Efficacy of laninamivir octanoate in mice with advanced inflammation stage caused by infection of highly lethal influenza virus.

Four neuraminidase (NA) inhibitors and an RNA synthesis inhibitor were recently approved and are currently in clinical use for influenza. Among NA inhibitors, oseltamivir phosphate (OSE, Tamiflu) and zanamivir are approved worldwide, whereas peramivir and laninamivir octanoate (LAN, Inavir) are regionally approved for human use. Therefore, OSE has been used to treat infections of highly pathogenic influenza viruses, such as H5N1 and H7N9, which caused epidemic in southeast Asia and Egypt, and China, respectively.

A novel sphingomyelin/cholesterol domain-specific probe reveals the dynamics of the membrane domains during virus release and in Niemann-Pick type C.

We identified a novel, nontoxic mushroom protein that specifically binds to a complex of sphingomyelin (SM), a major sphingolipid in mammalian cells, and cholesterol (Chol). The purified protein, termed nakanori, labeled cell surface domains in an SM- and Chol-dependent manner and decorated specific lipid domains that colocalized with inner leaflet small GTPase H-Ras, but not K-Ras. The use of nakanori as a lipid-domain-specific probe revealed altered distribution and dynamics of SM/Chol on the cell surface of Niemann-Pick type C fibroblasts, possibly explaining some of the disease phenotype.

Efficacy of a single intravenous administration of laninamivir (an active metabolite of laninamivir octanoate) in an influenza virus infection mouse model.

Laninamivir, a potent neuraminidase (NA) inhibitor, is an active metabolite of laninamivir octanoate (code name: CS-8958) which is a long acting NA inhibitor and is commercially available under the brand name Inavir in Japan to complete the treatment of influenza by a single inhalation. It is supposed that the long acting character is provided by the long retention of laninamivir in the respiratory tract after intranasal administration of laninamivir octanoate in mice and with stable binding of laninamivir to NA of various influenza viruses such as N1, N2 subtypes and NA of B virus. Peramivir, another NA inhibitor, is also approved in Japan as a single intravenous infusion.

Laninamivir octanoate and artificial surfactant combination therapy significantly increases survival of mice infected with lethal influenza H1N1 Virus.

Background: Patients with influenza virus infection can develop severe pneumonia and acute respiratory distress syndrome (ARDS) which have a high mortality. Influenza virus infection is treated worldwide mainly by neuraminidase inhibitors (NAIs). However, monotherapy with NAIs is insufficient for severe pneumonia secondary to influenza virus infection.

High and continuous exposure of laninamivir, an anti-influenza drug, may work suppressively to generate low-susceptibility mutants in animals.

Laninamivir octanoate (Inavir(®); Daiichi Sankyo, Tokyo, Japan) is an anti-influenza drug that provides complete treatment by a single inhalation. It works as a long-acting neuraminidase (NA) inhibitor by means of high and continuous exposure of laninamivir, its active metabolite, in the lungs of mice after intranasal administration. Even after 6 days after intranasal administration of 236 μg/kg laninamivir octanoate, the concentration of laninamivir in the lungs was maintained more than 2-3 orders higher than 50% inhibitory concentrations of laninamivir to N1 NAs, about 2 orders higher than N2 NA of seasonal influenza A viruses, and more than about 50 times higher than influenza B virus NA.

[In vitro and in vivo effects of a long-acting anti-influenza agent CS-8958 (laninamivir octanoate, Inavir) against pandemic (H1N1) 2009 influenza viruses].

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.

Efficacy of the new neuraminidase inhibitor CS-8958 against H5N1 influenza viruses.

Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed.

Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor, shows superior anti-influenza virus activity after a single administration.

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.

Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en.

A series of ester prodrugs of 7-O-methyl derivative of Zanamivir (compound 3) was synthesized and their efficacy was evaluated in an influenza infected mice model by intranasal administration. Compound 7c (CS-8958), octanoyl ester prodrug of the C-9 alcohol of compound 3, was found to be much longer-acting than Zanamivir. Furthermore, the in vivo efficacies of compounds 12a, 12b, and 12c, the linear alkyl ester prodrug of the carboxylic acid, were comparable to that exerted by compound 7c.

CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity.

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses.