Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5′-triphosphate (RTP). Its antiviral effect is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies.

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T-705, a substituted pyrazine compound, has been found to exhibit potent anti-influenza virus activity in vitro and in vivo. In a time-of-addition study, it was indicated that T-705 targeted an early to middle stage of the viral replication cycle but had no effect on the adsorption or release stage. The anti-influenza virus activity of T-705 was attenuated by addition of purines and purine nucleosides, including adenosine, guanosine, inosine, and hypoxanthine, whereas pyrimidines did not affect its activity. T-705-4-ribofuranosyl-5-triphosphate (T-705RTP) and T-705-4-ribofuranosyl-5-monophosphate (T-705RMP) were detected in MDCK cells treated with T-705. T-705RTP inhibited influenza virus RNA polymerase activity in a dose-dependent and a GTP-competitive manner. Unlike ribavirin, T-705 did not have an influence on cellular DNA or RNA synthesis. Inhibition of cellular IMP dehydrogenase by T-705RMP was about 150-fold weaker than that by ribavirin monophosphate, indicating the specificity of the anti-influenza virus activity and lower level of cytotoxicity of T-705. These results suggest that T-705RTP, which is generated in infected cells, may function as a specific inhibitor of influenza virus RNA polymerase and contributes to the selective anti-influenza virus activity of T-705.Influenza is responsible for much morbidity and mortality in the world (7), and effective treatment is required. We now have two classes of drugs for the treatment of influenza, the ion channel blockers and the neuraminidase inhibitors. The ion channel blockers amantadine and rimantadine are of limited use because of a lack of activity against influenza B virus, side effects, and the rapid emergence of resistant virus strains (9). Neuraminidase inhibitors are effective against both influenza A and B viruses, and their usefulness in clinical treatment has been reported (2, 11). Ribavirin is a guanosine analogue and inhibits various RNA and DNA viruses, including influenza viruses (19). Its clinical efficacy against influenza virus after aerosol treatment of infected individuals has been reported (5), but it has been approved for use in only a few countries. Influenza viruses are able to undergo rapid antigenic changes, especially in the surface glycoproteins, and novel influenza virus variants which have high levels of virulence may emerge in the human population and cause severe disease. Therefore, exploration for novel anti-influenza virus agents is of most importance.T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent inhibitory activity against RNA viruses in vitro, especially influenza A, B, and C viruses. The selectivity index (the ratio of the 50% cell-inhibitory concentration [CC 50 ]/50% influenza virus-inhibitory concentration [IC 50 ]) was more than 6,000 (Table 1) (6). T-705 showed therapeutic efficacy in mouse infection models and had a profile different from those of ribavirin and oseltamivir (16).The present study describes an experimental approach to clarifying the mode of action of T-705, and the ...

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC 50 s) of 0.013 to 0.48 g/ml, while it showed no cytotoxicity at concentrations up to 1,000 g/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitorresistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC 50 s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 ؋ 10 2 PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.

A series of pyrazinecarboxamide derivatives T-705 (favipiravir), T-1105 and T-1106 were discovered to be candidate antiviral drugs. These compounds have demonstrated good activity in treating viral infections in laboratory animals caused by various RNA viruses, including influenza virus, arenaviruses, bunyaviruses, West Nile virus (WNV), yellow fever virus (YFV), and foot-and-mouth disease virus (FMDV). Treatment has in some cases been effective when initiated up to 5-7 days after virus infection, when the animals already showed signs of illness. Studies on the mechanism of action of T-705 have shown that this compound is converted to the ribofuranosyltriphosphate derivative by host enzymes, and this metabolite selectively inhibits the influenza viral RNA-dependent RNA polymerase without cytotoxicity to mammalian cells. Interestingly, these compounds do not inhibit host DNA and RNA synthesis and inosine 5'-monophosphate dehydrogenase (IMPDH) activity. From in vivo studies using several animal models, the pyrazinecarboxamide derivatives were found to be effective in protecting animals from death, reducing viral burden, and limiting disease manifestations, even when treatment was initiated after virus inoculation. Importantly, T-705 imparts its beneficial antiviral effects without significant toxicity to the host. Prompt development of these compounds is expected to provide effective countermeasures against pandemic influenza virus and several bioweapon threats, all of which are of great global public health concern given the current paucity of highly effective broad-spectrum drugs.

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Sera from normal subjects were examined for reactivity to human herpesvirus 6 (HHV-6) by the anticomplement immunofluorescence test. Of a total of 179 serum specimens from donors aged from under 10 to 59 years, 141 specimens showed positive reactivity against HHV-6. The positive rate was 70 to 83% for all age groups, and there were no substantial differences in the positive rates. Sera from younger children aged from 0 to 21 months were then examined in detail. The antibody-positive rate of children aged from 0 to 5 months decreased from 52 to 5%, but it gradually increased by 12 months. Almost all children had the antibody against this virus after 13 months of age.

From 1997 to 2006, a total of 48,388 patients with herpes zoster, ranging from a 3-month-old girl to a 102-year-old woman, were monitored at the 46 dermatology clinics in the Miyazaki Prefecture, which has a population of about 1.2 million. The mean herpes zoster incidence was 4.15/1,000 person-years, ranging from 1.96 to 7.84/1,000 person-years among different age groups, and the herpes zoster incidence was significantly higher in females (4.58) than in males (3.67). The incidence by age group was 1.96-2.86/1,000 person-years below the age of 50 years, and it increased to 5.23-7.84/1,000 person-years in persons 50-59 and older, with a trough in the ages 30-39, forming the small and large peaks. Females showed a significantly higher incidence than males, and the difference between the sexes was small below age 40 but greater at 40-49, 50-59, and 60-69. The incidence of herpes zoster was highest in August and lowest in winter, mirroring the prevalence of varicella. The number of herpes zoster cases at 60 years and older increased more than in the population from 1997 to 2006, and this increased incidence of herpes zoster in the 60-69 years and older, especially in females, might have raised the rate in contrast to the stable incidence below the age of 60 years. This large-scale survey clarifies the epidemiology of herpes zoster by age, gender, and season in relation to the prevalence of varicella in the Miyazaki Prefecture in Japan.