inosine-pranobex and Orthomyxoviridae-Infections

Influenza pathogenesis comprises a complex cascade of impaired cellular processes resulting from the viral replication and exaggerated immune response accompanied by reactive oxygen species (ROS) burst and oxidative stress, destructing membranous structures and tissues. By classical virological and biochemical methods we compared and evaluated the therapeutic effects of 2.5mg/kg/day of the antiviral drug - oseltamivir (OS), 500mg/kg/day of the immune modulator - isoprinosine (IP) and 500mg/kg/day of the antioxidant agent ellagic acid (EA) with a focus on their combined activities in influenza H3N2 virus-infected mice. The survival, lung pathology and titers, as well as the oxidative stress biomarker thiobarbituric acid reactive substances (TBARS) in the lungs, liver and blood plasma, correlated to the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione reductase (GR) were assessed. We found that the viral inhibitor applied together with the immune modulator and the antioxidant exhibited strong therapeutic effects on the survival of the influenza-challenged mice. That effect was mostly pronounced for the triple combination - protection index (PI) of 75.2%, mean survival time (MST) extended by 5.8 days compared to the PBS control and significant reduction of the lung titers by 1.38 Δlg; 2.3 scores lower lung pathology and 8 times reduction of the accumulated TBARS in the lungs and liver on the 5

Topics: Animals; Antioxidants; Antiviral Agents; Cell Line; Dogs; Drug Therapy, Combination; Ellagic Acid; Influenza A Virus, H3N2 Subtype; Inosine Pranobex; Lung; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Inbred ICR; Orthomyxoviridae Infections; Oseltamivir; Oxidation-Reduction; Oxidative Stress; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The antiviral effect of rimantadine and isoprinosine applied in combination against fowl plague virus (FPV) in cell cultures of chick embryo fibroblasts and in experimental influenza infection in mice has been studied. Isoprinosine does not inhibit the reproduction of FPV when given alone and does not increase the antiviral activity of rimantadine. After oral application of both substances according to an appropriate scheme in mice infected with influenza virus A/Aichi (N3N2), an increase in the antiviral effect with an index of protection by 12% higher than the theoretically calculated one for additive effect was established. The results suggest that the combined effect is synergic.

Topics: Adjuvants, Immunologic; Animals; Birds; Chick Embryo; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Influenza in Birds; Inosine Pranobex; Mice; Mice, Inbred ICR; Orthomyxoviridae Infections; Rimantadine

It has been shown that the immunostimulant inosiplex (IP) is capable of inducing interferon production in mice and of stimulating interferon induction by high-molecular inducers. The combined use of IP and poly (G)-poly (C) or dsRNA (RFf2) leads to a longer interferon circulation in the blood. All the combination schemes ensuring the effect of interferon production prolongation were tested for anti-viral activity. The prophylactic administration of the drugs permitted the attainment in mice of the increased resistance to experimental influenza.

Topics: Animals; Antiviral Agents; Drug Therapy, Combination; Inosine; Inosine Pranobex; Interferon Inducers; Male; Mice; Orthomyxoviridae Infections; Poly C; Poly G; RNA, Double-Stranded; Tilorone

The influence of ISO, the antiviral drug of immunomodulating activity, on the course of experimental influenza infections and mixed, viral-bacterial infections was studied. Spleen leukocytes migration inhibition test, performed in vitro in the presence of specific antigens stimulating influence of the drug administered to the infected animals was observed.

Topics: Animals; Bacterial Infections; Immunity, Cellular; Influenza A virus; Inosine; Inosine Pranobex; Leukocyte Migration-Inhibitory Factors; Leukocytes; Lymphokines; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Spleen; Staphylococcus aureus; Time Factors

