Increasing the non-specific resistance of animals to pathogenic E. coli with preparations of RNA]

Yeast RNA and sodium nucleinate considerably increased the nonsusceptibility of mice to pathogenic escherichia and typhoid salmonellae. Ineffective single nucleonate doses created an intense resistance in repeated use; prolonged application was not accompanied by the appearance of tolerance to the preparation. The principal mechanism of the induced phenomenon consisted in the intensification of the bacterial elimination and the endotoxin detoxification chiefly realized by the activity of the mobile phagocytes.     

Use of sodium nucleinate and its combinations with bacterial polysaccharides for preventing the nephrotoxic action of aminoglycoside antibiotics

Possible prevention of the nephrotoxic effect of different doses of aminoglycoside antibiotics, such as monomycin, kanamycin and gentamicin was studied experimentally on chinchilla rabbits. Substances increasing the cell resistance (sodium nucleinate, prodigiosan and pyrogenal alone and sodium nucleinate combinations with the bacterial polysaccharides) were used. It was shown that sodium nucleinate prevented nephrotoxicity of the aminoglycosides in the doses 2.5 times higher than the therapeutic ones. The combined use of sodium nucleinate with pyrogenal or prodigiosan was most effective. It prevented the nephrotoxic effect of the antibiotics in the doses 5 times higher than the therapeutic ones.     

New data on the tachyphylactic properties of sodium nucleinate]

Sodium nucleinate, when injected into mice in combination with killed E. coli or prodigiozan, caused a decrease in side effects produced by the vaccine or polysaccharide. The combined injection of sodium nucleinate and prodigiozan in doses, ineffective if introduced separately, was accompanied by the potentiation of their tachyphylactic action. The use of sodium nucleinate in combination with polyvinylprrolidone (hemodez) prolonged the tachyphylactic action of sodium nucleinate and increased its effectiveness. The proposed principle is supposed to be suitable for decreasing the reactogenicity of bacterial vaccines and polysaccharides.     

Intensification of antibacterial and antiviral nonsusceptibility and of the immune response with an officinal RNA preparation]

Sodium nucleinate increased essentially the insusceptibility of mice to pathogenic escherichia, strain O26, Pr. vulgaris, Ps. aeruginosa, Ser. marcescens, and produced a total stimulating effect on the nonspecific bacterial resistance; analogous stimulating activity was found in the homologous low polymeric RNA from the liver. Sodium nucleinate intensified the insusceptibility of the animals to the tick-born encephalitis and encephalomyelitis viruses, and increased the antibody-forming cells count. The side-effect of heat-inactivated vaccine from pathogenic escherichia was reduced in animals inoculated with sodium nucleinate preliminarily.     

The effect of sodium nucleinate on allergic and immunological reactions

Experiments on immunized rabbits and guinea pigs indicated that sodium nucleinate (SN) was capable of weakening or entirely eliminating anaphylactic and skin reactions of delayed type hypersensitivity to repeated administration of staphyloanatoxin, APDT vaccine. The findings on patients with the infectious form of bronchial asthma and chronic rheumatism showed that sodium nucleinate attenuated reactions to the subcutaneous administration of staphylococcal and streptococcal allergens. The treatment of patients suffering from infectious-allergic bronchial asthma and rheumatism with SN resulted in the recovery of deficient T cells, T-suppressors, normalization of immunoglobulin concentrations. In children with acute glomerulonephritis sodium nucleinate normalized decreased T-suppressor cells and increased IgG and circulating immune complexes (CIC), resulting in a pronounced remission of disease. The mechanism of desensitization and elimination of CIC by SN has not been explored, however, the parameters of SN-induced immunomodulation are known rather completely. It is suggested that SN brings about accumulation in the cell of cyclic AMP which diminished membrane permeability, activates monoaminooxidase resulting in the degradation of histamine and other biogenic amines, enhances the synthesis of endogenous corticosteroids with their desensitizing properties. All these effects contribute to the elimination of delayed type hypersensitivity. The role of SN in the inhibition of delayed type hypersensitivity remains obscure.     

