonocytopoiesis and that the activation is due in many respects to increased functional activity of elements forming the hemopoiesis-inducing microenvironment. This was suggested by increased colony-stimulating activity of the marrow mononuclear cells and the content of hemopoietic islets in the marrow. The colony-stimulating activity of peripheral blood also increased. It was established that inflammation is also characterized by activation of bone-marrow erythropoiesis, which is linked with increased erythropoietic activity of the hemopoiesis-inducing microenvironment and blood. There was a relation between the hemopoietic changes and the kinetics of leukocytes in the focus of inflammation.

Solute trapping in rapid solidification of a binary dilute system: a phase-field study.

The phase-field model of Echebarria, Folch, Karma, and Plapp [Phys. Rev. E 70, 061604 (2004)] is extended to the case of rapid solidification in which local nonequilibrium phenomena occur in the bulk phases and within the diffuse solid-liquid interface. Such an extension leads to the fully hyperbolic system of equations given by the atomic diffusion equation and the phase-field equation of motion. This model is applied to the problem of solute trapping, which is accompanied by the entrapment of solute atoms beyond chemical equilibrium by a rapidly moving interface. The model predicts the beginning of complete solute trapping and diffusionless solidification at a finite solidification velocity equal to the diffusion speed in bulk liquid.

Clinical study of the efficiency of Poetam in the treatment of the anemic syndrome in pubertal uterine hemorrhages.

Clinical study of the efficiency of Poetam (affinity-purified antibodies to recombinant human erythropoietin) in the treatment of anemia in patients with pubertal uterine hemorrhages proved that combined therapy with Poetam and iron preparation normalized erythron parameters, structural and metabolic status of erythrocytes, and ferrokinetic parameters of the peripheral blood sooner than monotherapy with Poetam or sorbifer.

Role of adrenergic mechanisms of erythropoiesis regulation during severe hypoxia.

We studied the role of beta-adrenergic mechanisms of regulation of erythropoiesis in the formation of the erythron system reaction during severe hypoxia. Blockade of beta-adrenoceptors after the incidence of hypoxic encephalopathy of different genesis was followed by an increase in the number of committed precursors in the bone marrow, hyperplasia of the erythroid hemopoietic stem, and rise in the count of peripheral blood erythrocytes. These changes were accompanied by decreased formation of abnormal erythrocytes.

Reactions of the erythroid hemopoietic stem and their mechanisms during blood loss.

We studied changes in the erythroid hemopoietic stem during blood loss of different severity. Stimulation of erythropoiesis during the posthemorrhagic period was related to functional activation of erythroid precursors, which resulted from changes in feeder capacity of cells from the hemopoiesis-inducing microenvironment and erythropoietic activity of the plasma. The development of encephalopathy under conditions of massive blood loss was accompanied by a reduction of erythroid hyperplasia due to a decrease in the number of proliferating erythroid precursor cells, despite high secretory activity of adherent myelokaryocytes, rise in erythropoietic activity of the plasma, increased formation of erythroid hemopoietic islets, and accelerated maturation of hemopoietic cells.

Mechanisms of regulation of erythropoiesis during hemolytic anemia.

We studied changes in the erythroid hemopoietic stem during phenylhydrazine-induced hemolytic anemia. Stimulation of erythropoiesis was associated with increased functional activity of erythroid precursors, which resulted from changes in feeder capacity of hemopoiesis-inducing microenvironmental cells and erythropoietic activity of the plasma. The development of encephalopathy induced by a hemolytic poison was accompanied by a decrease in hyperplasia of bone marrow erythropoiesis. It was related to a decrease in the number of proliferating erythroid precursor cells. These changes accompanied the increase in the secretory function of adherent myelokaryocytes, rise in erythropoietic activity of the plasma, enhanced formation of erythroid hemopoietic islets, and accelerated maturation of hemopoietic cells.

Early and delayed effects of carboplatin on the blood system.

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.