Low Dose Oral Combination Chemoprophylaxis with Oseltamivir and Amantadine for Influenza a Virus Infections in Mice

Kn, Masihi; Schweiger, Brunhilde; Finsterbusch, Tim; Hengel, Hartmut

doi:10.1179/joc.2007.19.3.295

Cited by 29 publications

(23 citation statements)

References 29 publications

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“…Our data may have suggested a slight benefit of using amantadine against the resistant virus, but the dose used was high and may have had some inhibitory effect. These results are in contrast to the work of Masihi et al (22), who reported that amantadine provided a significant benefit in combination with oseltamivir against influenza A/PR/8/34 (H1N1) amantadine-resistant virus infection. Their virus may need to be verified for purity to determine whether amantadine-sensitive virus particles may also be present.…”

Section: Discussioncontrasting

confidence: 56%

“…A number of animal studies have been published illustrating the value of drug combinations for the treatment of influenza virus infections (9,16,17,20,22,26,28). The present experiments demonstrated that many of the drug interactions were additive or synergistic, particularly in the treatment of the wild-type virus infection.…”

Section: Discussionmentioning

confidence: 55%

“…Combination chemotherapy with the right medications may be the answer to both problems. Investigators over the years have studied various compounds in combination in vitro (10,13,14,21,26) and in mouse models (8,16,17,20,22,26,28) against the H1N1, H3N2, H5N1, and H9N2 strains of influenza viruses. These include the testing of M2 channel blockers amantadine and rimantadine; the neuraminidase inhibitors oseltamivir carboxylate, peramivir, and zanamivir; and the nucleoside analog ribavirin (an inhibitor of influenza virus RNA polymerase [7]).…”

mentioning

confidence: 99%

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

Smee

Hurst

Wong

et al. 2009

Antimicrob Agents Chemother

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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 amantadineresistant 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 oseltamivirribavirin (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.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

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

Smee

Hurst

Wong

et al. 2009

Antimicrob Agents Chemother

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“…The synergistic effect of rimantadine and oseltamivir against H3N2 in mice was characterized by Galabov et al (22). Amantadine, when combined with oseltamivir in laboratory animals, demonstrated enhanced protection as compared to monotherapy against H1N1, H3N2, A/Duck/MN/1525/81 (H5N1) (40,52,80). Peramivir with rimantadine in combination synergistically protected mice infected with H3N2 virus (2) ( Table 3).…”

Section: Combined Therapy With Ribavirinmentioning

confidence: 96%

Chemotherapy of Influenza: Current and Novel Approach

Simeonova

Galabov

2011

Biotechnology & Biotechnological Equipment

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“…Brown et al, unpublished data), with very similar outcomes. Consequently, one would like to administer combination chemotherapy to suppress resistance selection and amplification in a circumstance such as this, as has been done by others (15,23,27,34). We are currently testing this hypothesis and are actively seeking other compounds to form appropriate drug combinations for viral inhibition and resistance suppression.…”

Section: Discussionmentioning

confidence: 99%

In Vitro System for Modeling Influenza A Virus Resistance under Drug Pressure

Brown

McSharry

Weng

et al. 2010

Antimicrob Agents Chemother

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One of the biggest challenges in the effort to treat and contain influenza A virus infections is the emergence of resistance during treatment. It is well documented that resistance to amantadine arises rapidly during the course of treatment due to mutations in the gene coding for the M2 protein. To address this problem, it is critical to develop experimental systems that can accurately model the selection of resistance under drug pressure as seen in humans. We used the hollow-fiber infection model (HFIM) system to examine the effect of amantadine on the replication of influenza virus, A/Albany/1/98 (H3N2), grown in MDCK cells. At 24 and 48 h postinfection, virus replication was inhibited in a dose-dependent fashion. At 72 and 96 h postinfection, virus replication was no longer inhibited, suggesting the emergence of amantadine-resistant virus. Sequencing of the M2 gene revealed that mutations appeared at between 48 and 72 h of drug treatment and that the mutations were identical to those identified in the clinic for amantadine-resistant viruses (e.g., V27A, A30T, and S31N). Interestingly, we found that the type of mutation was strongly affected by the dose of the drug. The data suggest that the HFIM is a good model for influenza virus infection and resistance generation in humans. The HFIM has the advantage of being a highly controlled system where multiplicity parameters can be directly and accurately controlled and measured.

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Low Dose Oral Combination Chemoprophylaxis with Oseltamivir and Amantadine for Influenza a Virus Infections in Mice

Cited by 29 publications

References 29 publications

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

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

Chemotherapy of Influenza: Current and Novel Approach

In Vitro System for Modeling Influenza A Virus Resistance under Drug Pressure

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