cs-8958 and Disease-Models--Animal

Oseltamivir and zanamivir are currently licensed worldwide for influenza treatment and chemoprophylaxis. Both drugs require twice-daily administration for 5 days for treatment. A new influenza drug, laninamivir (code name R-125489), and its prodrug form, CS-8958 (laninamivir octanoate or laninamivir prodrug), which are long-acting neuraminidase inhibitors, are introduced in this review. Laninamivir potently inhibited the neuraminidase activities of various influenza A and B viruses, including subtypes N1-N9, pandemic (2009) H1N1 virus, highly pathogenic avian influenza (HPAI) H5N1 viruses and oseltamivir-resistant viruses. Because of the long retention of laninamivir in mouse lungs after an intranasal administration of CS-8958, therapeutic administration of a single dose of CS-8958 showed superior efficacy to repeated administrations of zanamivir or oseltamivir in animal infection models for influenza A and B viruses. These include pandemic (2009) H1N1 virus and HPAI H5N1 virus. Prophylactic single administration of CS-8958, as early as 7 days prior to infection, also showed superior efficacy. Finally, the potential of a single inhalation of CS-8958 for influenza patients was demonstrated by clinical studies, and CS-8958 has been approved and is commercially available as Inavir(®) (Daiichi Sankyo Co., Ltd, Tokyo) in Japan.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Guanidines; Humans; Influenza, Human; Mice; Neuraminidase; Orthomyxoviridae; Oseltamivir; Pandemics; Prodrugs; Pyrans; Rats; Sialic Acids; Zanamivir

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for use for the treatment and prophylaxis of influenza. We have reported on laninamivir (code name, R-125489), a novel neuraminidase inhibitor, and have discovered that the laninamivir prodrug CS-8958 worked as a long-acting neuraminidase inhibitor in a mouse influenza virus infection model when it is intranasally administered. In this study, CS-8958 was administered just once 7 days before infection and showed significant efficacy in vivo. The efficacy of a single administration of CS-8958 after viral infection was then compared with that of repeated administrations of oseltamivir phosphate or zanamivir in mice and ferrets. CS-8958 showed efficacy superior or similar to the efficacies of the two licensed NA inhibitors. CS-8958 also significantly reduced the titers of an oseltamivir-resistant H1N1 virus with a neuraminidase H274Y substitution in a mouse infection model. These results suggest that since CS-8958 is characteristically long lasting in the lungs, it may be ideal for the prophylaxis and treatment of influenza.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Ferrets; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Mice; Mice, Inbred BALB C; Neuraminidase; Orthomyxoviridae Infections; Oseltamivir; Prodrugs; Treatment Outcome; Zanamivir

Laninamivir is a novel neuraminidase inhibitor of influenza viruses and it has been reported that its prodrug, CS-8958 shows a long-lasting characteristics. Using viruses isolated in Nagasaki of pandemic (H1N1) 2009 influenza virus which cause pandemic in 2009, it was shown that laninamivir has a strong inhibitory activities against their neuraminidases and virus replication in cultured cells, and strong binding stability to the virus NA. Furthermore, a single intranasal administration of CS-8958 showed a superior reduction of virus load in lungs in mouse infection model. These suggest that CS-8958 will work as a long-acting neuraminidase inhibitor to an infection with pandemic (H1N1) 2009 influenza viruses as well.

Topics: Administration, Intranasal; Animals; Antiviral Agents; Cells, Cultured; Delayed-Action Preparations; Disease Models, Animal; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Lung; Mice; Mice, Inbred BALB C; Neuraminidase; Pandemics; Viral Load; Virus Replication; Zanamivir