Increase in the sensitivity of Shigella to antibiotics

Passages of 10 Shigella strains for 10 times in meat-peptone broth supplemented with sodium nucleinate provided an increase in sensitivity of the cultures to levomycetin for a period of 264 hours. In three strains of S. sonnei, S. flexneri and S. newcastle the authors observed an increase in sensitivity to tetracycline, benzylpenicillin and streptomycin. Some nitrous bases included in sodium nucleinate were also able to increase antibiotic sensitivity in Shigella.     

Sodium nucleinate increase of nonspecific macroorganism resistance to conditionally pathogenic and pathogenic microorganisms

Sodium nucleinate significantly increased the non-specific resistance of mice to E. coli O26, Ps. vulgaris, Ser. marcesens, Ps. aeruginosa, Kl. ozaenae and their associations and total resistance also accompanied by a significant decrease in the number of the bacteria in the spleen and blood, the total number of the cells in the peritoneal exudate and the number of the cells adhering to the glass (macrophages). The preparation is a low molecular RNA consisting mainly of fraction 3S and a small amount of fraction 4S. It contains 1.5 per cent of protein and 2 per cent of DNA and does not contain any polysaccharides. Repeated purification of sodium nucleinate lowering the levels of the admixtures 5 times did not change its efficacy. The low molecular RNA of the rat liver (4S) had a pronounced stimulating activity. On infection of the host stimulated with sodium nucleinate, formation of the post-infection immunity was not decreased.     

Comparative effectiveness of immunomodulators in the therapy of bronchopulmonary diseases

One hundred and fifty-one patients with bronchopulmonary diseases were examined and it was shown that they had secondary immune deficiency mainly in the T-cells which could not be recovered with the routine therapeutic agents. The use of hemodez, levamisole or sodium nucleinate in the combined therapy promoted correction of the immune deficiency and increased the treatment efficacy. Sodium nucleinate proved to be the most efficient.     

Comparative effectiveness of immunomodulators in the therapy of rheumatic heart defects

A total of 166 patients with rheumatic heart diseases were examined. It was shown that the patients had secondary immune deficiency mainly with respect to the T-cells, which could not be eliminated with the routine therapeutic agents. The use of hemodes, decaris or sodium nucleinate in the combined therapy of such patients promoted correction of the immune deficiency and increased the treatment efficacy. Sodium nucleinate proved to be the most active.     

Effects of essentiale forte on biosynthesis of nucleic acids and several hemodynamic parameters of the damaged myocardium in rabbits

Normalization of heart muscle phospholipid metabolism and reactivation of the activity of membrane-bound enzymes participating in the reactions of biosynthesis of nucleic acids have been studied. These investigations were carried out under the conditions of experimental myocardial infarction. The effects of essential forte have been examined when it was combined with both a tocopherol, and sodium nucleinate. It was pointed out that essential forte using without other reagents leads to the depression of nucleic acids biosynthesis in affected heart muscle, while the combinations of it with a-tocopherol, and especially with sodium nucleinate are accompanied by the significant intensification of reactions of formation of desoxynucleic and ribonucleic acids biosynthesis in necrotic areas as well as in peripheral regions of affected myocardial tissue. These positive changes are accompanied also by the pronounced normalization of haemodynamic activity of infarcted myocardium.     

Cardiomyocytes of the left ventricle of the heart in experimental infarct and pharmacostimulation (histochemical study)

Contents and activity of lactate dehydrogenase and succinic dehydrogenase of cardiomyocytes have been studied histochemically and cytophotometrically in the left ventricle of the rabbit heart under conditions of myocardial infarction experimentally induced by alpha-tocoferol and sodium nucleinate. The substances mentioned produce a protective effect on the energic metabolism of cardiomyocytes.     

Correction of immunologic reactivity depending on ABO system antigens in patients with purulent infections of soft tissue and shigellosis

The immunological study of more than 300 patients with purulent infection of soft tissues and shigellosis was carried out. The character and manifestation of the immunocorrecting action of sodium nucleinate were found to depend on the antigens of the AB0 system, which proved to be different in various type of pathology.     

