T-705, A Novel Anti-Influenza Virus Compound - the Safety, Tolerability and Pharmacokinetics in Human

Abstract

Background: Little is currently known about the immunopathogenesis of dengue virus infection. However, the complex interaction of host immune responses during dengue virus infection has important implications on the clinical outcome of patients. The role of Th genes during dengue virus infection is poorly defined.Methods: In this project, we determine which genes are differentially regulated in dengue type 2 virus-infected cell lines (HepG2 -hepatocytes, K562 -myelogenous leukaemia cell line and Jurkat -T cells). We used real-time PCR to profile the expression of 84 genes related to the three classes of helper T cells: Th1, Th2 and Th3. This array includes cytokine and chemokine genes representative of Th1, Th2 and Th3 cells, transcriptional factors that regulate the expression of these cytokines as well as genes involved in the antimicrobial humoral response.Results: The susceptibilities of the three cell lines to dengue type 2 virus were evident by detection of viral antigen and virus growth curve. Majority of the Th genes that are differentially regulated in all the three cell lines infected with dengue virus. However, Jurkat and K562 cells showed more common regulation as compared to HepG2 cells probably because both of them are leukocytes. Among the differentially regulated genes, TLR6 was significantly regulated in both dengue type 2 virus-infected K562 cells and Jurkat cells. Semi-quantitative PCR and Western detection were performed to confirm the up-regulation of TLR6. High level of IL-6 expression was also detected from K562 cells and Jurkat cells.Conclusion: K562 and Jurkat cells are permissive to dengue type 2 virus infection. TLR 6 is up-regulated which in turn leads to upregulation of IL-6 during dengue virus infection. This may have implications in the immunopathogenesis of dengue virus biology.

Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever

“…The longer elimination half-life of the parent drug can be explained by the expected impairment of renal function by the PICV infection. In humans, the principal elimination route of favipiravir is metabolism to M1, which is eliminated in the urine (Kobayashi et al, 2011). …”

“…It is also important to consider the impact of species differences in aldehyde oxidase (Pryde et al, 2010; Ueda et al, 2005), which can have a significant impact on the activity of favipiravir as the primary enzyme catalyzing the conversion of favipiravir to the inactive M1 metabolite (Kobayashi et al, 2011). …”

Update on therapeutic approaches and emerging therapies for SARS-CoV-2 virus

“…Broad-spectrum activity of favipiravir against RNA viruses such as West Nile virus, poliovirus, Ebola virus and norovirus (Rocha-Pereira et al, 2012) makes it a suitable candidate for SARS-CoV-2. Phase I clinical trials to evaluate its efficacy against SARs-CoV-2 have begun and doses ranging from 30 to 1600 mg/kg have shown no serious adverse effects (Kobayashi et al, 2008). Unfortunately, a more recent study (Furuta et al, 2017), has shown that favipiravir has teratogenic and/or embryotoxic effects.…”