In vitro and in vivo activities of T-705 and oseltamivir against influenza virus.
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has a potent and selective inhibitory activity against influenza virus. We studied the effects of an infectious dose on the anti-influenza virus activities of T-705 and oseltamivir, a commercially available neuraminidase inhibitor, both in vitro and in vivo. Plaque formation of influenza A/PR/8/34 virus was completely inhibited by 10 microg/ml of T-705 after 72 h incubation, whereas visible plaque formation was detected in the plate treated with GS 4071, the active form of oseltamivir (10 microg/ml). The antiviral activity of T-705 was not influenced by an increase in multiplicity of infection (MOI) from 0.0001 to 1, but that of GS 4071 was influenced in a yield reduction assay. No increase in viral yield was seen in either culture supernatant or cells after removal of T-705 (10 microg/ml) but, in contrast, productive infection recurred in culture supernatant and in cells after removal of GS 4071. In mice infected with a high challenge dose of influenza A/PR/8/34 virus, orally administered T-705 (200 and 400 mg/kg/day) completely prevented the death of mice and the survival rates of mice were significantly higher than those in mice treated with oseltamivir (P<0.01). When the treatment was delayed at 1, 13 and 25 h post infection, oral administration of 200 mg/kg of T-705 significantly prevented the death of mice (P<0.01), and the survival rates of mice treated with T-705 were comparable to those of mice treated with oseltamivir. These results suggest that T-705 has the potential to be a potent inhibitor of human influenza virus infections.
Takahashi
Kazumi
K
Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan. KAZUMI_TAKAHASHI@toyama-chemical.co.jp
Furuta
Yousuke
Y
Fukuda
Yoshiko
Y
Kuno
Masako
M
Kamiyama
Tomoko
T
Kozaki
Kyo
K
Nomura
Nobuhiko
N
Egawa
Hiroyuki
H
Minami
Shinzaburo
S
Shiraki
Kimiyasu
K
D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D053139:Oseltamivir; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015996:Survival Rate; D013997:Time Factors
D000081:Acetamides; D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D053139:Oseltamivir; C462182:favipiravir