Correction of secondary immunologic deficiency by using yeast RNA

In patients with rheumatism, chronic alcoholism and peptic ulcer immune deficiency mainly with respect to T-lymphocytes has been detected. The injection of sodium nucleinate simultaneously with the use of traditional therapeutic remedies induces the correction of secondary immune deficiency for a period of 6-9 months.     

Immunomodulating activity of RNA mononucleotides

The immunological action of RNA mononucleotides was studied in animal experiments. The most pronounced activation of macrophagal glycolysis urea cycle, oxidative phosphorylation, lysosomal hydrolases was induced by uridine 5'-monophosphate (5'-UMP) and guanosine 5'-monophosphate (5'-GMP); 5'-GMP also induced the maximum increase of the expression of FC gamma receptors. 5'-UMP ensured cell activation comparable with the total action of all mononucleotides. 5'-UMP and 5'-GMP, used in combination, produced the highest stimulating effect on macrophages, and the addition of low-active adenosine 5'-monophosphate (5'-AMP) to active 5'-UMP did not decrease the stimulating potency of the latter. The stimulating activity of sodium nucleinate exceeded that of all mononucleotides and their combinations. 5'-GMP and 5'-AMP induced the maximum activation of oxygen metabolism, evaluated by chemiluminescence, while 5'-UMP and cytidine 5'-monophosphate (5'CMP) proved to be inactive. The shift of the phosphate group to the third carbon atom or the production of the oligonucleotide 5'-UMP consisting of 5-15 nucleotides resulted in the appearance of the capacity for stimulating oxygen metabolism in macrophages. Their in vitro cultivation with 5'-GMP and 5'-AMP induced the maximum increase of cell spreading in comparison with other mononucleotides, while the maximum increase of phagocytosis was ensured only by 5'-UMP and 5'-GMP.2+ 5'-UMP and 5'-GMP enhanced nonospecific resistance to Salmonella typhi infection, and sodium nucleinate, to Pseudomonas pseudomallei and Pseudomonas mallei infections.     

A tetrahydrophthalazine derivative 'sodium nucleinate" exerts a potent suppressive effect upon LPS-stimulated mononuclear cells in vitro and in vivo

We described the use of a new chemical substance Sodium nucleinate (SN) as an immunomodulatory substance exhibiting antiinflammatory properties. Sodium nucleinate (SN) registrated in Russian Federation as Tamerit, is 2-amino-1,2,3,4-tetrahydrophthalazine-1,4-dione sodium salt dihydrate, derivative of well known chemical substance luminol. To comprehend the mechanisms of SN immunomodulatory activity, we examined the SN modulation of the innate inflammatory cytokine response of human PBMC stimulated with LPS in vitro. Furthermore, we studied the immunomodulatory effects of SN in mice challenged with E. coli LPS in vivo to investigate a possible novel approach to therapy of excessive inflammation that interfere with the response to endotoxin and inflammatory mediators. Our results demonstrated that SN is an efficient inhibitor of sepsis development in mice model of LPS-induced sepsis. The changes induced by SN include decreased mice plasma inflammatory cytokine production. Simmilary we demonstrated a decreased TNF-alpha, IFN-gamma and IL-6 response in human LPS-stimulated PBMNCs. SN was therefore shown to be a promising inhibitor of multiple inflammatory cytokine secretion.     

Redistribution of subpopulations of peritoneal macrophages with Fc gamma receptors under the effect of an immunomodulator

The heterogeneity of resident peritoneal macrophages and peritoneal macrophages was studied in different periods following oral administration of sodium nucleinate according to their ability to bind and phagocytize sheep erythrocytes opsonized by means of specific rabbit IgG. Using a mathematical method developed earlier, it has been possible to demonstrate that resident peritoneal macrophages can be divided into two subpopulations--actively and poorly binding macrophages but, after activation by sodium nucleinate--into three subpopulations. Fractionation of the macrophages according to their ability to adhesion within a temperature gradient has shown that the same peaks are traced in the fractions as in the overall pool of cells, but in different quantitative ratios. It has also been demonstrated that phagocytic activity is reduced in macrophages capable of adhesion to plastic at lower temperatures.     

