laninamivir and favipiravir

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

Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.. Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.. Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.. Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants.

Topics: Amides; Animals; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Female; Guanidines; Immunocompromised Host; Influenza A Virus, H1N1 Subtype; Lung; Mice; Mice, Inbred BALB C; Mice, Nude; Neuraminidase; Nucleic Acid Synthesis Inhibitors; Orthomyxoviridae Infections; Oseltamivir; Pyrans; Pyrazines; Sialic Acids; 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