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4 Table 1 Antiviral activities of inosiplex, adenine arabinoside (AraA) and adamantanamine (ADAM)
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6 Fig. 4 Survival effects of inosiplex on influenza virus infection in immunosuppressed mice Mice were given intraperitoneally cyclophosphamide, hydrocortisone or immunosuppressive acid glycoprotein (IAP) for 2 days and infected with 103 2TCID of influenza virus. Inosiplex was given orally at the dose of 100mg/kg/day for 14 days from the day after infection. *; p<0.05 Fig. 5 Survival effects of inosiplex on virus challenge in mice pre-sensitized with influenza virus Mice were pre-sensitized with 101.9TCID50 of influenza virus (A) and challenged with 104 2TCID50 of the same virus (A). a): Inosiplex was given for 7 days from the day after sensitization. b): Inosiplex was given for 7 days from the day before challenge. c): Inosiplex was given for 35 days from the day after sensitization. d): Lymphocyteswere separated from influenza virus-sensitized mice 14 days after 7-days treatment. Intact mice were transfered the lymphocytes and then were challenged with the same virus. Control (-), inosiplex 10mg/kg/day, po (-), inosiplex 30mg/kg/day, po (-), inosiplex 100mg/kg/day, po(-).*; p<0.05 Treatment before virus challengea) Treatment after virus challengeb) Continuous treatmentc) Lymphocyte transfer from medicated miced) Days after challenge
7 Fig. 6 Effects of inosiplex on antihemagglutinin and anti-neuraminidase antibody titer in mice Mice were pre-sensitized with 101.9TCID50 of influenza virus (A) and challenged with TCID50 of the same virus (A). Inosiplex was given orally for 7 days from the day after sensitization. Control ( œ- œ), inosiplex 100mg/ kg/day x7, po ( Z- Z).*; p<0.05,**; p<0.01 Days after challenge
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10 13) Aymard-henry, M., Coleman, M.T., Dowdle, W.R., Laver, W.G., Schild, G.C. and Webster, R.G.: Influenzavirus neuraminidase and 1) Muldon, R.L., Mezny, L. & Jackson, G.L.: neuraminidase-inhibition test procedures. Bull. Effect of isoprinosine against influenza and Wld. Hlth. Org., 48: , some other viruses causing respiratory diseases. Antimicrob. Agents Chemother., 2: , ) Gordon, P. & Brown, E.R.: The antiviral 15) Ginsberg, T. & Glasky, A.J.: Inosiplex: An activity of isoprinosine. Can. J. Microbiol., immunomodulation model for the treatment of 18: , ) Chang, T. & Weinstein, L.: Antiviral activity of isoprinosine in vitro and in vivo. Amer. J. Med. Sci., 265: , ) Gordon, P., Ronsen, B. & Brown, E.R.: Anti-herpes virus action of isoprinosine. Antimicrob. Agents Chemother., 5: , ) Waldman, R.H., Khakoo, R.A. & Watson, G.: Isoprinosine: Efficacy against influenza challenge infection in human. Proc. 10th Int. Congr. Chemother., 1977, Vol. 1: , ) Waldman, R.H. & Ganguly, R.: Therapeutic efficacy of inosiplex (isoprinosine) in rhinovirus infection. Ann. N. Y. Acad. Sci., 284: , ) Huttenlocher, P.R. & Mattson, R.H.: Isoprinosine in subacute sclerosing panencephalitis. Neurology, 29: , ) Azulay, R.D. & Azulay, E.: Application of new antiviral, isoprinosine, for herpes simplex and herpes zoster. Rev. Brazil. Med., 32: , ) Gordon, P.: Complex of inosine with dialkylaminoalkanol. U. S. Patent, 3, 646, 007: ) W.H.O. Group on Influenza Nomenclature: A revised system of nomenclature for influenza viruses. Bull. Wld. Hlth. Org., 45: , viral disease. Ann. N. Y. Acad. Sci., 284: , ) Hadden, J.W., Lopez, C., O'Reilly, R.J. & Hadden, E.M.: Levamisole and inosiplex: Antiviral agents with immunopotentiating action. Ann. N. Y. Acad. Sci., 284: , ) Vecchi, A., Sironi, M. & Spreafico, F.: Preliminary characterization in mice of the effect of isoprinosine on the immune system. Cancer Treatment Reports, 62: , ) Wybran, J., Govaerts, A. and Appelboom, T.: Inosiplex, a stimulating agent for normal human T cells and human leukocytes. J. Immunol., 121: , ) Simon, L.N., Settineri, R., Coats, H. and Glasky, A.J.: Isoprinosine: Integration of the antiviral and immunoproliferative effects. Proc. 10th Int. Congr. Chemother., 1977, Vol. 1: , ) Ronsen, B. and Gordon, P.: Methisoprinol enhancement of nucleocyteplasmic transport of putative messenger RNA in rat liver. Its relation to host defense against virus infection. Biochem. Pharmacol., 25: , ) Morris, J.A., Kasel, J.A., Saglam, M., Knight, V. & Loda, F.A.: Immunity to influenza as 11) Karbar, G.: Beitrag zur kollectiven Behandlung pharmakologischer Reihenversuche. Arch. 274: , related to antibody levels. New Engl. J. Med., Exp. Pathol. Pharmacol., 162: , ) Schulman, J.L., Khakpour, M. and Kilbourne, ED.: Protective effects of specific immunity to viral neuraminidase on influenza virus infection of mice. J. Virol., 2: , 1968.
11 Effects of Inosiplex on Viral Growth and Experimental Viral Infections Haruo OHNISHI, Hiroshi KOSUZUME, Hitoshi INABA, Masatsugu OKURA, Shigetoshi SHIMADA, Hideo TAJIMA and Yasuo SUZUKI Tokyo Research Laboratories, Mochida Pharmaceutical Co., Ltd. The effects of inosiplex, an antiviral agent, against viral growth in vitro and on experimental viral infections in vivo were examined. Inosiplex showed a relatively broad antiviral spectrum, inhibiting DNA viruses including herpes simplex virus (HSV) and vaccinia virus as well as RNA viruses including influenza virus (INFV) and parainfluenza virus. The survival of animals infected with a DNA virus (HSV) or an RNA virus (INFV) was increased by the administration of Inosiplex. The anti-infv action was also observed in immunosuppressed mice. The administration of Inosiplex after primary infection conferred strong resistance to secondary infection. This resistance could be passively transferred by transplantation of lymphocytes from Inosiplex-treated donors to susceptible recipients. The protective activity of Inosiplex against secondary INFV infections was also demonstrated when treatment was initiated after the start of the secondary infection. was given both before and after secondary infection. The effect was most striking when the substance Consideration of the above-described activity of Inosiplex, particularly its passive transferability, suggests that Inosiplex can exert its protective action against INFV infections both as a viral growth inhibitor, and as a potentiator of host defenses.
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