CORD-19_Custom_license_subset  

CORD-19:0329e0f2e3b8ab0eabe2afe0e5214cc88c61080e JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 0-181 Sentence denotes Journal Pre-proof Favipiravir, an anti-influenza drug against life-threatening RNA virus infections Favipiravir, an anti-influenza drug against life-threatening RNA virus infections
T2 183-191 Sentence denotes Abstract
T3 194-309 Sentence denotes Acyclovir enabled the first systemic antiviral therapy, and many antiviral agents have subsequently been developed.
T4 310-525 Sentence denotes Acyclovir targets herpes simplex virus and varicella-zoster infection, and individual antiviral agents target one viral infection caused by one virus or two viruses of the same family (Elion, 1982; Shiraki, , 2018 .
T5 526-831 Sentence denotes Among antiviral agents, one of the unique features of favipiravir (T-705) is its broad spectrum activity toward RNA viruses, including influenza virus, rhinovirus, and respiratory syncytial virus, but not DNA viruses, as shown in Fig. 1 (Furuta, et al., 2002; Furuta, et al., 2005; Furuta, et al., 2009) .
T6 832-1149 Sentence denotes Favipiravir shows better efficacy in treating influenza infections than oseltamivir (Tamiflu) (Takahashi, et al., 2003; Tanaka, et al., 2017) , and its efficacy in treating pathogenic avian influenza A(H5N1) and oseltamivir-resistant viruses has been confirmed in animals (Kiso, et al., 2010; Sidwell, et al., 2007) .
T7 1150-1344 Sentence denotes Clinical trials of treatments for seasonal influenza have been performed in Japan and US, and favipiravir was approved as a treatment for novel or re-emerging influenza viruses in Japan in 2014.
T8 1345-1529 Sentence denotes Favipiravir is considered for administration to patients only when the government judges that this drug will be used as a countermeasure against novel or re-emerging influenza viruses.
T9 1530-1692 Sentence denotes The Japanese government and Taiwanese Centers for Disease Control (CDCs) decided to stockpile favipiravir for the people as a countermeasure for severe influenza.
T10 1693-1882 Sentence denotes Favipiravir has been submitted for additional indications for severe fever with thrombocytopenia syndrome (SFTS) based on clinical trials (Yasukawa, 2016) in addition to influenza in Japan.
T11 1883-2130 Sentence denotes against influenza viruses at the cell culture level was confirmed, the use of favipiravir as an anti-influenza drug was confirmed by analyzing its efficacy in animal models of influenza infection, as described below, which led to drug development.
T12 2131-2359 Sentence denotes Favipiravir was effective against other RNA viruses, poliovirus, rhinovirus, and respiratory syncytial virus but not effective against DNA viruses, herpes simplex virus-1, cytomegalovirus, and adenovirus (Furuta, et al., 2002) .
T13 2360-2500 Sentence denotes Based on the antiviral activity toward four RNA viruses, we expected that favipiravir should be active against a broad range of RNA viruses.
T14 2501-2625 Sentence denotes Favipiravir has been evaluated and developed as a broad spectrum anti-RNA virus drug, including lethal RNA virus infections.
T15 2626-2817 Sentence denotes The anti-RNA virus activity of favipiravir was analyzed at the cellular level, and efficacy studies were performed in animal models of human lethal RNA virus infections, as shown in Table 1 .
T16 2818-3129 Sentence denotes Patients with an Ebola virus infection in West Africa in 2014 and patients with other RNA virus infections have been treated with favipiravir (Avigan®) based on the efficacy in human lethal RNA virus infections, clinical experience, efficacy in patients with seasonal influenza, and its licensure for human use.
T17 3130-3216 Sentence denotes We have identified two antipyretic steps in influenza infections, as shown in Fig. 2 .
T18 3217-3347 Sentence denotes Influenza infection and its replication in the epithelium of the upper respiratory tract induce levels in influenza-infected mice.
T19 3348-3476 Sentence denotes Cinnamyl compounds regulate cytokine levels by modulating the amount of NF-κB (Kurokawa, et al., 2003; Kurokawa, et al., 1998) .
T20 3477-3666 Sentence denotes Cinnamyl compounds and clarithromycin increase the levels of IL-12 on day 2 and IFN-γ on day 3 in the bronchoalveolar fluids of mice and decrease the area of pneumonia throughout the lungs.
T21 3667-3932 Sentence denotes The role of IL-12 on day 2 was confirmed through its direct nasal application, and nasal administration of IL-12 reduced the virus yield in the bronchoalveolar fluids from influenza-infected mice (Hama, et al., 2009; Kurokawa, et al., 2002; Tsurita, et al., 2001) .
T22 3933-4090 Sentence denotes Cinnamyl compounds that are mainly derived from medicinal herbs prevent the induction of fever in influenza-infected mice by decreasing the serum IL-1 level.
T23 4091-4330 Sentence denotes In contrast, aspirin suppresses fever by inhibiting hypothalamic cyclooxygenase activity and prostaglandin E 2 production without affecting the high level of IL-1 (Kurokawa, et al., 1996a; Kurokawa, et al., 1996b; Kurokawa, et al., 1998) .
T24 4331-4459 Sentence denotes We have determined two steps of antipyretic action by cinnamyl compounds and NSAIDs in the fever cascade in influenza infection.
T25 4460-4686 Sentence denotes Studies of the efficacy of favipiravir on influenza in animals ha ve been performed in our biosafety level 3 laboratory, and sterile and pyrogen-free distilled water for injections was used for drinking to ensure traceability.
T26 4687-4953 Sentence denotes As we have experience in conducting a pharmacological study for a famciclovir approval application in Japan, the efficacy and validation studies of favipiravir were conducted in mice and ferrets using the influenza infection system described above in our laboratory.
T27 4954-4978 Sentence denotes Tsurita, et al., 2001 ).
T28 4979-5090 Sentence denotes Our animal model for influenza was used to study the efficacy of favipiravir in the influenza-infected animals.
T29 5091-5214 Sentence denotes As favipiravir was effective in cell culture, its effectiveness in animals infected with influenza virus must be confirmed.
T30 5215-5280 Sentence denotes We first observed the prevention of a lethal influenza infection.
T31 5281-5472 Sentence denotes Oral administration of favipiravir was significantly effective in alleviating influenza infection in mice (Furuta, et al., 2002) , and its efficacy was characterized under various conditions.
T32 5473-5711 Sentence denotes We are convinced that favipiravir will be developed as an influenza drug for humans after the confirmation of its therapeutic activity in two species of animals, mice and ferrets, infected with influenza virus. (Takahashi, et al., 2003) .
T33 5712-5927 Sentence denotes Favipiravir and oseltamivir show similar efficacy in low-dose infections, but the efficacy of favipiravir as an influenza drug is clearly increased compared with oseltamivir in high-titer virus infections (Fig. 3) .
T34 5928-6096 Sentence denotes Mice in the control group die on day 3 after a high-dose infection, and an oseltamivir treatment prolongs the survival period for three days but does not prevent death.
T35 6097-6353 Sentence denotes The favipiravir treatment cures lethal infection, and all mice survive. ineffective in this model, favipiravir effectively improves survival in all cases, indicating the importance of administering a drug with a mechanism of action that reduces viral load.
T36 6354-6650 Sentence denotes TNF-α production is induced through recognition of the single-strand RNA or double-strand RNA of the influenza virus genome by Toll-like receptor-7/8 (Yang & Chen, 2012) or 3 (Diebold, et al., 2003; Guillot, et al., 2005; Poux, et al., 2019; Wong, et al., 2009) , respectively, in infected cells.
