Abstract
A Kegin-type polyoxometalate, PM-523, in combination with ribavirin, was tested for its therapeutic effectiveness against influenza virus (FluV) A (H1N1) infection in tissue culture and in mice. PM-523 [(PriNH3)6H [PTi2W10O38(O2)2] x H2O, where Pri is isopropanol] and ribavirin individually inhibited FluV A-induced cytopathic effects in Madin-Darby canine kidney (MDCK) cells at median effective concentrations (EC50s) of 30 and 34 microM, respectively, and at 70% effective concentrations (EC70s) of 48 and 72 microM, respectively. On the other hand, a combination of PM-523 and ribavirin at a ratio of 1:16 exhibited lower EC50s and EC70s than each compound used singly, and combination indices were less than 1. A wide range of combinations of PM-523 and ribavirin at ratios of from 1:128 to 1:1 exhibited additive or synergistic anti-FluV effects in MDCK cells. When these compounds were tested for their anti-FluV A activities in vivo by aerosol exposure of mice which had been infected with a lethal dose of FluV A by an intranasal route, a 1:16 combination of PM-523 and ribavirin was found to have a significantly better therapeutic effect than a single dose of either compound used singly with respect to both the survival rate of the mice and the virus titer in the lungs of the infected mice. PM-523 was effective for the treatment of experimental FluV infection, and in combination with ribavirin, PM-523 exhibited enhanced anti-FluV effects in vitro and in vivo compared with the effect of PM-523 alone.
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- Ablashi D. V., Twardzik D. R., Easton J. M., Armstrong G. R., Luetzeler J., Jasmin C., Chermann J. C. Effects of 5-tungsto-2-antimoniate in oncogenic DNA and RNA virus-cell systems. Eur J Cancer. 1977 Jul;13(7):713–720. doi: 10.1016/0014-2964(77)90058-5. [DOI] [PubMed] [Google Scholar]
- Bartholomeusz A., Tomlinson E., Wright P. J., Birch C., Locarnini S., Weigold H., Marcuccio S., Holan G. Use of a flavivirus RNA-dependent RNA polymerase assay to investigate the antiviral activity of selected compounds. Antiviral Res. 1994 Aug;24(4):341–350. doi: 10.1016/0166-3542(94)90080-9. [DOI] [PubMed] [Google Scholar]
- Berenbaum M. C. What is synergy? Pharmacol Rev. 1989 Jun;41(2):93–141. [PubMed] [Google Scholar]
- Cholewa M., Legge G. J., Weigold H., Holan G., Birch C. J. The use of a scanning proton microprobe to observe anti-HIV drugs within cells. Life Sci. 1994;54(21):1607–1612. doi: 10.1016/0024-3205(94)90032-9. [DOI] [PubMed] [Google Scholar]
- Gilbert B. E., Knight V. Biochemistry and clinical applications of ribavirin. Antimicrob Agents Chemother. 1986 Aug;30(2):201–205. doi: 10.1128/aac.30.2.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ikeda S., Nishiya S., Yamamoto A., Yamase T., Nishimura C., De Clercq E. Activity of the Keggin polyoxotungstate PM-19 against herpes simplex virus type 2 infection in immunosuppressed mice: role of peritoneal macrophage activation. J Med Virol. 1993 Nov;41(3):191–195. doi: 10.1002/jmv.1890410304. [DOI] [PubMed] [Google Scholar]
- Moore P. S., Jones C. J., Mahmood N., Evans I. G., Goff M., Cooper R., Hay A. J. Anti-(human immunodeficiency virus) activity of polyoxotungstates and their inhibition of human immunodeficiency virus reverse transcriptase. Biochem J. 1995 Apr 1;307(Pt 1):129–134. doi: 10.1042/bj3070129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mori S., Watanabe W., Shigeta S. A colorimetric LDH assay for the titration of infectivity and the evaluation of anti-viral activity against ortho- and paramyxoviruses. Tohoku J Exp Med. 1995 Dec;177(4):315–325. doi: 10.1620/tjem.177.315. [DOI] [PubMed] [Google Scholar]
- Take Y., Tokutake Y., Inouye Y., Yoshida T., Yamamoto A., Yamase T., Nakamura S. Inhibition of proliferation of human immunodeficiency virus type 1 by novel heteropolyoxotungstates in vitro. Antiviral Res. 1991 Feb;15(2):113–124. doi: 10.1016/0166-3542(91)90029-q. [DOI] [PubMed] [Google Scholar]
- Wilson S. Z., Gilbert B. E., Quarles J. M., Knight V., McClung H. W., Moore R. V., Couch R. B. Treatment of influenza A (H1N1) virus infection with ribavirin aerosol. Antimicrob Agents Chemother. 1984 Aug;26(2):200–203. doi: 10.1128/aac.26.2.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson S. Z., Knight V., Wyde P. R., Drake S., Couch R. B. Amantadine and ribavirin aerosol treatment of influenza A and B infection in mice. Antimicrob Agents Chemother. 1980 Apr;17(4):642–648. doi: 10.1128/aac.17.4.642. [DOI] [PMC free article] [PubMed] [Google Scholar]