Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice
Natalia A Ilyushina1, Erich Hoffmann, Rachelle Salomon
1Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.
Background:
The clinical management of H5N1 influenza virus infection in humans remains unclear. Combination chemotherapy with drugs that target different viral proteins might be more effective than monotherapy.
Methods:
BALB/c mice were treated by oral gavage for 5 days with amantadine (1.5, 15 or 30 mg/kg/day) and oseltamivir (1 or 10 mg/kg/day) separately or in combination. Mice were challenged 24 h after initiation of treatment with 10 mouse 50% lethal doses of either amantadine-sensitive (having S31 in the M2 protein) or amantadine-resistant (having N31 in the M2 protein) recombinant A/Vietnam/1203/04 (H5N1) virus.
Results:
Combination treatment with amantadine (15 or 30 mg/kg/day) and oseltamivir (10 mg/kg/day) provided greater protection (60% and 90%, respectively) against lethal infection with amantadine-sensitive H5N1 virus than did monotherapy. Moreover, spread of the virus to the brain was prevented by both combination regimens. The efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Oseltamivir produced a dose-dependent effect against both recombinant H5N1 viruses (P < 0.05) but did not provide complete protection against lethal infection. Importantly, no mutations in the HA, NA and M2 proteins were detected when the two drugs were used in combination.
Conclusions:
Combination chemotherapy provided a survival advantage over single-agent treatment of mice inoculated with neurotropic H5N1 influenza virus. This strategy might be an option for the control of pandemic influenza viruses that are sensitive to amantadine. Combinations that include other drugs should be explored.
Insights
Combination therapy with amantadine and oseltamivir improved survival in mice infected with H5N1 influenza virus. This combination strategy shows promise for controlling pandemic influenza strains sensitive to amantadine.
Area of Science:
- Virology
- Pharmacology
- Infectious Diseases
Background:
- Clinical management of H5N1 influenza virus in humans requires further investigation.
- Combination chemotherapy targeting multiple viral proteins may offer superior efficacy over monotherapy.
Purpose of the Study:
- To evaluate the efficacy of combination therapy using amantadine and oseltamivir against H5N1 influenza virus in a murine model.
- To assess the effectiveness of these drugs against both amantadine-sensitive and amantadine-resistant H5N1 strains.
Main Methods:
- BALB/c mice were administered amantadine and oseltamivir orally, alone or in combination.
- Mice were challenged with amantadine-sensitive or amantadine-resistant recombinant A/Vietnam/1203/04 (H5N1) virus.
Main Results:
- Combination treatment (15 or 30 mg/kg/day amantadine + 10 mg/kg/day oseltamivir) significantly increased survival rates against amantadine-sensitive H5N1 compared to monotherapy.
- Viral spread to the brain was inhibited by combination regimens.
- The efficacy of combination therapy against amantadine-resistant H5N1 was similar to oseltamivir monotherapy.
- Oseltamivir demonstrated a dose-dependent effect but did not achieve complete protection.
- No drug resistance mutations (HA, NA, M2) were detected with combination therapy.
Conclusions:
- Combination chemotherapy provides a survival advantage against neurotropic H5N1 influenza virus in mice.
- This combination approach may be a viable strategy for managing pandemic influenza viruses susceptible to amantadine.
- Further research exploring other drug combinations is warranted.
