Specific binding of the sigma-1 receptor (Sigma1R) ligand [ 3 H]-(+)-pentazocine was determined in the P2 and P3 fractions of brain homogenates from inbred BALB/c and C57BL/6 mice after emotional stress in the open-field (OF) test and outbred CD-1 mice after administration of the anxiolytic afobazole. Exposure in the OF test increased specific binding of [ 3 H]-(+)-pentazocine to the P3 fraction of BALB/c mice brain homogenates as characterized by catatonia in the OF test and did not affect ligand binding in C57BL/6 mice with active behavior in the OF test. Afobazole at a dose of 5 mg/kg increased specific binding of [ 3 H]-(+)-pentazocine to the P2 fraction of outbred CD-1 mice brain homogenates. The results indicated that Sigma1R was involved in the formation mechanism of emotional stress responses and in afobazole pharmacodynamics.

Материалы V съезда фармакологов России «Научные основы поиска и создания новых лекарств» (14-18 мая 2018 года, г. Ярославль)

Материалы V съезда фармакологов России «Научные основы поиска и создания новых лекарств» (14-18 мая 2018 года, г. Ярославль)

Radioligand analysis was used to study the interaction between afobazole and sigma-1 receptors (Sigmar1) in the brains of inbred C57B1/6, BALB/c, and mongrel CD-1 mice. Afobazole binding sites were found to be identical to those of the prototype Sigmar1 agonists (+)-pentazocine and PRE-084. Depending on the structure of the prototype ligand and the in vitro incubation conditions, the specific binding of afobazole with Sigmar1 in brain homogenates from inbred mice was characterized by different receptor interaction models. In competitive displacement of [G-3H]PRE-084, the affinity of Sigmar1 for afobazole in BALB/c mice was significantly greater than that in C57B1/6 and CD-1 mice.

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.

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.

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.

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.).

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.

A method for determining thermal characteristics of materials in multilayered objects is proposed. The method is based on the use of an additional layered structure with present thermal characteristics that is named the standard layer (SL). The error associated with a finite size of the SL is assessed. A technique that considerably simplifies the procedure of determining the thermal resistance of multilayered objects is proposed. This technique is simpler than the state-of-the-art methods that are based on numerical integration of the heat-conduction equation and used for solving inverse problems. A possible structure of the SL is presented.

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.

We studied the role of β-adrenergic mechanisms of regulation of erythropoiesis in the formation of the erythron system reaction during severe hypoxia. Blockade of β-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.

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.

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.

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.