Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1980 Oct;18(4):536–541. doi: 10.1128/aac.18.4.536

Enhancement of activity against influenza viruses by combinations of antiviral agents.

F G Hayden, R G Douglas Jr, R Simons
PMCID: PMC284045  PMID: 7447417

Abstract

In an investigation of alternative therapeutic approaches for the treatment of influenza virus infections, the antiviral activities of rimantadine hydrochloride, amantadine hydrochloride, ribavirin, and combinations of these drugs were assessed in vitro. Madin-Darby canine kidney cell monolayers were inoculated with recent isolates of influenza viruses at low multiplicities of infection, and virus titers were determined after 24 h. The combination of rimantadine and ribavirin resulted in an enhanced antiviral effect (a decrease in virus titer of > 1.0 log10 plaque-forming unit per ml at 24 h relative to the maximal effect of a single drug) against A/USSR/90/77/H1N1, A/Texas/1/77/H3N2, A/New Jersey/76/HSW1N1, and A/PR/834/H0N1 viruses. The degree of inhibition depended on the virus strain used, the drug concentrations, and the virus inoculum. Amantadine and ribavirin showed enhanced activity. Ribavirin in combination with high (50 micrograms/ml), but not low (1.56 to 25 micrograms/ml), concentrations of rimantadine showed an enhanced antiviral effect against B/Hong Kong/72 virus. An assay of Madin-Darby canine kidney cell proliferation in the presence of drugs showed that the enhanced inhibitory effect of drug combinations was not due to increased cytotoxicity.

