favipiravir and peramivir

Influenza is a major cause of substantial morbidity and mortality in humans every year. Vaccination is the main strategy to prevent influenza infection, but antiviral agents also play an important role in the control of both seasonal and pandemic influenza. During the influenza A/H1N1 pandemic in 2009, early prompt antiviral therapy may have reduced the severity of the influenza outcomes including pneumonia, hospitalization and mortality in the Republic of Korea. Since the 2009 H1N1 pandemic, there have been increasing usages of antiviral agents for the treatment of patients with seasonal influenza. Although currently rare, antiviral resistance among influenza viruses may emerge and increase with increased use of neuraminidase inhibitors. New agents with different modes of action are under investigation, including favipiravir, DAS181, nitazoxanide and broad-spectrum neutralizing monoclonal antibodies. Data are limited with respect to high-dose and combination antiviral therapies. So, clinical trials are warranted to evaluate diverse antiviral combinations that may be synergistic and less likely to induce breakthrough resistance.

Topics: Acids, Carbocyclic; Amides; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drug Resistance, Viral; Guanidines; Hospitalization; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Pyrans; Pyrazines; Republic of Korea; Sialic Acids; Zanamivir

Antiviral agents for the treatment of influenza are urgently needed to circumvent the limitations of current drugs in several critical areas: high frequencies of resistance to M2 inhibitors among currently circulating strains and variable frequencies of resistance to oseltamivir among A(H1N1) strains, limited efficacy of treatment and treatment-emergent antiviral resistance in cases of avian influenza A(H5N1) illness in humans, and lack of parenteral agents for seriously ill patients. Two neuraminidase inhibitors (NAIs), zanamivir and peramivir, have undergone or are undergoing clinical trials for use by intravenous or intramuscular administration, and one long-acting NAI, designated CS-8958, is under study for use by inhalation. Advances in understanding the mechanisms involved in influenza virus replication have revealed a number of potential targets that might be exploited in the development of new agents. Among these agents are T-705, a polymerase inhibitor, and DAS181, an attachment inhibitor. Combination therapy with currently available agents is supported by data from animal models but has received limited clinical study to date.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; Cyclopentanes; Drug Discovery; Drug Resistance, Viral; Drug Therapy, Combination; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza, Human; Neuraminidase; Pyrazines; Recombinant Fusion Proteins; Zanamivir

Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; Cell Line; Dibenzothiepins; Dogs; Drug Combinations; Drug Resistance, Viral; Drug Synergism; Guanidines; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Madin Darby Canine Kidney Cells; Morpholines; Neuraminidase; Nucleic Acid Synthesis Inhibitors; Orthomyxoviridae Infections; Oseltamivir; Pyrazines; Pyridones; Ribavirin; Triazines; Viral Proteins; Virus Replication; Zanamivir

We evaluated the environmental fate of new three anti-influenza drugs, favipiravir (FAV), peramivir (PER), and laninamivir (LAN), and an active prodrug of LAN, laninamivir octanoate (LANO), in comparison with four conventional drugs, oseltamivir (OS), oseltamivir carboxylate (OC), amantadine (AMN), and zanamivir (ZAN) by photodegradation, biodegradation, and sorption to river sediments. In addition, we conducted 9-month survey of urban rivers in the Yodo River basin from 2015 to 2016 (including the influenza season) to investigate the current status of occurrence of these drugs in the river environment. The results clearly showed that FAV and LAN rapidly disappeared through photodegradation (half-lives 1 and 8 h, respectively), followed by LANO which gradually disappeared through biodegradation (half-life, 2 days). The remained PER and conventional drugs were, however, persistent and transported from upstream to downstream sites. Rates of their sorption to river sediments were negligibly small. Detected levels remained were in the range from N.D. to 89 ng/L for the river waters and from N.D. to 906 ng/L in sewage effluent. However, all of the remained drugs were effectively removed by ozonation after chlorination at a sewage treatment plant. These findings suggest the importance of introducing ozonation for reduction of pollution loads in rivers, helping to keep river environments safe. To the best of our knowledge, this is the first evaluation of the removal effects of natural sunlight, biodegradation, and sorption to river sediments on FAV, PER, LAN, LANO, and a conventional drug, AMN.

