In vitro and in vivo sensitivity of a non-mouse-adapted influenza A (Beijing) virus infection to amantadine and ribavirin.
A clinically isolated non-mouse-adapted influenza A/Beijing/32/92 virus was assayed for sensitivity to amantadine and ribavirin in vitro and in mice. When multiple concentrations of each drug were assayed for ability to inhibit the virus-induced cytopathic effect in MDCK cells, the 50% effective (virus-inhibitory) concentration was 0.12 microgram/ml for amantadine and 1.9 micrograms/ml for ribavirin. The 50% cytotoxic concentrations were 25 and 100 micrograms/ml, respectively. It is known that intranasal challenge of mice with high concentrations of non-mouse-adapted influenza virus will induce a toxic pneumonitis in the absence of significant viral replication in the lung. Treatment of such virus-infected mice with approximately 1,250, approximately 625 and approximately 313 mg/kg/day of amantadine in the drinking water resulted in significant inhibition of lung scores and weights and a lessened decline in arterial oxygen saturation (SaO2) in the mice, but virus was in low titer or not recoverable from drug- or placebo-treated animals. Intraperitoneal treatment with 75, 37.5 and 18.8 mg/kg/day of ribavirin given twice daily for 5 days was effective only in preventing SaO2 decline, which contrasts with strong inhibition of infections induced by mouse-adapted viruses seen in other studies. These in vivo data indicate that when non-mouse-adapted influenza virus infections are used to evaluate potential antiviral drugs, false-negative results may be obtained.
Institute for Antiviral Research, Utah State University, Logan 84322-5600, USA.
R W
RW
Sidwell
K W
KW
Bailey
M H
MH
Wong
J H
JH
Huffman
D000547:Amantadine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D009980:Influenza A virus / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D010100:Oxygen / Q000097:blood; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*
D000998:Antiviral Agents; D012254:Ribavirin; D000547:Amantadine; D010100:Oxygen