The effect of inosiplex (Isoprinosine) on viral replication, experimental viral infections and host immune functions has been examined. Inosiplex was found to have a broad spectrum of antiviral activity, inhibiting the RNA viruses, influenza (INFV) and parainfluenza (PIV), as well as the DNA viruses, herpes simplex (HSV) and vaccinia (VACV). However, the antiviral effects were modest when compared to amantadine and adenine arabinoside (ARA-A). Inosiplex in vivo caused a statistically significant increase in survival of treated animals (hamster, mice) infected with RNA or DNA viruses. This effect of inosiplex was apparent in animals which were previously immunosuppressed. Inosiplex, at optimal dose, conferred total protection in treated mice against secondary influenza infection. Since this was accompanied by statistically significant increases in serum anti-hemagglutinin and anti-neuraminidase titers, an effect of inosiplex on host defenses against secondary viral infection was implicated. This effect was further demonstrated by passive transfer of protection by splenocytes from inosiplex-treated donors to untreated recipients. Inosiplex was found to enhance the mitogen- (PHA-, ConA and MLC-) induced blastogenesis of lymphocytes from untreated mice. The LPS response was not affected. Inosiplex added in vitro caused a dose-dependent increase in the primary immune anti-SRBC response in vitro, as determined by direct and indirect PFC; there was also a dose-dependent effect on the secondary in vitro direct and indirect PFC responses. Inosiplex in vivo enhanced the primary immune response to SRBC, as determined by direct PFC assay; this was also the case for immunosuppressed mice. The drug enhanced delayed type hypersensitivity to picryl chloride in the mouse. Macrophage function was also enhanced by inosiplex, as was apparent from phagocytosis of SRBC. Gamma interferon production from murine lymphocytes was augmented by inosiplex in vitro. Treatment with inosiplex had no effect on natural killer cells or on antibody dependent cellular cytotoxicity. Thus, the pronounced effect of inosiplex on secondary viral infections may result through two different mechanisms: a direct antiviral effect and an elevation of multiple parameters of host immunity, which are usually compromised during viral infection. The latter mechanism may be the more important.

Topics: Adjuvants, Immunologic; Animals; Cricetinae; Female; Hemolytic Plaque Technique; Herpes Simplex; Inosine; Inosine Pranobex; Interferons; Lymphocyte Activation; Male; Mesocricetus; Mice; Mice, Inbred Strains; Orthomyxoviridae Infections; Phagocytosis; Vaccinia; Virus Diseases

The mechanism of influenza virus (INFV)-induced immunosuppression and the mode of inosiplex action against INFV infection were studied. INFV suppressed both anti-lipopolysaccharide and anti-sheep erythrocyte antibody production in mice. INFV infection caused viral mRNA synthesis and increased total RNA synthesis in lymphocytes, but total mRNA synthesis was decreased. The translational ability of INFV-infected lymphocytes was also suppressed. Thus, INFV seemed to cause suppression of both mRNA synthesis and the translational ability of lymphocytes, resulting in suppression of lymphocyte functions. Inosiplex potentiated antibody production against sheep erythrocytes but not against lipopolysaccharide in normal and INFV-infected mice. Adamantanamine did not produce such a potentiating effect. The lymphocytes obtained from INFV-immunized and inosiplex-treated mice conferred resistance against INFV infection. This resistance was partially inhibited by anti-Thy 1.2 antibody treatment of the lymphocytes. In an adoptive cell transfer system, inosiplex treatment of T-cell donors potentiated antibody production when a non-immunosuppressive carrier (human serum albumin) was used. When an immunosuppressive carrier (INFV) was used, inosiplex treatment of either B-cell donors or T-cell donors increased antibody production. Direct introduction of inosiplex into lymphocytes by a cell fusion technique stimulated anti-sheep erythrocyte antibody production more effectively than the addition of inosiplex to cultures. Inosiplex increased total RNA and total mRNA syntheses in phytohemagglutinin-treated lymphocytes. In INFV-infected lymphocytes, inosiplex decreased syntheses of total RNA, total mRNA, and viral mRNA and restored translational ability. From these results, we concluded that inosiplex penetrates into lymphocytes and suppresses viral RNA synthesis and that it supports lymphocyte functions by promoting RNA synthesis and translational ability, both of which are necessary for hosts.

Topics: Animals; Antibody Formation; Female; Immune Tolerance; Immunization, Passive; Inosine; Inosine Pranobex; Lymphocytes; Mice; Mice, Inbred DBA; Orthomyxoviridae Infections; Protein Biosynthesis; RNA; RNA, Messenger; RNA, Viral

Topics: Adjuvants, Immunologic; Animals; BCG Vaccine; Herpes Simplex; Inosine Pranobex; Levamisole; Macrophages; Mice; Mycobacterium; Orthomyxoviridae Infections; Phagocytosis; Propionibacterium acnes; Virus Diseases