cs-8958 and Influenza--Human

Influenza is a century-old disease that continues to baffle humans by its frequently changing nature, seasonal epidemics, and occasional pandemics. Approximately 9% of the world's population is infected by the influenza virus annually. The emergence of novel strains because of rapid mutations as well as interspecies disease contamination, limits the efficiency of strain-specific vaccines. Anti-influenza drugs such as neuraminidase inhibitors, M2 ion channel inhibitors, etc. have become the first line of defense in prophylaxis and early containment of the disease. But the growing drug resistance due to drug-induced selective pressure has also limited the efficacy of those drugs. Because we can't predict the next strain types, their virulence, or the severity of the next epidemic/pandemic caused by influenza virus, we ought to gear up for the development of novel anti-influenza drugs with a broad spectrum of reactivity against all strains and subtypes, better bioavailability, easier administrative pathways, and lesser adverse effects. Various new compounds with each having significantly different target molecules and pharmacologic activity have shown potential against influenza virus strains in laboratory situations as well as clinical trials. We should also consider combination therapy to boost the efficacy of existing drugs. This review is aiming to succinctly document the recent signs of progress regarding anti-influenza drugs both in the market and under investigation.

Topics: Antiviral Agents; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Neuraminidase; Orthomyxoviridae

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

We conducted a double-blind, randomized controlled trial to compare a long-acting neuraminidase inhibitor, laninamivir octanoate, with oseltamivir. Eligible patients were children 9 years of age and under who had febrile influenza symptoms of no more than 36-h duration. Patients were randomized to 1 of 3 treatment groups: a group given 40 mg laninamivir (40-mg group), a group given 20 mg laninamivir (20-mg group), and an oseltamivir group. Laninamivir octanoate was administered as a single inhalation. Oseltamivir (2 mg/kg of body weight) was administered orally twice daily for 5 days. The primary end point was the time to alleviation of influenza illness. The primary analysis included 184 patients (61, 61, and 62 in the 40-mg group, 20-mg group, and oseltamivir group, respectively). Laninamivir octanoate markedly reduced the median time to illness alleviation in comparison with oseltamivir in patients infected with oseltamivir-resistant influenza A (H1N1) virus, and the reductions were 60.9 h for the 40-mg group and 66.2 h for the 20-mg group. On the other hand, there were no significant differences in the times to alleviation of illness between the laninamivir groups and oseltamivir group for patients with influenza A (H3N2) or B virus infection. Laninamivir octanoate was well tolerated. The most common adverse events were gastrointestinal events. Laninamivir octanoate was an effective and well-tolerated treatment for children with oseltamivir-resistant influenza A (H1N1) virus infection. Further study will be needed to confirm clinical efficacy against influenza A (H3N2) or B virus infection. Its ease of administration is noteworthy, because a single inhalation is required during the course of illness.

Topics: Administration, Inhalation; Administration, Oral; Antiviral Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Male; Neuraminidase; Oseltamivir; Treatment Outcome; Virus Shedding; Zanamivir

Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2-nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.

Topics: Antiviral Agents; Catalysis; Guanidines; Humans; Influenza, Human; Pyrans; Sialic Acids; 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

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. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.

Topics: Animals; Antiviral Agents; Cell Line; Dogs; HeLa Cells; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Mice; Neuraminidase; Prodrugs; Zanamivir