This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Smee, D. F.
Right arrow Articles by Morrey, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smee, D. F.
Right arrow Articles by Morrey, J. D.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2009, p. 2120-2128, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01012-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effects of Double Combinations of Amantadine, Oseltamivir, and Ribavirin on Influenza A (H5N1) Virus Infections in Cell Culture and in Mice{triangledown}

Donald F. Smee,* Brett L. Hurst, Min-Hui Wong, Kevin W. Bailey, and John D. Morrey

Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah

Received 28 July 2008/ Returned for modification 2 October 2008/ Accepted 20 February 2009

An amantadine-resistant influenza A/Duck/MN/1525/81 (H5N1) virus was developed from the low-pathogenic North American wild-type (amantadine-sensitive) virus for studying treatment of infections in cell culture and in mice. Double combinations of amantadine, oseltamivir (or the cell culture-active form, oseltamivir carboxylate), and ribavirin were used. Amantadine-oseltamivir carboxylate and amantadine-ribavirin combinations showed synergistic interactions over a range of doses against wild-type virus in Madin-Darby canine kidney (MDCK) cell culture, but oseltamivir carboxylate-ribavirin combinations did not. Primarily additive interactions were seen with oseltamivir carboxylate-ribavirin combinations against amantadine-resistant virus. The presence of amantadine in drug combinations against the resistant virus did not improve activity. The wild-type and amantadine-resistant viruses were lethal to mice by intranasal instillation. The resistant virus infection could not be treated with amantadine up to 100 mg/kg body weight/day, whereas the wild-type virus infection was treatable with oral doses of 10 (weakly effective) to 100 mg/kg/day administered twice a day for 5 days starting 4 h prior to virus exposure. Drug combination studies showed that treatment of the amantadine-resistant virus infection with amantadine-oseltamivir or amantadine-ribavirin combinations was not significantly better than using oseltamivir or ribavirin alone. In contrast, the oseltamivir-ribavirin (25- and 75-mg/kg/day combination) treatments produced significant reductions in mortality. The wild-type virus infection was markedly reduced in severity by all three combinations (amantadine, 10 mg/kg/day combined with the other compounds at 20 or 40 mg/kg/day) compared to monotherapy with the three compounds. Results indicate a lack of benefit of amantadine in combinations against amantadine-resistant virus, but positive benefits in combinations against amantadine-sensitive virus.

* Corresponding author. Mailing address: Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322-5600. Phone: (435) 797-2897. Fax: (435) 797-3959. E-mail: don.smee{at}usu.edu

{triangledown} Published ahead of print on 9 March 2009.

Antimicrobial Agents and Chemotherapy, May 2009, p. 2120-2128, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01012-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»