T37 6651-6844 Sentence denotes Influenza infection induces TNF-α production in mouse macrophage-derived P388D1 cells, and the suppressive effects of favipiravir and oseltamivir were compared in this P388D1 cell-based system.
T38 6845-7016 Sentence denotes Favipiravir significantly suppresses the production of TNF-α in influenza virus-infected P388D1 cells compared with the active form of oseltamivir (Tanaka, et al., 2017) .
T39 7017-7261 Sentence denotes TNF-α appears first and disappears first in P338D1 cells among TNF-α, IL-1, and IL-6 (Kurokawa, et al., 2003) , and we observed a significant reduction in the levels of TNF-α in P388D1 cells and influenza-infected mice treated with favipiravir.
T40 7262-7658 Sentence denotes The antiviral activity of favipiravir has been attributed to a decrease in the pulmonary viral load and TNF-α level in the airways of influenza virus-infected mice compared with oseltamivir, and the reduction in the viral RNA load induced by favipiravir might have resulted in a reduction in TNF-α production and alleviation of lung pathogenesis (Damjanovic, et al., 2011; Tanaka, et al., 2017) .
T41 7659-7803 Sentence denotes Based on these findings, the intracellular viral RNA is less recognized by intracellular Toll-like receptors and results in a decrease in drugs.
T42 7804-7927 Sentence denotes The viral hemagglutinin binds to sialic acid on the cell surface, and the viral particle is incorporated into the endosome.
T43 7928-8146 Sentence denotes When the endosome is acidified and the pH decreases to a value of 5, which is characteristic of the late endosome, the structure of the hemagglutinin changes through a process mediated by the Matrix-2 (M2) ion channel.
T44 8147-8291 Sentence denotes Then, the endosomal membrane and the viral envelope fuse, and the viral genome in the viral particle is released into the cytoplasm (uncoating).
T45 8292-8425 Sentence denotes The viral genome and RdRp complex are transported to the nucleus where the transcription (replication) of viral RNA synthesis begins.
T46 8426-8703 Sentence denotes The synthesized RNA does not contain the Cap structure required for mRNA, and the Cap structure from the host mRNA is excised and transferred to the viral RNA by the Cap-dependent endonuclease of viral RdRp complex, resulting in the formation of the viral mRNA (Cap-snatching).
T47 8704-8770 Sentence denotes After the viral mRNA is produced, the viral protein is translated.
T48 8771-8877 Sentence denotes The viral proteins and RdRp-RNA complex form viral particles that subsequently bud from the cell membrane.
T49 8878-9060 Sentence denotes Hemagglutinin However, influenza A virus becomes resistant, even in an epidemic occurring in a closed facility, and the current influenza A viruses are not susceptible to amantadine.
T50 9061-9165 Sentence denotes Favipiravir inhibits viral RNA synthesis, and therefore viral RNA is not produced in the infected cells.
T51 9166-9425 Sentence denotes The NA inhibitors (NAIs) zanamivir, oseltamivir, peramivir, and laminamivir inhibit the NA activity of viral particles on the surface of the infected cell and the release of viral particles from the cell surface to other cells for the next round of infection.
T52 9426-9539 Sentence denotes NAIs result in the accumulation of viral particles on the cell surface and inhibit the spread of virus infection.
T53 9540-9599 Sentence denotes NAIs are currently the main choice of anti-influenza drugs.
T54 9600-9653 Sentence denotes Cap-dependent endonuclease of the viral RdRp complex.
T55 9654-9857 Sentence denotes Baloxavir inhibits mRNA synthesis and subsequent viral protein synthesis, but genomic RNA without the Cap structure is synthesized by the incorporated RdRp-viral RNA complex in the presence of baloxavir.
T56 9858-9921 Sentence denotes Favipiravir inhibits viral RNA synthesis as a chain terminator.
T57 9922-10270 Sentence denotes This inhibition of genomic RNA synthesis is the most important difference from other anti-influenza drugs, which substantially forms the pool of genomic RNA containing drug-resistant mutants There is a high probability that the resistant virus is already present in the virus that grew rapidly and in large quantities before the start of treatment.
T58 10271-10409 Sentence denotes In addition, the viral RNA formed in the cells in patients treated with anti-influenza drugs serves as a source of drug-resistant viruses.
T59 10410-10539 Sentence denotes Subsequently, drug-resistant influenza viruses should appear more readily from the mutant genomic RNA pool during drug treatment.
T60 10540-10737 Sentence denotes The replication cycle of influenza viruses is approximately 6 hours from entry to the production of new virus, and robust growth begins after infection at a rate of four replication cycles per day.
T61 10738-10919 Sentence denotes The course of influenza virus infection was analyzed in 56 different studies with 1,280 healthy participants after an experimental influenza virus infection (Carrat, et al., 2008) .
T62 10920-11127 Sentence denotes The A(H1N1) and A(H3N2) infections resulted in a substantial increase in viral shedding on the first day after experimental influenza virus infection, and they reached their maximum values on the second day.
T63 11128-11180 Sentence denotes Fever was reported in 34.9% of infected individuals.
T64 11181-11344 Sentence denotes Systemic symptoms (fever, muscle aches, fatigue, and headache) peaked earlier, by day 2 after inoculation, and resolved faster than respiratory or nasal symp toms.
T65 11345-11660 Sentence denotes The presence of a preexisting antibody modified the mean duration of illness of 4.4 days in participants with pre-hemagglutinin inhibition titers of <1/8 compared with 1.0 day in participants with pre-hemagglutinin inhibition titers of >1/8 after the inoculation of a wild-type A(H1N1) virus (Doyle, et al., 1994) .
T66 11661-11914 Sentence denotes Influenza causes dry cough (90%), fever (83.8%), and headache (82.5%), J o u r n a l P r e -p r o o f Journal Pre-proof and immunocompromised patients exhibit a significantly longer length of illness with delayed virus clearance (Memoli, et al., 2014) .
T67 11915-12133 Sentence denotes The mean durations of viral shedding in immunocompromised and non-immunocompromised patients are 19.4 and 6.38 days with median values of 8.0 and 5.0 days, respectively, indicating that viral replication persists for a
T68 12134-12181 Sentence denotes week after the disappearance of major symptoms.
T69 12182-12289 Sentence denotes Preexisting immunity and immunocompetence are important in modifying the severity of symptoms of influenza.
T70 12290-12452 Sentence denotes Seasonal influenza strains that are adapted to humans include A(H1N1), A(H3N2), and B influenza and cause seasonal epidemics of influenza among humans every year.
T71 12453-12700 Sentence denotes Seasonal influenza viruses mainly infect the epithelium of the upper respiratory tract because their hemagglutinins bind to their receptor, sialic acid linked to galactose by an alpha-2,6 linkage that is distributed in the upper respiratory tract.
T72 12701-12865 Sentence denotes Although these strains cause epidemics every year, the susceptibility and severity of illness are modified by the degree of immunity of the host as described above.
T73 12866-12979 Sentence denotes Novel influenza is derived from avian influenza A and is a source of concern as a cause of an influenza pandemic.
T74 12980-13199 Sentence denotes Avian influenza is divided into highly pathogenic avian influenza and low-pathogenicity avian influenza based on the molecular characteristics of the virus and their abilities to cause disease and mortality in chickens.
T75 13200-13348 Sentence denotes Both low-pathogenicity avian influenza and highly pathogenic avian influenza viruses have caused severe and lethal infections in humans (CDC, 2017).