Tetrahydrophthalazine derivative "sodium nucleinate" exert its anti-inflammatory effects through inhibition of oxidative burst in human monocytes

We described the use of a new chemical substance Sodium nucleinate (SN) as an immunomodulatory substance exhibiting antiinflammatory properties. Sodium nucleinate (SN) registrated in Russian Federation as Tamerit, is 2-amino-1,2,3,4-tetrahydrophthalazine-1,4-dione sodium salt dihydrate, derivative of well known chemical substance luminol. To comprehend the mechanisms of SN immunomodulatory activity, we examined the SN modulation of the oxidative burst responses of whole blood human monocytes and polimorphonuclear cells (PMC) stimulated with phorbol 12-myristate 13-acetate (PMA) or E. coli suspension in vitro. SN did not inhibit the proportion of neutrophils and monocytes phagocytosing E. coli. Oxidative burst responses of monocytes stimulated with PMA were strongly inhibited at SN concentration ranging from 10-500 mg/ml, less efficient inhibitor was SN in E. coli stimulated monocytes (inhibition range was from 50-500 mg/ml SN). SN inhibited PMC oxidative burst only in range 100-500 mg/ml SN. In conclusion, we found SN as an efficient inhibitor of oxidative burst in monocytes. Since ROS generation in monocytes/macrophages has been found to be important for LPS-driven production of several proinflammatory cytokines, SN may exsert its antiinflammatory effects through monocyte/macrophage oxidative burst inhibition.     

Study of the process of interaction of the causative agent with the cells of the body and with a macrophage culture in experimental typhoid infection and carrier state]

Experiments were conducted on 117 rabbits and cells of the macrophage cultures in vitro by the methods of clinico-laboratory, quantitative microbiological, immunological, electron microscopic and microcinematographic examination; a study was made of the interaction of the typhoid causative agent with the cells of the organism and the macrophage cultures and also of some aspects of the immune response during acute typhoid infection and carrier state. Infection was modelled by the enteral, subconjunctival and intrabonemarrow infection with 24-hour culture of the typhoid bacillus (strain Ty2 4446). Experiments demonstrated that structural reconstruction of both the causative agent and of the cells of the organism, of the culture macrophages and their organoids occurred in the course of the first hour after the infection. Homogenates of the lymphoid and myeloid tissues and also of the macrophages and polymorphonuclears possessed bactericidal activity against S. typhi. The degree of this activity largely depended on the pH of the medium. It was also shown that under conditions of the macrophage culture sodium aside inhibited the bactericidal activity of macrophages obtained from the intact and immune animals.     

The inhibiting effect of a low-dose ionizing radiation on the primary humoral immunity in the early period of an postnatal ontogeny

The single exposition of 3- and 4-week mice in a dose 0.1 Gy resulted in depressing primary T-dependent humoral immune response. Unlike juvenile ones at adult 16-week animals the stimulation antibody-formation took place. As a result of the administration of immunomodulating drugs, thymogene and nucleinate of a sodium in irradiation mice of 3-week age was an augmentation of the number of antibody-producing cells relatively in 2 and 4 times. At the same time at irradiated in dose 0.1 Gy of adult mice thymogene abrogated the stimulating effect of radiation. It is suggested that the probable cause of the immunosuppressing effect of a small dose of radiation can be an inactivation of a radiosensitive subpopulation of helper cells or selective stimulation of the functional activity of neonatal suppressor cells.     

The effect of an artificial magnetic field on Salmonella infection in mice]

Experimental Salmonella infection in mice, developing simultaneously with the prolonged action of an artificial constant magnetic field with induction equal to 3 x 10(-4) T, was found to induce a pronounced decrease in nonspecific resistance in the animals. The study of Salmonella population structure revealed that the cells selected the animals subjected to the action of the artificial magnetic field had mostly a lesser number of signs of antibiotic resistance. By the end of the experiment Salmonella cultures isolated from the mice subjected to the action of the artificial magnetic field were characterized by greater virulence and resistance to the bactericidal action of blood serum. The use of sodium nucleinate under the conditions of the action of the artificial magnetic field enhanced the level of anti-infectious protection in the animals, which changed the direction of cell selection in Salmonella population towards cells with a greater number of markers of antibiotic resistance.