Lower Clinical Effectiveness of Oseltamivir against Influenza B Contrasted with Influenza A Infection in Children

Sugaya, Norio; Mitamura, Keiko; Yamazaki, Masahiko; Tamura, Daisuke; Ichikawa, Masataka; Kimura, Kazuhiro; Kawakami, Chiharu; Kiso, Maki; Ito, Mutsumi; Hatakeyama, S.; Kawaoka, Yoshihiro

doi:10.1086/509925

Cited by 166 publications

(133 citation statements)

References 17 publications

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“…However, since recent clinical studies have shown that the antipyretic effect of OP on type A influenza is stronger than that on type B influenza, 33,34) the antipyretic effect of OP is considered to be due to not only direct pharmacological effects on thermoregulation, but also anti-influenza virus activity.…”

Section: )mentioning

confidence: 99%

Oseltamivir, an Anti-influenza Virus Drug, Produces Hypothermia in Mice

Ono

Nagano

Matsunami

et al. 2008

Biological & Pharmaceutical Bulletin

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The anti-influenza drug oseltamivir (Ro64-0796) is hydrolyzed to the active metabolite oseltamivir calboxylate (Ro64-0802, OC) by human liver carboxylesterase (CES), and OC inhibits the influenza virus-specific neuraminidase. [1][2][3][4] Oral administration of the parent compound oseltamivir (OP) relieves the symptoms of influenza (cough, myalgia, nasal obstruction, sore throat, fatigue, headache, feverishness).5) OP has strong antipyretic effects, which become apparent within 24 h after taking the drug.6) In addition, an adverse event (unknown casual relationship)-hypothermia-after ingestion of OP has been reported. Fortyfour cases of hypothermia had been reported to the MHLW (Ministry of Health, Labour and Welfare, Japan) up to March 20, 2007. 7) Data released by the Food and Drug Administration (FDA) have also described hypothermia to 34°C in 2 cases. 8)In the present study, we investigated the effects of OP on normal core body temperature using mice, and found relatively strong hypothermic effects. Zanamivir, which is also a neuraminidase inhibitor and an anti-influenza virus drug, was compared with the effects of OP. Absorbed OP is hydrolyzed by human liver CES1 to the active metabolite OC.1,2) The hydrolysis is strongly inhibited by the anti-platelet drug clopidogrel, which is metabolized by the same esterase CES1. 9)Therefore, clopidogrel was used to inhibit hydrolysis of OP in an attempt to study the involvement of OP or OC in hypothermia after OP administration.As the antipyretic diclofenac carries a warning of possible severe hypothermia in children and the elderly with high fever in the package insert and an interview form, 10,11) the effects of diclofenac on body temperature and its interaction with OP were also studied. MATERIALS AND METHODS AnimalsOne hundred forty-six male mice (ddY strain, SLC Shizuoka, Japan) were kept for at least 7 d under a 12/12 h light-dark cycle before experiments with full access to water and food, except those used for oral administration of OP, which were fasted for more than 15 h.All experimental protocols used were approved by the Animal Care and Use Committee of Nagoya City University and were conducted in accordance with the guidelines of the Japanese Pharmacological Society.Measurement of Rectal Temperature At 5 weeks of age, the mice were used to study the effects of drugs on body temperature in an experimental room for animal behavior, which was maintained at 23-25°C. Each mouse was placed individually in a Plexiglas cage (19ϫ12ϫ11 cm (depth)), then removed every 10 min, held loosely in a small cloth bag, and the core body temperature was measured using a digital thermometer with a resolution of 0.1°C (MT-132, Mother Tool, Ueda, Japan). The thermometer probe was inserted 25 mm into the rectum. 12) After each measurement, the mouse was returned to its cage. Mice whose rectal temperature before drug administration was below 37°C were not used for experiments. Drugs were administered after the temperature became stable.Drugs The drugs used were oseltamivir phosp...

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Section: )mentioning

confidence: 99%

Oseltamivir, an Anti-influenza Virus Drug, Produces Hypothermia in Mice

Ono

Nagano

Matsunami

et al. 2008

Biological & Pharmaceutical Bulletin

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“…The licensed influenza virus neuraminidase inhibitors zanamivir and oseltamivir carboxylate are beneficial when treatment is initiated early, but this is increasingly offset by viral resistance (15)(16)(17). Despite extensive research, no vaccines are currently available for paramyxoviruses such as RSV and the HPIVs, and declining mumps vaccine uptake in several developed countries has, in conjunction with primary and secondary vaccine failures, resulted in a recent resurgence of mumps (14).…”

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confidence: 99%

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Yan

Krumm

Sun

et al. 2013

J Virol

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f As we are confronted with an increasing number of emerging and reemerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting of host factors required for virus replication presents a tangible approach toward obtaining novel hits with a broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource efficiency and pan-myxovirus activity as the central developmental parameters, we explored coscreening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired coreplication of both viruses, generated suitable firefly and Renilla luciferase reporter constructs, respectively, and validated the protocol for up to a 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with a broadened antimyxovirus profile, in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broadspectrum lead that does not block viral entry but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof of concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para-and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class.

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“…In Japan, more than 90% of infl uenza cases in children are administered antiviral drugs, mostly oseltamivir and occasionally amantadine (Sugaya et al 2007). In this study, only 42 of 424 infl uenza patients (9.9%) did not receive antiviral drug (non-antiviral group).…”

Section: Discussionmentioning

confidence: 66%

Recurrence and Persistence of Fever in Children Who Developed Amantadine-Resistant Influenza Viruses after Treatment

Shobugawa

Saito

Sato³

et al. 2008

Tohoku J. Exp. Med.

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In recent years, a dramatic increase of amantadine-resistant infl uenza A has occurred globally, but limited data have been available on the clinical course of patients developed amantadine-resistant viruses. We compared fever reduction between patients who developed resistance or remained sensitive in a pediatric clinic in Niigata, Japan, from 2000 to 2006. A total of 2,802 clinical samples were collected from patients who visited the pediatric outpatient clinic with infl uenza like illness during the seven infl uenza epidemic seasons. Patients were divided into 4 groups and analyzed for the fever reduction after amantadine treatment: emerged amantadine-resistant (n = 15); amantadine-sensitive (n = 35); patients administered no antiviral drugs (n = 42); and oseltamivir-treated patients (n = 320), which served as references. All 4 groups showed alleviation of fever up to day 3. The amantadine-resistant group had a signifi cant recurrence of fever on day 4 and/or 5, and as a consequence, the course of illness was prolonged. Considering the pattern of fever, recurrent and persistent patterns were found signifi cantly at higher rates in children with emerged resistant virus compared to other groups, and the age tended to be younger in amantadine-resistant compared to amantadine-sensitive group (3.9 ± 3.0 vs 6.7 ± 4.1 years old, n.s.). Therefore, we concluded that younger children were prone to develop amantadine-resistance after treatment and showed a signifi cant recurrence of fever on day 4 and/or 5, and the course of illness was consequently prolonged. infl uenza; amantadine; infl uenza; amantadine; antiviral-resistance; children; recurrence of fever.Tohoku

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Lower Clinical Effectiveness of Oseltamivir against Influenza B Contrasted with Influenza A Infection in Children

Cited by 166 publications

References 17 publications

Oseltamivir, an Anti-influenza Virus Drug, Produces Hypothermia in Mice

Oseltamivir, an Anti-influenza Virus Drug, Produces Hypothermia in Mice

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Recurrence and Persistence of Fever in Children Who Developed Amantadine-Resistant Influenza Viruses after Treatment

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