T76 13349-13627 Sentence denotes Since the novel influenza strain is transmitted in the original host bird, the avian receptor is sialic acid linked to galactose by an alpha-2,3 linkage, and this receptor is distributed in respiratory bronchioles and alveolar epithelial cells in humans (Shinya, et al., 2006) .
T77 13628-13946 Sentence denotes Although the name of the influenza virus is common to both seasonal influenza and J o u r n a l P r e -p r o o f Journal Pre-proof novel influenza, a new subtype of influenza causes severe influenza in humans because it is a completely new subtype of virus, and humans have neither a history of infection nor immunity.
T78 13947-14105 Sentence denotes Seasonal influenza mainly infects the upper respiratory tract, while novel influenza causes pneumonia, mainly due to an infection of the pulmonary epithelium.
T79 14106-14237 Sentence denotes Furthermore, unlike the presence of a certain level of immunity to seasonal influenza, immunity does not exist for novel influenza.
T80 14238-14405 Sentence denotes Therefore, the severity of the infection appears to be caused by a prolonged virus growth period and the affinity for the pulmonary epithelium (Shinya, et al., 2006) .
T81 14406-14645 Sentence denotes As described above, novel influenza causes severe diseases, particularly pneumonia, compared to seasonal influenza, and the mortality rate is 53.5% (483/903) for A(H5N1) (Lai, et al., 2016) and 34% (47/137) for A(H7N9) (Li, et al., 2014) .
T82 14646-14724 Sentence denotes Oseltamivir, an NAI, has been the treatment of choice for influenza infection.
T83 14725-15023 Sentence denotes The emergence of a resistant virus (after day 1) was detected in 43/1,207 (3.56%) oseltamivir-treated influenza A-infected patients, with a higher frequency observed in 1-to 5-year-olds (11.8%) than in children aged > 5 years (1.4%), and viral clearance occurred in 8-10 days (Lina, et al., 2018) .
T84 15024-15193 Sentence denotes The overall incidence of an oseltamivir-resistant virus was 10 of 182 (5.5%) (Whitley, et al., 2001) and 9 of 50 (18%) (Kiso, et al., 2004) oseltamivir-treated children.
T85 15194-15272 Sentence denotes Oseltamivir-resistant influenza appears and becomes dominant during treatment.
T86 15273-15389 Sentence denotes Another concern is the prevalence of oseltamivir-resistant strains that was observed during the 2008 to 2009 season.
T87 15390-15627 Sentence denotes Oseltamivir-resistant seasonal A(H1N1) viruses possessing an NA H275Y substitution spread globally, 12.3% (142/1,155) in the US (Dharan, et al., 2009 ), 64% in South Africa, Oceania and SE Asia (Hurt, et al., 2009) , and 20.1% in Europe.
T88 15628-15863 Sentence denotes In particular, a prevalence of 67% (184/272) was observed in Norway, with a gradual increase observed in Europe from approximately 0% in week 19 to 56% in week 40 (Meijer, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2009).
T89 15864-15984 Sentence denotes Thus, once the oseltamivir-resistant virus has adapted to humans, it will become or replace an epidemic virus worldwide.
T90 15985-16219 Sentence denotes Single-dose baloxavir is superior to the placebo in alleviating influenza symptoms and to both oseltamivir and placebo in reducing the viral load 1 day after initiation in patients with uncomplicated influenza (Hayden, et al., 2018) .
T91 16220-16390 Sentence denotes The emergence of baloxavir-resistant mutants with PA/I38X substitutions occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and phase 3 trials, respectively.
T92 16391-16682 Sentence denotes Patients with a substitution at position I38 in the viral polymerase acidic protein (PA/I38X) of the baloxavir-resistant virus exhibited sustained alleviation and virus clearance, and baloxavir-resistant viruses were not cross-resistant to favipiravir and oseltamivir (Omoto, et al., 2018) .
T93 16683-16871 Sentence denotes Baloxavir-resistant viruses were identified after 3-9 days in 9.7% (36/370) of baloxavir-treated immunocompetent adults and adolescents (Uehara, et al., 2019) . (Takashita, et al., 2016) .
T94 16872-17068 Sentence denotes Although the number of cases is limited, 57 pairs might be sufficient to detect a virus resistant to the current anti-influenza drug, suggesting that favipiravir-resistant mutants will not appear.
T95 17069-17328 Sentence denotes Favipiravir alone may maintain its efficacy from the beginning to the end of an influenza pandemic without replacement by resistant strains for J o u r n a l P r e -p r o o f which the effectiveness of drugs is reduced during treatment or during the pandemic.
T96 17329-17401 Sentence denotes An influenza pandemic is a global outbreak of a novel influenza A virus.
T97 17402-17564 Sentence denotes Pandemics occur when novel influenza A viruses emerge that are able to infect people easily and spread from person to person in an efficient and sustained manner.
T98 17565-17743 Sentence denotes Two decades have elapsed since an avian influenza case was reported in Hong Kong in 1997, and a decade has elapsed since the most recent influenza pandemic that occurred in 2009.
T99 17744-17985 Sentence denotes Sporadic cases of A(H5N1) and A(H7N9) influenza infections have been accumulating, and we must prepare for these strains or other novel influenza strains that might progress to an influenza pandemic and spread globally, such as A(H1N1)pdm09.
T100 17986-18324 Sentence denotes Influenza pandemics can cause severe pneumonia, Favipiravir is significantly more effective in treating mice with severe influenza infections characterized by a high viral load than oseltamivir (Takahashi, et al., 2003) , and a J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir-resistant virus does not emerge during treatment.
T101 18325-18526 Sentence denotes This outstanding feature of favipiravir as an anti-influenza drug has been exploited in treating patients with severe influenza in combination with oseltamivir in China (Cao, 2018; Wang et al., 2019) .
T102 18527-18661 Sentence denotes Favipiravir and oseltamivir combination therapy accelerated clinical recovery compared to oseltamivir monotherapy in severe influenza.
T103 18662-18915 Sentence denotes The dose of favipiravir used in the study mentioned above was 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 9 days, and the approved favipiravir dose in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days.
T104 18916-19032 Sentence denotes The viral replication period is 6 days or longer for seasonal influenza (Lina, et al., 2018; Memoli, et al., 2014) .
T105 19033-19175 Sentence denotes When drug administration is stopped during the virus replication period or when resistant strains appear, virus replication and fever relapse.
T106 19176-19428 Sentence denotes Thus, 10 days of administration may be required for severe influenza or novel influenza. whether the next pandemic will occur are difficult to determine, but researchers are currently concerned about the A(H5N1) and A(H7N9) strains with high lethality.
T107 19429-19550 Sentence denotes When these strains adapt to humans and become pandemic, their pathogenicity may be milder, similar to previous pandemics.
T108 19551-19670 Sentence denotes If an influenza pandemic causes severe disease, it may cause substantial damage to human health and social dysfunction.
T109 19671-19739 Sentence denotes The need for pandemic countermeasures is an important consideration.
T110 19740-19904 Sentence denotes Favipiravir has a broad spectrum of activity toward RNA viruses, including life-threatening RNA viruses, and exhibits efficacy in animal models of these infections.
T111 19905-19989 Sentence denotes Table 1 summarizes the efficacy of favipiravir in animal models of human infections.
T112 19990-20270 Sentence denotes Based on the efficacy in animal models, it ha s been used to treat humans with diseases such as Ebola virus infection (Bai, et al., 2016; Jacobs, et al., 2015; Sissoko, et al., 2016) , Lassa fever (Raabe, et al., 2017) , norovirus (Ruis, et al., 2018) , and rabies (Baker, 2017) .
T113 20271-20441 Sentence denotes Notably, as a broad spectrum anti-RNA virus drug, favipiravir has been submitted for additional indications for SFTS in Japan, based on clinical trials (Yasukawa, 2016) .
T114 20442-20768 Sentence denotes The broad spectrum of activity of favipiravir toward RNA viruses has been reviewed, including anti-RNA virus activity in vitro and in vivo in animal models (Delang, Abdelnabi, prophylaxis (PEP) was shown in a mouse model (Smither, et al., 2014) and a therapeutic mouse model of Ebola virus disease (Oestereich, et al., 2014) .
T115 20769-20990 Sentence denotes Treatment with favipiravir from 6 to 13 days after lethal infection with Ebola virus cured all mice when the treatment was started at the initiation of liver damage (elevation of AST and ALT) and virus detection in blood.
T116 20991-21142 Sentence denotes However, the administration of favipiravir from 8 to 14 days prolonged survival, but four of five mice died when the liver damage and viremia advanced.
T117 21143-21415 Sentence denotes Early treatment with favipiravir was effective, but when the disease is advanced, including liver damage, the efficacy in prolonging survival is limited to one of five mice, indicating that treatment should be started before liver damage progresses to irreversible levels.
T118 21416-21607 Sentence denotes Thus, favipiravir may be able to cure an Ebola virus infection in the early phase of infection, but the curative activity of favipiravir may be limited in patients with an advanced infection.
T119 21608-21812 Sentence denotes The dose of favipiravir used to treat a human with an Ebola virus infection is 6,000 mg on the first day and 2,400 mg/day on days 1-9 for a total of 27,600 mg when administered for both PEP and treatment.
T120 21813-22108 Sentence denotes Four of eight health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, were administered PEP with favipiravir alone or favipiravir with other anti-Ebola agents and did not develop Ebola virus disease (Jacobs, et al., 2015) .
T121 22109-22350 Sentence denotes Although the needle stick had not been confirmed to result in infection, the probability of infection was high based on previous observations, and PEP was considered effective, as observed in PEP using a mouse model (Smither, et al., 2014 ).
T122 22351-22492 Sentence denotes An Ebola study conducted in Guinea included 126 patients, and 111 were analyzed and compared with 540 patients as a historical control group.
T123 22493-22759 Sentence denotes Favipiravir treatment reduced the mortality rate in the low viral load group to 33% compared with the historical control group that was not treated with favipiravir, but this reduction in the mortality rate was not statistically significant (Sissoko, et al., 2016) .
T124 22760-22822 Sentence denotes An Ebola study conducted in Sierra Leone (Bai, et al., 2016) .
T125 22823-23218 Sentence denotes During the 2014 epidemic of Ebola virus infection in West Africa, patients who were treated without favipiravir in the period before preparation for favipiravir treatment were classified as historical controls, and the therapeutic efficacy of favipiravir was compared between the patient group treated with favipiravir and the historical patient group in the two clinical trials described above.
T126 23219-23468 Sentence denotes Randomized placebo-controlled trials are desirable for confirming therapeutic effects in clinical trials, but the placebo group has an ethical problem of not being able to receive an effective drug that can recover fatal infections in animal models.
T127 23469-23763 Sentence denotes The studies were conducted to compare the effectiveness of favipiravir treatment between patients who were not treated in the period prior to the start of drug administration as the historical control patient group and those who were treated with favipiravir after the clinical study was ready.
T128 23764-23917 Sentence denotes The number of patients is limited, and favipiravir has been used as an emergency or compassionate treatment for Lassa fever, norovirus, and rabies cases.
T129 23918-24015 Sentence denotes This review focuses on human administration in terms of the broad spectrum of RNA virus activity.
T130 24016-24151 Sentence denotes Therefore, favipiravir has been positioned as a valuable anti-influenza drug and a broad spectrum anti-RNA drug, as listed in Table 1 .
T131 24152-24390 Sentence denotes Favipiravir has been used in human therapy for Ebola hemorrhagic fever (Jacobs, et al., 2015; Sissoko, et al., 2016) , Lassa fever (Raabe, et al., 2017) , norovirus (Ruis, et al., 2018) , rabies (Baker, 2017) , and SFTS (Yasukawa, 2016) .
T132 24391-24487 Sentence denotes Some treatments were used in emergencies, and some were used in the setting of a clinical trial.
T133 24488-24805 Sentence denotes In addition, combination therapy of favipiravir with the other existing therapies is also an option and favipiravir and oseltamivir combination therapy showed accelerated clinical recovery J o u r n a l P r e -p r o o f compared to oseltamivir monotherapy in severe influenza in China (Cao, 2018; Wang et al., 2019) .
T134 24806-25056 Sentence denotes The antiviral activity (EC 50 ) of favipiravir against influenza and Ebola viruses is different from the range of 0.014-0.55 μg/mL in medium without adenosine and guanosine and 10 μg/mL, respectively (Furuta, et al., 2002; Oestereich, et al., 2014) .
T135 25057-25248 Sentence denotes Addition of 10 x EC 50 (63.7 μM) of adenine, guanine, adenosine, guanosine, and inosine in the assay medium abolishes the anti-influenza virus activity of favipiravir (Furuta, et al., 2005) .
T136 25249-25567 Sentence denotes The intracellular concentration of ATP is 1-9 mM in various tissues (Beis & Newsholme, 1975 The approved favipiravir dose for influenza in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days, and the dose for Ebloa virus infection is 6,000 mg on the first day and 2,400 mg/day on days 1-9.
T137 25568-25845 Sentence denotes The antiviral concentration of favipiravir in influenza is achieved in the lung epithelium by diffusion from the blood, and in the case of Ebola virus infection, direct perfusion of blood reaches target tissues, vascular endothelial cells, hematopoietic cells, and hepatocytes.
T138 25846-25981 Sentence denotes Differences in the two factors between antiviral concentrations and target cells do not appear to be significantly reflected in dosage.
T139 25982-26072 Sentence denotes Intravenous preparations are being prepared to improve oral administration of favipiravir.
T140 26073-26121 Sentence denotes J o u r n a l P r e -p r o o f Journal Pre-proof
T141 26122-26272 Sentence denotes Favipiravir inhibits viral RdRp by terminating elongation at the incorporation site as a chain terminator (Jin, et al., 2013; Sangawa, et al., 2013) .
T142 26273-26416 Sentence denotes Favipiravir functions as a purine analogue, as expected from the chemical structure, and it is incorporated instead of guanosine and adenosine.
T143 26417-26700 Sentence denotes Favipiravir terminates elongation after the incorporation of a single favipiravir molecule (Sangawa, et al., 2013) and after the incorporation of two consecutive favipiravir molecules (Jin, et al., 2013) , and the synthesis of this complementary viral RNA strand cannot be completed.
T144 26701-26882 Sentence denotes In contrast, the anti-RNA virus drug ribavirin is incorporated into the replicating strand, which further elongates and accumulates mismatched nucleotides at the incorporated sites.
T145 26883-27114 Sentence denotes Base pairing with ribavirin in the complementary strand during replication, transcription, and translation of the RNA strand causes mismatched base pairing, the production of nonfunctional proteins, and a loss of viral infectivity.
T146 27115-27320 Sentence denotes Accumulated mutations (mismatched nucleotides) cause the replicated viruses to lose their replicative capability, which is known as "lethal mutagenesis" (Vignuzzi, Stone, & Andino, 2005) , as shown in Fig.
T147 27322-27445 Sentence denotes RdRp that affect ribavirin incorporation are produced, drug-resistant viruses can be selected in the presence of ribavirin.
