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

Kubo, Shuku; Tokumitsu, Akane; Tomozawa, Takanori; Kakuta, Masayo; Yamashita, Makoto

doi:10.1007/s10156-011-0292-4

Cited by 6 publications

(7 citation statements)

References 21 publications

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“…The inhibitory effects of laninamivir against the neuraminidase activity of the influenza A/H1 pdm 2009 virus that were observed in this study are consistent with the effects on activity that were reported by Kubo et al []. However, the magnitude of the inhibitory effects of laninamivir on viral release into supernatants that was observed in this study was more potent than that observed in an animal model [Kubo et al, ]; this difference may be caused by differences between cell culture and animal models.…”

Section: Discussionsupporting

confidence: 91%

“…Likewise, the mean concentration of zanamivir in the epithelial lining fluid 12 after inhalation was 2.7 µM [Shelton et al, ]. Furthermore, in mouse lungs, the concentration of laninamivir 12 hr after intranasal administration was more than 1.0 µM [Kubo et al, ]. The concentrations of the neuraminidase inhibitors reported in these studies demonstrate that the typical clinical concentrations of neuraminidase inhibitors are 1 nM or higher.…”

Section: Discussionmentioning

confidence: 95%

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The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium

et al. 2014

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Defining the effects of neuraminidase inhibitors on influenza virus infection may provide important information for the treatment of patients. The effects of neuraminidase inhibitors have been examined using various methods, including viral release from kidney cells. However, the effects of neuraminidase inhibitors on viral release from primary cultures of human tracheal epithelial cells, which retain functions of the original tissues, have not been studied. The effects of neuraminidase inhibitors on the replication of the pandemic influenza virus [A/Sendai-H/N0633/2009 (H1N1) pdm09] and the seasonal influenza virus [A/Sendai-H/216/2009 (H1N1)] that was isolated during the 2008-2009 season were examined. The virus stocks were generated by infecting tracheal cells with the pandemic or seasonal influenza virus. Four types of inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) reduced pandemic viral titers and concentrations of the cytokines interleukin-6 and tumor necrosis factor-α in supernatants and viral RNA in cells. However, oseltamivir did not reduce seasonal viral titers, cytokine concentrations and viral RNA, and the 50% inhibitory concentration (IC50 ) of oseltamivir for neuraminidase activity in the seasonal virus was 300-fold higher than that observed for the pandemic influenza virus. The seasonal influenza virus had an oseltamivir-resistant genotype. The magnitude of the IC50 values of the neuraminidase inhibitors for the seasonal influenza virus was inversely related to the magnitude of the inhibitory effects on viral release. These methods for measuring the release of virus and inflammatory cytokines from primary cultures of human tracheal epithelium may provide useful information regarding the effects of neuraminidase inhibitors on influenza viruses.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium

et al. 2014

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Section: Discussioncontrasting

confidence: 46%

“…Laninamivir octanoate is inhaled, then converted to laninamivir in the lung, and the binding of laninamivir to virus NA is relatively more stable and lasts longer than has been observed for other NAIs. 13,24 In this study, laninamivir was almost equally as effective as oseltamivir or zanamivir, estimated clinically by the duration of fever; nevertheless, the IC 50 of laninamivir tended to be higher than that of the other NAIs. Kubo, et al recently reported that 6 days after intranasal administration of 236 lg ⁄ kg laninamivir octanoate, the concentration of laninamivir in the lungs of mice was maintained about 730-fold the IC 50 for A(H1N1)pdm09, 77-fold that of A(H3N2), and 70-fold that of B.…”

Section: Discussionmentioning

confidence: 54%

Increased symptom severity but unchanged neuraminidase inhibitor effectiveness for A(H1N1)pdm09 in the 2010-2011 season: comparison with the previous season and with seasonal A(H3N2) and B

Kawai

Ikematsu

Kawashima

et al. 2012

Influenza and Other Respiratory Viruses

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Background No studies of the clinical symptoms before starting therapy or of the effectiveness of neuraminidase inhibitors (NAIs) have been carried out of the 2009–2010 and 2010–2011 seasons that compare A(H1N1)pdm09 or the three circulating types of influenza virus. Methods The clinical symptoms and duration of fever (body temperature ≥37·5°C) after the first dose of an NAI (oseltamivir, zanamivir, laninamivir) were analyzed. PCR was carried out for 365 patients with A(H1N1)pdm09 in the 2009–2010 season and for 388 patients with one of the three types of influenza circulating in the 2010–2011 season. IC50 for the three NAIs was also analyzed in 51 patients in the 2010–2011 season. Results The peak body temperature was significantly higher in 2010–2011 than in 2009–2010 for patients under 20 years with A(H1N1)pdm09, and in the 2010–2011 season for children 15 years or younger with A(H1N1)pdm09 than for those with other virus types. The percentage of A(H1N1)pdm09 patients with loss of appetite or fatigue was significantly higher in 2010–2011 than in the previous season. The duration of fever was not affected by the kind of NAI or by age in multiple regression analysis. The percentage of patients afebrile at 48 hours after the first dose of NAI was significantly higher for A(H1N1)pdm09 than for A(H3N2) (laninamivir) or B (oseltamivir and laninamivir). Conclusion Although the clinical symptoms of A(H1N1)pdm09 were slightly more severe in the 2010–2011 season, the effectiveness of the NAIs remained high in comparison with 2009–2010 and with other types of seasonal influenza.

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“…It was shown to inhibit the NA activity of the N1-N9 subtypes of influenza A and influenza B viruses in vitro (Yamashita et al, 2009). The metabolized plasma drug concentration in vivo is reported to be 1100 nM after 144 hours (Ishizuka et al, 2010), which is approximately 50 times higher than the level necessary to inhibit influenza B virus replication (Kubo et al, 2012). Based on this pharmacokinetic characteristic, influenza can be treated with a single administration of laninamivir octanoate by oral inhalation.…”

Section: Investigational Naismentioning

confidence: 99%

Neuraminidase inhibitors for influenza B virus infection: Efficacy and resistance

2013

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Many aspects of the biology and epidemiology of influenza B viruses are far less studied than for influenza A viruses, and one of these aspects is effectiveness and resistance to the clinically available antiviral drugs, the neuraminidase (NA) inhibitors (NAIs). Acute respiratory infections are one of the leading causes of death in children and adults, and influenza is among the few respiratory infections that can be prevented and treated by vaccination and antiviral treatment. Recent data has suggested that influenza B virus infections are of specific concern to pediatric patients because of the increased risk of severe disease. Treatment of influenza B is a challenging task for the following reasons: NAIs (e.g., oseltamivir and zanamivir) are the only FDA-approved class of antivirals available for treatment;the data suggest that oseltamivir is less effective than zanamivir in pediatric patients;zanamivir is not prescribed to patients younger than 7;influenza B viruses are less susceptible than influenza A viruses to NAIs in vitro;although the level of resistance to NAIs is low, the number of different molecular markers of resistance is higher than for influenza A viruses, and they are not well defined;the relationship between levels of NAI phenotypic resistance and known molecular markers, frequency of emergence, transmissibility, and fitness of NAI-resistant variants are not well established. This review presents current knowledge of the effectiveness of NAIs for influenza B virus and antiviral resistance in clinical, surveillance, and experimental studies.

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

Cited by 6 publications

References 21 publications

The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium

The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium

Increased symptom severity but unchanged neuraminidase inhibitor effectiveness for A(H1N1)pdm09 in the 2010-2011 season: comparison with the previous season and with seasonal A(H3N2) and B

Neuraminidase inhibitors for influenza B virus infection: Efficacy and resistance

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