Full text

PDF
539

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bleidner W. E., Harmon J. B., Hewes W. E., Lynes T. E., Hermann E. C. Absorption, distribution and excretion of amantadine hydrochloride. J Pharmacol Exp Ther. 1965 Dec;150(3):484–490. [PubMed] [Google Scholar]
  2. Browne M. J. Mechanism and specificity of action of ribavirin. Antimicrob Agents Chemother. 1979 Jun;15(6):747–753. doi: 10.1128/aac.15.6.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cochran K. W., Maassab H. F., Tsunoda A., Berlin B. S. Studies on the antiviral activity of amantadine hydrochloride. Ann N Y Acad Sci. 1965 Jul 30;130(1):432–439. doi: 10.1111/j.1749-6632.1965.tb12579.x. [DOI] [PubMed] [Google Scholar]
  4. Cohen A., Togo Y., Khakoo R., Waldman R., Sigel M. Comparative clinical and laboratory evaluation of the prophylactic capacity of ribavirin, amantadine hydrochloride, and placebo in induced human influenza type A. J Infect Dis. 1976 Jun;133 (Suppl):A114–A120. doi: 10.1093/infdis/133.supplement_2.a114. [DOI] [PubMed] [Google Scholar]
  5. Couch R. B., Jackson G. G. Antiviral agents in influenza--summary of Influenza Workshop VIII. J Infect Dis. 1976 Nov;134(5):516–527. doi: 10.1093/infdis/134.5.516. [DOI] [PubMed] [Google Scholar]
  6. GRUNERT R. R., MCGAHEN J. W., DAVIES W. L. THE IN VIVO ANTIVIRAL ACTIVITY OF 1-ADAMANTANAMINE (AMANTADINE). I. PROPHYLACTIC AND THERAPEUTIC ACTIVITY AGAINST INFLUENZA VIRUSES. Virology. 1965 Jun;26:262–269. doi: 10.1016/0042-6822(65)90273-4. [DOI] [PubMed] [Google Scholar]
  7. Galegov G. A., Pushkarskaya N. L., Obrosova-Serova N. P., Zhdanov V. M. Combined action of ribovirin and rimantadine in experimental myxovirus infection. Experientia. 1977 Jul 15;33(7):905–906. doi: 10.1007/BF01951273. [DOI] [PubMed] [Google Scholar]
  8. Greenblatt D. J., DiMascio A., Harmatz J. S., Bernardo D. L., Marder J. E. Pharmacokinetics and clinical effects of amantadine in drug-induced extrapyramidal symptoms. J Clin Pharmacol. 1977 Nov-Dec;17(11-12):704–708. doi: 10.1002/j.1552-4604.1977.tb01545.x. [DOI] [PubMed] [Google Scholar]
  9. Hayden F. G., Cote K. M., Douglas R. G., Jr Plaque inhibition assay for drug susceptibility testing of influenza viruses. Antimicrob Agents Chemother. 1980 May;17(5):865–870. doi: 10.1128/aac.17.5.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Huffman J. H., Sidwell R. W., Khare G. P., Witkowski J. T., Allen L. B., Robins R. K. In vitro effect of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrob Agents Chemother. 1973 Feb;3(2):235–241. doi: 10.1128/aac.3.2.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Larsson A., Stenberg K., Oberg B. Reversible inhibition of cellular metabolism by ribavirin. Antimicrob Agents Chemother. 1978 Feb;13(2):154–158. doi: 10.1128/aac.13.2.154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lubeck M. D., Schulman J. L., Palese P. Susceptibility of influenza A viruses to amantadine is influenced by the gene coding for M protein. J Virol. 1978 Dec;28(3):710–716. doi: 10.1128/jvi.28.3.710-716.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Magnussen C. R., Douglas R. G., Jr, Betts R. F., Roth F. K., Meagher M. P. Double-blind evaluation of oral ribavirin (Virazole) in experimental influenza A virus infection in volunteers. Antimicrob Agents Chemother. 1977 Oct;12(4):498–502. doi: 10.1128/aac.12.4.498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Monto A. S., Gunn R. A., Bandyk M. G., King C. L. Prevention of Russian influenza by amantadine. JAMA. 1979 Mar 9;241(10):1003–1007. [PubMed] [Google Scholar]
  15. NEUMAYER E. M., HAFF R. F., HOFFMAN C. E. ANTIVIRAL ACTIVITY OF AMANTADINE HYDROCHLORIDE IN TISSUE CULTURE AND IN OVO. Proc Soc Exp Biol Med. 1965 Jun;119:393–396. doi: 10.3181/00379727-119-30191. [DOI] [PubMed] [Google Scholar]
  16. Oxford J. S. Inhibition of the replication of influenza A and B viruses by a nucleoside analogue (ribavirin). J Gen Virol. 1975 Sep;28(3):409–414. doi: 10.1099/0022-1317-28-3-409. [DOI] [PubMed] [Google Scholar]
  17. Scholtissek C. Inhibition of influenza RNA synthesis by virazole (ribavirin). Arch Virol. 1976;50(4):349–352. doi: 10.1007/BF01317961. [DOI] [PubMed] [Google Scholar]
  18. Skehel J. J., Hay A. J., Armstrong J. A. On the mechanism of inhibition of influenza virus replication by amantadine hydrochloride. J Gen Virol. 1978 Jan;38(1):97–110. doi: 10.1099/0022-1317-38-1-97. [DOI] [PubMed] [Google Scholar]
  19. Smith C. B., Charette R. P., Fox J. P., Cooney M. K., Hall C. E. Lack of effect of oral ribavirin in naturally occurring influenza A virus (H1N1) infection. J Infect Dis. 1980 May;141(5):548–554. doi: 10.1093/infdis/141.5.548. [DOI] [PubMed] [Google Scholar]
  20. Subak-Sharpe J. H., Timbury M. C., Williams J. F. Rifampicin inhibits the growth of some mammalian viruses. Nature. 1969 Apr 26;222(5191):341–345. doi: 10.1038/222341a0. [DOI] [PubMed] [Google Scholar]
  21. Tobita K., Sugiura A., Enomote C., Furuyama M. Plaque assay and primary isolation of influenza A viruses in an established line of canine kidney cells (MDCK) in the presence of trypsin. Med Microbiol Immunol. 1975 Dec 30;162(1):9–14. doi: 10.1007/BF02123572. [DOI] [PubMed] [Google Scholar]
  22. Togo Y., McCracken E. A. Double-blind clinical assessment of ribavirin (virazole) in the prevention of induced infection with type B influenza virus. J Infect Dis. 1976 Jun;133 (Suppl):A109–A113. doi: 10.1093/infdis/133.supplement_2.a109. [DOI] [PubMed] [Google Scholar]
  23. Wingfield W. L., Pollack D., Grunert R. R. Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man. N Engl J Med. 1969 Sep 11;281(11):579–584. doi: 10.1056/NEJM196909112811102. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES