Epistemic_Statements  

CORD-19:0329e0f2e3b8ab0eabe2afe0e5214cc88c61080e JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 832-1149 Epistemic_statement 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) .
T2 2360-2500 Epistemic_statement denotes Based on the antiviral activity toward four RNA viruses, we expected that favipiravir should be active against a broad range of RNA viruses.
T3 2501-2625 Epistemic_statement denotes Favipiravir has been evaluated and developed as a broad spectrum anti-RNA virus drug, including lethal RNA virus infections.
T4 7017-7261 Epistemic_statement 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.
T5 7262-7658 Epistemic_statement 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) .
T6 8292-8425 Epistemic_statement denotes The viral genome and RdRp complex are transported to the nucleus where the transcription (replication) of viral RNA synthesis begins.
T7 8878-9060 Epistemic_statement 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.
T8 9600-9653 Epistemic_statement denotes Cap-dependent endonuclease of the viral RdRp complex.
T9 9922-10270 Epistemic_statement 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.
T10 10410-10539 Epistemic_statement denotes Subsequently, drug-resistant influenza viruses should appear more readily from the mutant genomic RNA pool during drug treatment.
T11 11915-12133 Epistemic_statement 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
T12 12134-12181 Epistemic_statement denotes week after the disappearance of major symptoms.
T13 12866-12979 Epistemic_statement denotes Novel influenza is derived from avian influenza A and is a source of concern as a cause of an influenza pandemic.
T14 13628-13946 Epistemic_statement 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.
T15 14238-14405 Epistemic_statement 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) .
T16 14646-14724 Epistemic_statement denotes Oseltamivir, an NAI, has been the treatment of choice for influenza infection.
T17 15194-15272 Epistemic_statement denotes Oseltamivir-resistant influenza appears and becomes dominant during treatment.
T18 15273-15389 Epistemic_statement denotes Another concern is the prevalence of oseltamivir-resistant strains that was observed during the 2008 to 2009 season.
T19 16872-17068 Epistemic_statement 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.
T20 17069-17328 Epistemic_statement 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.
T21 17744-17985 Epistemic_statement 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.
T22 17986-18324 Epistemic_statement 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.
T23 19033-19175 Epistemic_statement denotes When drug administration is stopped during the virus replication period or when resistant strains appear, virus replication and fever relapse.
T24 19176-19264 Epistemic_statement denotes Thus, 10 days of administration may be required for severe influenza or novel influenza.
T25 19265-19428 Epistemic_statement denotes 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.
T26 19429-19550 Epistemic_statement denotes When these strains adapt to humans and become pandemic, their pathogenicity may be milder, similar to previous pandemics.
T27 19551-19670 Epistemic_statement denotes If an influenza pandemic causes severe disease, it may cause substantial damage to human health and social dysfunction.
T28 19671-19739 Epistemic_statement denotes The need for pandemic countermeasures is an important consideration.
T29 20271-20441 Epistemic_statement 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) .
T30 20991-21142 Epistemic_statement 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.
T31 21143-21415 Epistemic_statement 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.
T32 21416-21607 Epistemic_statement 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.
T33 22109-22350 Epistemic_statement 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 ).
T34 23219-23468 Epistemic_statement 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.
T35 23764-23917 Epistemic_statement 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.
T36 24152-24390 Epistemic_statement 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) .
T37 24391-24487 Epistemic_statement denotes Some treatments were used in emergencies, and some were used in the setting of a clinical trial.
T38 25846-25981 Epistemic_statement denotes Differences in the two factors between antiviral concentrations and target cells do not appear to be significantly reflected in dosage.
T39 27322-27445 Epistemic_statement denotes RdRp that affect ribavirin incorporation are produced, drug-resistant viruses can be selected in the presence of ribavirin.
T40 27446-27843 Epistemic_statement 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) .
T41 30387-30481 Epistemic_statement denotes These observations are consistently explained by the chain termination induced by favipiravir.
T42 31117-31253 Epistemic_statement denotes However, the incorporated acyclovir is removed by the proofreading activity of viral DNA polymerase, and viral DNA elongation continues.
T43 32217-32534 Epistemic_statement 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.
T44 32535-32766 Epistemic_statement 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.
T45 32767-32856 Epistemic_statement denotes This possibility is inconsistent with the mechanism of favipiravir as a chain terminator.
T46 32857-33075 Epistemic_statement 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.
T47 33081-33215 Epistemic_statement denotes Favipiravir is unlikely to induce mismatches upon its incorporation into the RNA strand and transitions in the influenza virus genome.
T48 33573-33715 Epistemic_statement 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.
T49 34127-34286 Epistemic_statement 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.
T50 35025-35129 Epistemic_statement denotes These results indicate the low fidelity of the RdRp activity of influenza lacking proofreading activity.
T51 35701-35943 Epistemic_statement 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.
T52 37449-37518 Epistemic_statement denotes A subsequent new infection by the resistant virus has been confirmed.
T53 37519-37756 Epistemic_statement 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.
T54 38103-38184 Epistemic_statement denotes Then, we decided to deny the possibility of replacement with the resistant virus.
T55 38657-38826 Epistemic_statement denotes Therefore, every type of mutant should be generated during replication, and continuous cultivation for a month might increase the favipiravir-resistant virus population.
T56 38827-39032 Epistemic_statement 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.
T57 39340-39503 Epistemic_statement denotes Therefore, theoretical resistant mutants should be generated but are unable to replicate or replicate with reduced fidelity to replace the entire virus population.
T58 39762-39883 Epistemic_statement denotes Our results are consistent with the absence of a resistant virus in the entire virus population treated with favipiravir.
T59 39884-39997 Epistemic_statement denotes Many laboratories have attempted to isolate favipiravir-resistant influenza viruses but have not been successful.
T60 40718-40838 Epistemic_statement denotes However, the virus was artificially produced and grown as a clone and is not considered a dominant virus in the culture.
T61 41885-42094 Epistemic_statement 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.
T62 42626-42799 Epistemic_statement 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.
T63 42800-43093 Epistemic_statement 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) .
T64 43094-43247 Epistemic_statement denotes Thus, researchers should consider the possibility of changes in the susceptibility to favipiravir when these types of influenza viruses cause a pandemic.
T65 43893-44201 Epistemic_statement 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.
T66 44202-44555 Epistemic_statement 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.
T67 44556-44669 Epistemic_statement denotes Causes of death from severe infections may be liver failure, renal failure, respiratory failure and encephalitis.
T68 44670-44891 Epistemic_statement 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) .
T69 44991-45183 Epistemic_statement 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.
T70 45184-45319 Epistemic_statement denotes The residual function necessary for the recovery of each organ can be estimated from the indication criteria for organ transplantation.
T71 46009-46131 Epistemic_statement denotes Since pneumonia is the main cause of death by influenza, it may progress to some extent even after the start of treatment.
T72 46441-46732 Epistemic_statement 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) .
T73 46794-46856 Epistemic_statement denotes Liver and renal dysfunction in SFTS may be the cause of death.
T74 47439-47600 Epistemic_statement 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.
T75 47601-47678 Epistemic_statement denotes Severe human RNA infections are sporadic, and the number of cases is limited.
T76 48204-48412 Epistemic_statement 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.
T77 48761-48936 Epistemic_statement 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).
T78 49165-49318 Epistemic_statement 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.
T79 49319-49652 Epistemic_statement 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) .
T80 49653-49864 Epistemic_statement 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.
T81 49865-50177 Epistemic_statement 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.
T82 51067-51239 Epistemic_statement 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.
T83 52352-52620 Epistemic_statement 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) .