T148 27446-27843 Sentence denotes Favipiravir treatment increases the frequency of transition (Delang, et al., 2014; Goldhill, et al., 2019; Vanderlinden, et al., 2016) and transversion (Baranovich, et al., 2013) in viral genomes, and these mutations are hypothesized to be caused by favipiravir, resulting in lethal mutagenesis (Baranovich, et al., 2013; Delang, et al., 2014; Goldhill, et al., 2019; Vanderlinden, et al., 2016) .
T149 27844-28189 Sentence denotes We observed a transition of influenza virus and poliovirus in cultures treated with favipiravir but did not assess the frequency because we were unable to J o u r n a l P r e -p r o o f Journal Pre-proof compare the transition rate with the proper antiviral agents with similar mechanisms as a control Daikoku, Yoshida, Okuda, & Shiraki, 2014) .
T150 28190-28258 Sentence denotes Ribavirin is known to cause lethal mutagenesis, as shown in Fig. 5 .
T151 28259-28426 Sentence denotes Ribavirin is incorporated into the elongating RNA strand, resulting in the production of multiple mismatches that lead to lethal mutagenesis (Vignuzzi, et al., 2005) .
T152 28427-28630 Sentence denotes Favipiravir inhibits RNA synthesis through chain termination, and this inhibitory mechanism more consistently explains the observations reported than a mechanism similar to ribavirin, as described below.
T153 28631-28824 Sentence denotes Favipiravir-4-ribofuranosyl-5'-triphosphate (RTP) has a higher affinity for the RdRp of influenza virus than GTP and functions as a chain terminator (Jin, et al., 2013; Sangawa, et al., 2013) .
T154 28825-29014 Sentence denotes Favipiravir-RTP and ribavirin TP inhibit the RdRp activity in a dose-dependent manner, with 50% inhibitory concentrations (IC 50 s) of 0.14 and 2.4 μM, respectively (Furuta, et al., 2005) .
T155 29015-29123 Sentence denotes The RdRp activity was determined by measuring the incorporation of labeled GTP in the elongating RNA strand.
T156 29124-29287 Sentence denotes Favipiravir-RTP has a higher affinity for RdRp than GTP, and when incorporated, favipiravir-RTP stops the elongation of the RNA strand in which it is incorporated.
T157 29288-29435 Sentence denotes This termination prevents the incorporation of radioactivity, and thus favipiravir-RTP exhibits high inhibitory activity and a low IC 50 (0.14 μM).
T158 29436-29659 Sentence denotes On the other hand, ribavirin induces competitive inhibition with GTP, and incorporation results in mismatch mutations; the strand continues to elongate and incorporate labeled GTP without stopping at the incorporation site.
T159 29660-29786 Sentence denotes Thus, ribavirin has a high IC 50 value (2.4 μM) because its RNA strand is further elongated by incorporating radiolabeled GTP.
T160 29787-29907 Sentence denotes Therefore, its ability to inhibit enzyme activity becomes weaker, and it displays a higher IC 50 value than favipiravir.
T161 29908-30094 Sentence denotes Furthermore, a marked decrease in the amount of the viral genome has been observed in favipiravir-treated cultures compared with ribavirin-treated cultures (Vanderlinden, et al., 2016) .
T162 30095-30386 Sentence denotes Favipiravir is incorporated into the viral genome and terminates elongation, resulting in shorter genome sizes and the marked loss of the viral genome in favipiravir-treated cultures J o u r n a l P r e -p r o o f Journal Pre-proof (Rocha-Pereira, et al., 2012; Vanderlinden, et al., 2016) .
T163 30387-30481 Sentence denotes These observations are consistently explained by the chain termination induced by favipiravir.
T164 30482-30681 Sentence denotes Proofreading activity mediated by enzymes such as the 3'-5' exonuclease of herpesvirus DNA polymerase removes the terminal mismatched base and corrects the base pairing during the elongation process.
T165 30682-30826 Sentence denotes Viral RdRp lacks proofreading activity and is unable to complete the elongation step when favipiravir-RTP is incorporated as a chain terminator.
T166 30827-30945 Sentence denotes Coronavirus has been reported to expresses a 3'-to-5'exoribonuclease and its proofreading function among RNA viruses .
T167 30946-31116 Sentence denotes Acyclovir causes chain termination at the incorporated site during the elongation of herpes simplex virus and varicella-zoster virus DNA and prevents viral DNA synthesis.
T168 31117-31253 Sentence denotes However, the incorporated acyclovir is removed by the proofreading activity of viral DNA polymerase, and viral DNA elongation continues.
T169 31254-31736 Sentence denotes Therefore, the sequence containing the guanosine homopolymeric string (G-string) in the genome is the target of the incorporation and removal of acyclovir, and the incorporation of guanosine followed by repeated corrections by the proofreading machinery create a hot spot of mutations in G-strings of our laboratory and clinical acyclovir-resistant isolates (Akahoshi, et al., 2017; Daikoku, et al., 2016; Ida, et al., 1999; Shimada, et al., 2007; Talarico, Phelps, & Biron, 1993) .
T170 31737-32053 Sentence denotes Penciclovir (famciclovir) and ganciclovir (valganciclovir), which are guanosine analogues, function as an anti-herpes simplex virus and varicella-zoster virus agent and anti-cytomegalovirus agent, respectively, with mechanisms similar to acyclovir, but they do not induce mutations or have hot spots in the G-string.
T171 32054-32216 Sentence denotes These compounds do not prevent elongation at the incorporation site but are incorporated, and elongation pauses at normal nucleotides after the incorporated site.
T172 32217-32534 Sentence denotes Therefore, mutations associated with proofreading do not occur in the G-string, and this J o u r n a l P r e -p r o o f difference in the mode of chain termination and proofreading activity causes a lower mutation frequency in subjects treated with penciclovir and ganciclovir than in subjects treated with acyclovir.
T173 32535-32766 Sentence denotes If favipiravir induces mismatches as a mutagen, favipiravir should allow elongation after its incorporation into the elongating RNA strand and induce mismatches at the favipiravir-incorporated sites in the new complementary strand.
T174 32767-32856 Sentence denotes This possibility is inconsistent with the mechanism of favipiravir as a chain terminator.
T175 32857-33080 Sentence denotes Thus, the increased mutation rates observed in response to favipiravir treatment are unlikely to be due to the incorporation of favipiravir into viral RNA followed by elongation, similar to ribavirin or acyclovir (Fig. 5) .
T176 33081-33215 Sentence denotes Favipiravir is unlikely to induce mismatches upon its incorporation into the RNA strand and transitions in the influenza virus genome.
T177 33216-33437 Sentence denotes The increased rate of transition mutations observed after favipiravir treatment is presumed to be due to the biased nucleotide pool induced by the increase in the level of favipiravir-RTP and the properties of viral RdRp.
T178 33438-33572 Sentence denotes A biased nucleotide pool is a major factor that promotes polymerase-induced mutation synthesis (Wheeler, Rajagopal, & Mathews, 2005) .
T179 33573-33715 Sentence denotes Influenza RdRp complex is composed of PB1, PB2, and PA and requires four nucleotides, ATP, GTP, CTP, and UTP, as substrates for RNA synthesis.
T180 33716-33967 Sentence denotes Influenza RdRp incorporates mismatched nucleotides in a primer-extension-based misincorporation assay in the presence of completely biased nucleotide pools consisting of only three nucleotides instead of all four nucleotides (Aggarwal, et al., 2010) .