Topics: Acids, Carbocyclic; Amides; Antiviral Agents; Biodegradation, Environmental; Cyclopentanes; Environmental Monitoring; Fresh Water; Guanidines; Half-Life; Humans; Influenza, Human; Japan; Prodrugs; Pyrans; Pyrazines; Rivers; Seasons; Sewage; Sialic Acids; Water Pollutants, Chemical; Zanamivir

A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from three patients and was identified as H7N9 in China. Antiviral agents are required to treat patients with avian influenza H7N9 virus infection.. In this study, we assessed the antiviral potential of oseltamivir, peramivir, favipiravir (T-705), amantadine and rimantadine against novel reassortant avian-origin influenza H7N9 virus in vitro.. All three avian influenza H7N9 virus strains were sensitive to oseltamivir, peramivir and favipiravir (T-705), but resistant to amantadine and rimantadine.. Our data show a pattern of antiviral sensitivity for this novel H7N9 strain of influenza that suggests the compounds oseltamivir, peramivir and favipiravir should be useful for therapy.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; Cyclopentanes; Dogs; Drug Resistance, Viral; Guanidines; Influenza A Virus, H7N9 Subtype; Madin Darby Canine Kidney Cells; Oseltamivir; Pyrazines; Reassortant Viruses

Antiviral drugs are being used for therapeutic purposes against influenza illness in humans. However, antiviral-resistant variants often nullify the effectiveness of antivirals. Combined medications, as seen in the treatment of cancers and other infectious diseases, have been suggested as an option for the control of antiviral-resistant influenza viruses. Here, we evaluated the therapeutic value of combination therapy against oseltamivir-resistant 2009 pandemic influenza H1N1 virus infection in DBA/2 mice. Mice were treated for five days with favipiravir and peramivir starting 4 hours after lethal challenge. Compared with either monotherapy, combination therapy saved more mice from viral lethality and resulted in increased antiviral efficacy in the lungs of infected mice. Furthermore, the synergism between the two antivirals, which was consistent with the survival outcomes of combination therapy, indicated that favipiravir could serve as a critical agent of combination therapy for the control of oseltamivir-resistant strains. Our results provide new insight into the feasibility of favipiravir in combination therapy against oseltamivir-resistant influenza virus infection.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; Body Weight; Cyclopentanes; Dogs; Drug Resistance, Viral; Drug Synergism; Drug Therapy, Combination; Female; Guanidines; Influenza A Virus, H1N1 Subtype; Lung; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred DBA; Orthomyxoviridae Infections; Oseltamivir; Pyrazines; Survival Rate

Favipiravir, an influenza virus RNA polymerase inhibitor, and peramivir, an influenza virus neuraminidase inhibitor, were evaluated alone and in combination against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Infected mice were treated twice daily for 5 d starting 4 h after virus challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100 mg/kg/d. Peramivir was 30% protective at 0.5 mg/kg/d, but ineffective at lower doses when used as monotherapy. Combinations of favipiravir and peramivir increased the numbers of survivors by 10-50% when the 0.025, 0.05, and 0.1 mg/kg/d doses of peramivir were combined with 20 mg/kg/d favipiravir and when all doses of peramivir were combined with 40 mg/kg/d favipiravir. Three-dimensional analysis of drug interactions using the MacSynergy method indicates strong synergy for these drug combinations. In addition, an increase in lifespan for groups of mice treated with drug combinations, compared to the most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1 mg/kg/d doses of peramivir combined with favipiravir at the 20 mg dose level. Therefore, the 20 mg/kg/d dose of favipiravir was selected for further combination studies. Increased survival was exhibited when this dose was combined with peramivir doses of 0.1, 0.25 and 0.5 mg/kg/d (1 mg/kg/d of peramivir alone was 100% protective in this experiment). Improved body weight relative to either compound alone was evident using 0.25, 0.5, and 1 mg/kg/d of peramivir. Significant reductions in lung hemorrhage score and lung weight were evident on day 6 post-infection. In addition, virus titers were reduced significantly on day 4 post-infection by combination therapy containing favipiravir combined with peramivir at 0.25 and 0.5 mg/kg/d. These data demonstrate that combinations of favipiravir and peramivir perform better than suboptimal doses of each compound alone for the treatment of influenza virus infections in mice.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; California; Cyclopentanes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Mice; Mice, Inbred BALB C; Pandemics; Pyrazines