Views: 64 Author: Site Editor Publish Time: 2020-06-12 Origin: Site
Chemical name: Favipiravir; 6-fluoro-3-hydroxypyrazine-2-carboxamide.
Molecular formula: C24H29N5O3
DMSO: 29 mg/mL (184.6 mM)
Ethanol: 12 mg/mL (76.4 mM)
Water: 5 mg/mL (31.82 mM), warmed
(< 1 mg/ml refers to the product slightly soluble or insoluble).
Discovered by Toyama Chemical Co., Ltd. in Japan, favipiravir is a modified pyrazine analog that was initially approved for therapeutic use in resistant cases of influenza. The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes.
Not only does favipiravir inhibit replication of influenza A and B, but the drug has shown promise in the treatment of avian influenza, and may be an alternative option for influenza strains that are resistant to neuramidase inhibitors. Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.
RNA-dependent RNA polymerase
In vitro activity
Favipiravir shows anti-influenza virus activities with IC50 ranged from 0.013 to 0.48 μg/ml for the influenza A viruses, from 0.039 to 0.089 μg/ml for the influenza B viruses, and from 0.030 to 0.057 μg/ml for the influenza C viruses. In mammalian cell lines (MDCK cells, Vero cells, HEL cells, A549 cells, HeLa cells, and HEp-2 cells), Favipiravir shows no cytotoxicity at concentrations up to 1,000 μg/ml. In MDCK cells inoculated with seasonal influenza A (H1N1) viruses, Favipiravir induces lethal mutagenesis.
In vivo activity
|In influenza virus-infected mice, Favipiravir (200 mg/kg/day, p.o.) protects the mice from death from influenza virus infection.  In mice experimentally infected with Ebola virus, Favipiravir efficiently blocks viral production, reaching an antiviral effectiveness of 95% and 99.6% at 2 and 6days after initiation of treatment, respectively. |
The cytotoxicity of T-705 is evaluated by an assay with XTT. XTT is converted to aqueous formazan by an enzyme in MDCK cells, Vero cells, HEL cells, A549 cells, HeLa cells, and HEp-2 cells. The compounds are diluted to the appropriate concentrations (volume, 100 μl) with test medium (EMEM containing 10% FCS) in 96-well culture plates in which each well contains a concentration of 2 × 103 cells/100 μL. The test plates are incubated for 3 days at 37°C in 100% humidity and 5% CO2. After 3 days, 50 μl of the XTT reagent (1 mg/ml in FCS-free EMEM containing 5 mM phenazine methosulfate) is added, and the reaction product is assayed by measurement of the absorbance at 450 nm with a microplate reader. Cytotoxicity is expressed as the 50% cell-inhibitory concentration (CC50).(Only for Reference)
Animal model:Mice infected with influenza virus A/PR/8/34
Based on single-dose toxicity studies, the lethal dose for oral and intravenous favipiravir in mice is estimated to be >2000 mg/kg.In rats, the lethal dose for oral administration is >2000 mg/kg, while the lethal dose in dogs and monkeys is >1000 mg/kg. Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.
In repeat-dose toxicity studies involving dogs, rats, and monkeys, notable findings after administration of oral favipiravir included: adverse effects on hematopoietic tissues such as decreased red blood cell (RBC) production, and increases in liver function parameters such as aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin, and increased vacuolization in hepatocytes.Testis toxicity was also noted.
Favipiravir is known to be teratogenic; therefore, administration of favipiravir should be avoided in women if pregnancy is confirmed or suspected.
Favipiravir for COVID-19
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its caused coronavirus disease 2019 (COVID-19) have been reported in China since December 2019. More than 16% of patients developed acute respiratory distress syndrome, and the fatality ratio was about 1%–2%. No specific treatment has been reported. Herein, we examined the effects of Favipiravir (FPV) versus Lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19. Patients with laboratory-confirmed COVID-19 who received oral FPV (Day 1: 1600 mg twice daily; Days 2–14: 600 mg twice daily) plus interferon (IFN)-α by aerosol inhalation (5 million U twice daily) were included in the FPV arm of this study, whereas patients who were treated with LPV/RTV (Days 1–14: 400 mg/100 mg twice daily) plus IFN-α by aerosol inhalation (5 million U twice daily) were included in the control arm. Changes in chest computed tomography (CT), viral clearance, and drug safety were compared between the two groups. For the 35 patients enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms. A shorter viral clearance time was found for the FPV arm versus the control arm (median (interquartile range, IQR), 4 (2.5–9) d versus 11 (8–13) d, P < 0.001). The FPV arm also showed significant improvement in chest imaging compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004).
After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest imaging. Multivariable Cox regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse events were found in the FPV arm than in the control arm. In this open-label before-after controlled study, FPV showed better therapeutic responses on COVID-19 in terms of disease progression and viral clearance. These preliminary clinical results provide useful information of treatments for SARS-CoV-2 infection.
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