T181 33968-34126 Sentence denotes Even if one of the four nucleotides is missing, its absence is compensated by other nucleotides, and the RNA strand continues to elongate, causing mismatches.
T182 34127-34286 Sentence denotes Therefore, even in the absence of a mutagen, mismatches should occur during RNA synthesis under biased nucleotide pool conditions as if the mutagen is present.
T183 34287-34535 Sentence denotes Influenza RdRp displays a significantly higher fidelity than human immunodeficiency virus-1 reverse transcriptase and T7 RNA polymerase and an equivalent or higher fidelity than murine leukemia virus reverse transcriptase (Aggarwal, et al., 2010) .
T184 34536-35024 Sentence denotes The mutation frequency of influenza RdRp is 7.06 x 10 -4 nucleotides in wild-type H3N2 virus (Cheung, et al., 2014 ) and > 7.26 x 10 -5 nucleotides deduced from 108 sequenced clones of an average of 849 bases from the database (Drake, 1993) , and these values are much larger than those of herpesvirus DNA polymerases with proofreading activity at the levels of 1.38 x 10 -7 per nucleotide (Lee, et al., 2015) to 3 x 10 -9 substitutions per site per year (McGeoch, Dolan, & Ralph, 2000) .
T185 35025-35129 Sentence denotes These results indicate the low fidelity of the RdRp activity of influenza lacking proofreading activity.
T186 35130-35329 Sentence denotes Jurkat cells exposed to 500 μM guanosine for 24 h show an increase in GTP pools to 600% of the control and a decrease in ATP to 40% of the control (Batiuk, Schnizlein-Bick, Plotkin, & Dagher, 2001) .
T187 35330-35519 Sentence denotes Thus, the intracellular condition of biased nucleotide pools alone is sufficient to increase the ratios of mismatched transition mutations without treatment with mutagens such as ribavirin.
T188 35520-35700 Sentence denotes Ribavirin reduces GTP levels by inhibiting inosine monophosphate dehydrogenase, but favipiravir has little effect on GTP levels (Furuta, et al., 2005; Vanderlinden, et al., 2016) .
T189 35701-35943 Sentence denotes As a guanosine analogue, extracellular favipiravir may bias the nucleotide pools, and favipiravir-RTP competes with GTP or ATP, resulting in an increase in the transition mutations, although data are not available to support this speculation.
T190 35944-36158 Sentence denotes An observed increase in the transition frequency is presumed to be due to the low fidelity of RdRp of influenza virus and misincorporation of nucleotides by the biased nucleotide pools in favipiravir-treated cells.
T191 36159-36364 Sentence denotes Favipiravir is a chain terminator without direct mutagenic activity but increases the number of mismatches in the genome due to the induction of biased nucleotide pools in the favipiravir-treated cultures.
T192 36365-36385 Sentence denotes Journal Pre-proof 7.
T193 36386-36415 Sentence denotes Favipiravir-resistant mutants
T194 36416-36962 Sentence denotes We have isolated a herpes simplex virus resistant to acyclovir, phosphonoacetic acid, and foscarnet, a varicella-zoster virus resistant to acyclovir, penciclovir, foscarnet, and vidarabine, and a cytomegalovirus resistant to ganciclovir, foscarnet, and mizoribine by culturing the virus in the presence of these antiviral agents (Ida, et al., 2000; Ida, et al., 1999; Kamiyama, Kurokawa, & Shiraki, 2001; Kuramoto, et al., 2010; Kurosaki, et al., 2004; Miwa, et al., 2005; Mori, et al., 1988; Shiraki, Ogino, Yamanishi, & Takahashi, 1983 , 1985 .
T195 36963-37065 Sentence denotes These resistant viruses replace the virus population in the presence of drug in vitro and in patients.
T196 37066-37254 Sentence denotes The emergence and replacement of resistant strains occurs in the herpetic lesions in immunocompromised individuals when a lesion with viral growth is treated for at least one or two weeks.
T197 37255-37448 Sentence denotes An oseltamivir-or baloxavir marboxil (baloxavir)-resistant virus has emerged in patients with seasonal influenza during treatment, and the isolated virus has been replaced by a resistant virus.
T198 37449-37518 Sentence denotes A subsequent new infection by the resistant virus has been confirmed.
T199 37519-37756 Sentence denotes Therefore, we investigated the possibility that a favipiravir-resistant virus appeared in cultured cells while influenza virus was growing in the presence of favipiravir and that the proliferating virus was replaced by a resistant virus.
T200 37757-38102 Sentence denotes We tried to isolate favipiravir-resistant influenza virus and poliovirus from 28 and 10 25 cm 2 flasks, respectively, after independent cultures in the presence of increasing concentrations of favipiravir for a month, but no resistant virus was isolated (Daikoku, et al., J o u r n a l P r e -p r o o f Journal Pre-proof Daikoku, et al., 2014) .
T201 38103-38184 Sentence denotes Then, we decided to deny the possibility of replacement with the resistant virus.
T202 38185-38363 Sentence denotes Spontaneous mutation rates of the influenza virus RdRp complex and poliovirus 3D RdRp are both approximately 1 x 10 -4 (Cheung, et al., 2014; Drake, 1993; Gubareva & Fry, 2019) .
T203 38364-38656 Sentence denotes Titers of influenza virus and poliovirus in the culture reach approximately 10 8 viral particles/mL in 5 mL of media in a 25 cm 2 flask, and their genomes contain approximately 13,600 and 7,500 base pairs, respectively, stochastically indicating 10 4 alterations per nucleotide in the genome.
T204 38657-38826 Sentence denotes Therefore, every type of mutant should be generated during replication, and continuous cultivation for a month might increase the favipiravir-resistant virus population.
T205 38827-39032 Sentence denotes If favipiravir induces mutations more frequently than natural processes, mutants resistant to favipiravir should be isolated easily, and the culture should be replaced by the favipiravir-resistant mutants.
T206 39033-39339 Sentence denotes We isolated susceptibility variants of influenza virus and poliovirus in the cultures treated with favipiravir for a month and identified nucleotide substitutions (mutations) in their RdRp genes, but these mutations were not related to resistance or mutations common to favipiravir Daikoku, et al., 2014) .
T207 39340-39503 Sentence denotes Therefore, theoretical resistant mutants should be generated but are unable to replicate or replicate with reduced fidelity to replace the entire virus population.
T208 39504-39761 Sentence denotes The favipiravir-resistant mutant replicates as an artificially generated clone but does not become dominant among the entire virus population that grows in the presence of favipiravir (Abdelnabi, et al., 2017; Delang, et al., 2014; Goldhill, et al., 2019) .
T209 39762-39883 Sentence denotes Our results are consistent with the absence of a resistant virus in the entire virus population treated with favipiravir.
T210 39884-39997 Sentence denotes Many laboratories have attempted to isolate favipiravir-resistant influenza viruses but have not been successful.
T211 39998-40239 Sentence denotes Recently, mutants of influenza virus (Goldhill, et al., 2018) and chikungunya virus (Abdelnabi, et al., 2017; Delang, et al., 2014) that are less susceptible to J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir have been reported.
T212 40240-40472 Sentence denotes Mutated sequences of these viruses have been detected in cultures treated with favipiravir, and reverse-engineered viruses showed favipiravir resistance with altered RdRp activity related to the fidelity and reduced growth property.
T213 40473-40717 Sentence denotes The K229R mutation in motif F of the PB1 gene was observed in the virus population cultivated in the presence of favipiravir, and a virus with the K229R mutation was created by reverse engineering and confirmed as a favipiravir-resistant virus.
