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Concept: Neuraminidase inhibitors

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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.

Concepts: Oseltamivir, Neuraminidase, Viral neuraminidase, Neuraminidase inhibitor, Neuraminidase inhibitors, Laninamivir

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Despite being a common viral disease, influenza has very negative consequences, causing the death of around half a million people each year. A neuraminidase located on the surface of the virus plays an important role in viral reproduction by contributing to the release of viruses from infected host cells. The treatment of influenza is mainly based on the administration of neuraminidase inhibitors. The neuraminidase inhibitors zanamivir, laninamivir, oseltamivir and peramivir have been commercialized and have been demonstrated to be potent influenza viral neuraminidase inhibitors against most influenza strains. In order to create more potent neuraminidase inhibitors and fight against the surge in resistance resulting from naturally-occurring mutations, these anti-influenza drugs have been used as templates for the development of new neuraminidase inhibitors through structure-activity relationship studies. Here, we review the synthetic routes to these commercial drugs, the modifications which have been performed on these structures and the effects of these modifications on their inhibitory activity.

Concepts: Organism, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors

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Long-term chemoprophylaxis using neuraminidase inhibitors may be needed during influenza epidemics but safety data are limited to several weeks. We sought to assess the tolerability of oseltamivir and zanamivir as primary prophylaxis over 16 weeks.

Concepts: Health care, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors

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Neuraminidase inhibitors are recommended for children hospitalized with influenza-related respiratory infections, and oseltamivir is the first choice of treatment in most situations. However, little is known regarding the recent trend in using neuraminidase inhibitors and their difference in health economy. The aim of this study was to reveal recent trends in neuraminidase inhibitor use and compare hospitalization costs across different treatment regimens.

Concepts: Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors, Peramivir

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The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

Concepts: Influenza, 2009 flu pandemic, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors

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An earlier study using the number of abnormal behaviors reported to the study group as the numerator and the number of influenza patient prescribed each neuraminidase inhibitor (NI) estimated by respective pharmaceutical companies found no significant difference among incidence rates of the most severe abnormal behaviors by type of NI throughout Japan. However, the dataset for the denominator used in that earlier study was the estimated number of prescriptions. In the present study, to compare the incidence rates of abnormal behavior more precisely among influenza patients administered several sorts of NI or administered no NI, we used data obtained from the National Database of Electronic Medical Claims (NDBEMC) as the denominator to reach a definitive conclusion. Results show that patients not administered any NI (hereinafter un-administered) or those administered peramivir sometimes showed higher risk of abnormal behavior than those administered oseltamivir, zanamivir, or laninamivir. However, the un-administered or peramivir patients were fewer than those taking other NI. Therefore, accumulation of data through continued research is expected to be necessary to reach a definitive conclusion about the relation between abnormal behavior and NI in influenza patients. Since severe abnormal behaviors with all types of NI or of un-administered patients have been reported, there are some risks in the administration of NI or even in un-administered cases. Therefore, we infer that the policy mandating package inserts in all types of NI.

Concepts: Abnormal psychology, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors, Peramivir

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An influenza A(H1N1)pdm09 virus carrying a G147R substitution in combination with an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir, was detected from an immunocompromised inpatient in Japan, March 2016. This dual H275Y/G147R mutant virus exhibited enhanced cross-resistance to both drugs compared with the single H275Y mutant virus and reduced susceptibility to zanamivir, although it showed normal inhibition by laninamivir.

Concepts: Antiviral drug, Influenza, 2009 flu pandemic, Oseltamivir, Neuraminidase, Viral neuraminidase, Neuraminidase inhibitor, Neuraminidase inhibitors

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Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. In October 2010, an additional indication for pediatric use was approved. We conducted a pediatric drug use investigation of peramivir from October 2010 to February 2012 and evaluated its real-world safety and effectiveness in pediatric patients. We collected the data of 1254 peramivir-treated pediatric patients from 161 facilities across Japan and examined the safety in 1199 patients and effectiveness in 1188 patients. In total, 245 adverse events were observed with an incidence rate of 14.01% (168/1199). Of these, 115 events were adverse drug reactions (ADRs) with an incidence rate of 7.67% (92/1199). Common ADRs were diarrhea and abnormal behavior, with incidence rates of 2.50% (30/1199) and 2.25% (27/1199), respectively. Fourteen serious ADRs were observed in 12 patients (1.00%), including 5 cases each of abnormal behavior and neutrophil count decreased. While 87.0% (100 events) of ADRs occurred within 3 days after the initiation of peramivir administration, 87.8% (101 events) resolved or improved within 7 days after onset. Multivariate analyses indicated that the presence or absence of underlying diseases/complications was significantly related to ADR incidence. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. Thus, this study confirms the pediatric safety of peramivir without any concerns about effectiveness under routine clinical settings.

Concepts: Clinical trial, Adverse drug reaction, Oseltamivir, Neuraminidase, Viral neuraminidase, Neuraminidase inhibitor, Neuraminidase inhibitors, Peramivir

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The neuraminidase inhibitors (NAIs) oseltamivir phosphate (Tamiflu(®)), zanamivir (Relenza(®)), laninamivir octanoate (Inavir(®)), and peramivir (Rapiacta(®)) have been available for the treatment of influenza in Japan since 2010. The emergence of resistant virus to any of the NAIs is a great concern for influenza treatment. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of each NAI for influenza virus isolates in the 2012-2013 influenza season and compared the results to those of the 2010-2011 and 2011-2012 influenza seasons. Viral isolation of specimens obtained prior to treatment was done using Madine-Darby canine kidney cells, and the type and subtype of influenza, A(H1N1)pdm09, A(H3N2), or influenza B, was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 329 influenza viruses were isolated:5 influenza A(H1N1)pdm09 (1.5%), 316 influenza A(H3N2) (96.1%), and 8 influenza B (2.4%). No isolate showed an IC50 value exceeding 50 nM for any of the neuraminidase inhibitors. The IC50 values for A(H3N2) and B were similar to those of the 2010-2011 and 2011-2012 seasons. No isolate showed an increased IC50 value for A(H1N1)pdm09. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC50 values to increase at present.

Concepts: Antiviral drug, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors

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Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. We conducted a drug use investigation of peramivir from October 2010 to February 2012 and evaluated its safety and effectiveness under routine clinical settings. We collected data of 1309 patients from 189 facilities across Japan and examined safety in 1174 patients and effectiveness in 1158 patients. In total, 143 adverse events were observed with an incidence rate of 7.33% (86/1174). Of these, 78 events were adverse drug reactions (ADRs) with an incidence rate of 4.34% (51/1174). The most frequently reported ADRs were diarrhea, vomiting, and nausea, with incidence rates of 1.87% (22/1174), 0.85% (10/1174), and 0.68% (8/1174), respectively. Moreover, no ADR was reported as serious. ADR onset was within 3 days after the start of peramivir administration in 91.0% (71 events) of the 78 ADRs, and ADRs were resolved or improved within 7 days after onset in 96.2% (75 events) of the 78 ADRs. Neither patient characteristics nor treatment factors appeared to significantly affect drug safety. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. The present study demonstrates the safety and effectiveness of peramivir under routine clinical settings.

Concepts: Clinical trial, Adverse drug reaction, Oseltamivir, Neuraminidase, Viral neuraminidase, Neuraminidase inhibitor, Neuraminidase inhibitors, Peramivir