T214 40718-40838 Sentence denotes However, the virus was artificially produced and grown as a clone and is not considered a dominant virus in the culture.
T215 40839-40944 Sentence denotes A K229R mutation in P1 shows reduced polymerase activity and acquired P653L in the PA during replication.
T216 40945-41083 Sentence denotes The acquisition of the additional PA P653L mutation restores the polymerase activity and favipiravir resistance (Goldhill, et al., 2018) .
T217 41084-41374 Sentence denotes The K291R mutation in the F1 motif of the RdRp (nsP4) in chikungunya virus is less susceptible to favipiravir, displays a reduced growth property and acquired an additional Y543C mutation in the helicase-protease (nsP2) during passages in the absence of favipiravir (Delang, et al., 2014) .
T218 41375-41613 Sentence denotes The corresponding K-to-R substitution (K159R) of the chikungunya virus K291R mutation was introduced in the coxsackievirus B3 RdRp, but the engineered virus with the K159R mutation in RdRp was a nonviable virus (Abdelnabi, et al., 2017) .
T219 41614-41741 Sentence denotes The replication competence of the K159R variant is restored by the additional acquisition of an A239G substitution in the RdRp.
T220 41742-41884 Sentence denotes The variant virus with the K159R and K291R mutations is more susceptible to favipiravir and exhibited lower fidelity than the wild-type virus.
T221 41885-42094 Sentence denotes A common feature of less susceptible viruses is high fidelity of RdRp that may distinguish favipiravir-RTP and GTP and replicate in the presence of favipiravir by avoiding the incorporation of favipiravir-RTP.
T222 42095-42478 Sentence denotes Since their proliferative ability is not high, clones that are less susceptible to favipiravir grow well alone or are not viable, but an additional alteration that modulates RdRp activity restores the replication capability and the susceptibility to favipiravir (Abdelnabi, et al., 2017; Delang, et al., 2014; Goldhill, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2019).
T223 42479-42625 Sentence denotes Favipiravir-resistant mutants of influenza virus have been created by reverse-engineering and replicate as a clone with a reduced growth property.
T224 42626-42799 Sentence denotes Therefore, this virus is unlikely to replace the entire growing virus population when it is produced during favipiravir treatment, as has been observed in many laboratories.
T225 42800-43093 Sentence denotes Two highly pathogenic A(H5N1) influenza viruses from chicken and Muscovy duck and one H3 influenza virus from ruddy turnstone and two swine (H1N1) origin influenza viruses possess the PB1-V43I mutation that may result in a high-fidelity RdRp but has not been confirmed (Cheung, et al., 2014) .
T226 43094-43247 Sentence denotes Thus, researchers should consider the possibility of changes in the susceptibility to favipiravir when these types of influenza viruses cause a pandemic.
T227 43248-43420 Sentence denotes Antiviral susceptibility was examined in 57 pairs of influenza viruses isolated from patients before and after the administration of favipiravir in phase 3 clinical trials.
T228 43421-43519 Sentence denotes No viruses displayed reduced susceptibility to favipiravir, although two of 20 paired A(H1N1)pdm09
T229 43520-43727 Sentence denotes isolates, one of 17 paired A(H3N2) isolates and one of 20 paired B viruses possessed amino acid substitutions in the RdRp subunits PB1, PB2 and PA after favipiravir administration (Takashita, et al., 2016) .
T230 43728-43892 Sentence denotes These amino acid substitutions in the RdRp had nothing to do with the susceptibility of favipiravir and seemed to have occurred regardless of favipiravir treatment.
T231 43893-44201 Sentence denotes This trial was a limited clinical study to assess the emergence of favipiravir-resistant virus, but the appearance of oseltamivir or baloxavir resistance might be observed in clinical trials of influenza treatment with oseltamivir and baloxavir with a similar number of patients, as described in Section 4.3.
T232 44202-44555 Sentence denotes The lack of the emergence and replacement of resistant viruses during favipiravir treatment in vitro and in humans indicates that the same effectiveness of favipiravir is expected to be maintained from the beginning to the end of the J o u r n a l P r e -p r o o f Journal Pre-proof influenza pandemic and that all patients could be treated effectively.
T233 44556-44669 Sentence denotes Causes of death from severe infections may be liver failure, renal failure, respiratory failure and encephalitis.
T234 44670-44891 Sentence denotes Ebola virus infection seemed to be difficult for patients when they had the chance of infection or fever after infection, and the amount of virus was used as an indicator of the time of infection (Sissoko, et al., 2016) .
T235 44892-44990 Sentence denotes Renal function represented by creatinine levels was found to be an important factor for prognosis.
T236 44991-45183 Sentence denotes The factor that determines survival and death rate with favipiravir treatment seems to be residual organ function at the start of treatment in fatal infections caused by cytotoxic RNA viruses.
T237 45184-45319 Sentence denotes The residual function necessary for the recovery of each organ can be estimated from the indication criteria for organ transplantation.
T238 45320-45511 Sentence denotes One of the criteria for lung function for lung transplant patients is a forced expiratory volume in 1 second (FEV1) less than 25-30% (Maurer, Frost, Estenne, Higenbottam, & Glanville, 1998) .
T239 45512-45678 Sentence denotes Concerning renal function, hemodialysis starts when renal function falls to 10-15%, and death occurs within one to several weeks when dialysis is stopped (NKF, 2019).
T240 45679-45913 Sentence denotes Concerning liver function, the donor 's liver is left as a residual liver volume of at least 30% of the total liver volume to ensure hepatic graft with excellent results and low donor morbidity (Pomfret, Pomposelli, & Jenkins, 2001) .
T241 45914-46008 Sentence denotes It is important to begin treatment before losing the recoverable function of the target organ.
T242 46009-46131 Sentence denotes Since pneumonia is the main cause of death by influenza, it may progress to some extent even after the start of treatment.
T243 46132-46440 Sentence denotes Time from illness onset to oseltamivir treatment in avian influenza A(H7N9) virus infection is 6 days (5-9 days), and time from illness onset to the development of acute respiratory distress syndrome (ARDS) is 7 days (5-9 days) (Li, et al., 2014) , indicating the importance of early diagnosis and treatment.
T244 46441-46732 Sentence denotes In Ebola virus infection, other than the direct cause of death related to bleeding such as hemorrhagic shock, the degree of liver dysfunction and renal dysfunction seems to be related to survival and death rate as seen in an animal model treated with favipiravir (Oestereich, et al., 2014) .
T245 46733-46793 Sentence denotes SFTS is mainly caused by tick bites and develops with fever.
T246 46794-46856 Sentence denotes Liver and renal dysfunction in SFTS may be the cause of death.
T247 46857-47028 Sentence denotes In Yamaguchi Prefecture, where the first patient was found in Japan, dermatologists who have examined tick bites monitor the development of SFTS to enable early treatment.
T248 47029-47206 Sentence denotes Favipiravir has been developed as an anti-influenza drug with efficacy against severe infections caused by a high viral load and was approved as an anti-influenza drug in Japan.
T249 47207-47312 Sentence denotes Favipiravir is contraindicated in pregnant women due to its teratogenicity and embryotoxicity in animals.
T250 47313-47438 Sentence denotes Subsequent stockpiling of doses for 2 million people has been performed as a countermeasure against novel influenza in Japan.
T251 47439-47600 Sentence denotes Favipiravir has been used to treat lethal infections in humans because its efficacy has been confirmed in a wide range of animal models of lethal RNA infections.
T252 47601-47678 Sentence denotes Severe human RNA infections are sporadic, and the number of cases is limited.
T253 47679-47855 Sentence denotes In patients with these infections, favipiravir has been used for urgent and life-saving purposes because there is no standard effective treatment, rather than to show efficacy.
T254 47856-48087 Sentence denotes Clinical trials have been performed to compare historical control patients and patients treated with favipiravir for Ebola virus infection (Bai, et al., 2016; Jacobs, et al., 2015; Sissoko, et al., 2016) and SFTS (Yasukawa, 2016) .
T255 48088-48203 Sentence denotes Subsequently, favipiravir has been submitted for additional indications based on clinical trials for SFTS in Japan.
T256 48204-48412 Sentence denotes The establishment of a placebo group that does not receive an effective drug in a le thal animal model is a challenging problem to confirm the efficacy of favipiravir by a randomized placebo-controlled trial.
T257 48413-48760 Sentence denotes As an example of this situation, PEP of human immunodeficiency J o u r n a l P r e -p r o o f Journal Pre-proof virus has been performed to protect against needle sticks or occupational exposures and has become a standard procedure in the guideline due to its prophylactic effect as a result of many years of implementation (Kuhar, et al., 2013) .
T258 48761-48936 Sentence denotes Since children died of avian influenza A(H5N1) in Hong Kong in 1997 (Ku & Chan, 1999 , concern has been expressed about novel influenza pandemics, such as A(H5N1) and A(H7N9).
T259 48937-49164 Sentence denotes An influenza pandemic consisting of a global outbreak of influenza A(H1N1)pdm09 virus occurred in 2009, and although the pathogenicity of this virus was milder than A(H5N1) and A(H7N9), it caused a pandemic and health problems.
T260 49165-49318 Sentence denotes Although there was immunity against influenza A(H1N1)pdm09 among the elderly, it caused health problems for young people and a substantial social impact.
T261 49319-49652 Sentence denotes As a next candidate for a pandemic influenza, avian influenza, such as A(H5N1) or A(H7N9), causes a severe infection and pneumonia due to the prolonged viral replication caused by the lack of immunity and its tropism to the pulmonary epithelium with a high mortality rate (Lai, et al., 2016; Li, et al., 2014; Shinya, et al., 2006) .
T262 49653-49864 Sentence denotes The ability to predict whether a pandemic will occur remains challenging, but a necessary strategy appears to be to stockpile vaccines and anti-influenza drugs for novel influenza strains to cope with pandemics.
T1 49865-50177 Sentence denotes The specific features and mechanism of action of favipiravir and the fact that favipiravir alone does not produce resistant viruses among anti-influenza drugs suggests that Influenza infection induces interferon (IFN) production that subsequently induces interleukin (IL)-1 production to act on the hypothalamus.
T2 50178-50274 Sentence denotes Next, cyclooxygenase is expressed to induce prostaglandin (PG)E 2 production and generate fever.
T3 50275-50448 Sentence denotes Cinnamyl compounds from medicinal herbs, anti-IFN antibody, anti-IL-1 antibody, and nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin) act at each step of this process.
T4 50449-50609 Sentence denotes Cinnamyl compounds and NSAIDs inhibit the induction of IFN and cyclooxygenase activity, respectively, in the fever cascade to work as antipyretics in influenza.
T5 50610-50876 Sentence denotes Regarding pneumonia, IL-12 and IFN-γ production are induced in the bronchoalveolar fluid (BALF) on the second and third day of infection, respectively, and an increase in IL-12 levels reduces the viral load in the BALF and the area of pneumonia throughout the lungs.
T6 50877-51066 Sentence denotes indicates inhibitory action. (NA) on the surface of the virus particle, and the virus particle is released from the surface of the infected cell and proceeds to the next round of infection.
T7 51067-51239 Sentence denotes Amantadine blocks uncoating by inhibiting acidification mediated by the M2 protein in the virus particle in late endosome, and thus the infection is unable to be completed.
T8 51240-51379 Sentence denotes Favipiravir inhibits viral RNA synthesis by terminating chain elongation at its incorporated site, and no new RNA is generated in the cell.
T9 51380-51531 Sentence denotes Baloxavir marboxil prevents Cap-snatching, and the viral mRNA is not produced, resulting in a failure to produce viral proteins and infectious viruses.
T10 51532-51583 Sentence denotes Genomic RNA is synthesized and remains in the cell.
T11 51584-51736 Sentence denotes NA inhibitors block the cleavage of the sialic acid-HA bond in the virus on the surface of infected cells and prevent the spread of the viral infection.
T12 51737-51779 Sentence denotes NA inhibitors allow genomic RNA synthesis.
T13 51780-51873 Sentence denotes Favipiravir inhibits viral RNA synthesis, while baloxavir and NAIs allow viral RNA synthesis.
T14 51874-52060 Sentence denotes Although viral spread is inhibited by baloxavir and NAIs, viral RNA is synthesized, and the pool of genomic RNA serves as a rich source of resistant viruses. indicates inhibitory action.
T15 52061-52102 Sentence denotes Chain termination and lethal mutagenesis.
T16 52103-52195 Sentence denotes Favipiravir is converted to favipiravir-RTP and incorporated into the elongating RNA strand.
T17 52196-52351 Sentence denotes Then, chain elongation stops at the site of favipiravir incorporation, and elongation does not proceed because favipiravir functions as a chain terminator.
T18 52352-52620 Sentence denotes This RNA-favipiravir (-RdRp) J o u r n a l P r e -p r o o f complex will not be repaired by the proofreading enzyme and would be disposed of as unnecessary RNA, resulting in the extinction of the viral genome (Rocha-Pereira, et al., 2012; Vanderlinden, et al., 2016) .
T19 52621-52733 Sentence denotes Ribavirin is incorporated into the elongating RNA strand, and viral RdRp continues to elongate until completion.
T20 52734-52876 Sentence denotes Next, the RNA strand with multiple ribavirin incorporation sites further incorporates ribavirin or serves as mRNA for viral protein synthesis.
T21 52877-53101 Sentence denotes The incorporation of ribavirin in the viral RNA causes the mismatch of base pairs (transition mutation), and translation of this RNA causes mutations in the amino acid sequence of the protein, resulting in impaired function.
T22 53102-53224 Sentence denotes Viral proteins with impaired function fail to replicate or produce infectious viral particles, and viral infection ceases.
T23 53225-53330 Sentence denotes Thus, lethal mutagenesis terminates viral infection through a different mechanism than chain termination.
T24 53331-54247 Sentence denotes J o u r n a l P r e -p r o o f (Bai, et al., 2016; Bixler, et al., 2018; Jacobs, et al., 2015; Oestereich, Ludtke, et al., 2014; Sissoko, et al., 2016; Smither, et al., 2014) Severe fever with thrombocytopenia syndrome (SFTS) caused by a virus infection 12-30% b (Gowen, Westover, Miao, et al., 2017a; Tani, et al., 2016; Yasukawa, 2016) Severe influenza (Cao, 2018; Wang et al., 2019) Lassa virus infection 1% a , severe cases 15% a (Gowen, Westover, Sefing, et al., 2017b; Mendenhall, et al., 2011; Oestereich, et al., 2016; Raabe, et al., 2017; Safronetz, et al., 2015) Rabies Approximately 100% a, b (Baker, 2017; Yamada, Noguchi, Komeno, Furuta, & Nishizono, 2015) Norovirus infection 50,000 deaths/year b (Arias, Thorne, & Goodfellow, 2014; Ruis, et al., 2018) Avian influenza A(H5N1) 52.8% (Sep 9, 2019) a Favipiravir is effective against influenza in animals and humans and has J o u r n a l P r e -p r o o f