Comparison of the effects of #peramivir and #oseltamivir on the rise in #platelet count in patients with or without proven #influenza (Int J Clin Pharmacol Ther., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Int J Clin Pharmacol Ther. 2018 Dec 11. doi: 10.5414/CP203366. [Epub ahead of print]

Comparison of the effects of peramivir and oseltamivir on the rise in platelet count in patients with or without proven influenza.

Kim YG, Ko SY, Lee SW.

 

Abstract

OBJECTIVE:

Neuraminidase (sialidase) inhibitors are considered to delay platelet clearance through the inhibition of platelet desialylation. A novel neuraminidase inhibitor, peramivir, was recently approved for intravenous administration by the US FDA. We aimed to compare the effects of peramivir and oseltamivir on patient platelet count.

MATERIALS AND METHODS:

Consecutive patients who were treated with peramivir or tested positive for influenza between January 2015 and December 2017 were analyzed. The analysis included 461 patients with platelet counts available; the patients were divided into three groups: patients with proven influenza treated with peramivir (n = 305); those treated with peramivir without proven influenza (n = 83), and those with proven influenza treated with oseltamivir (n = 73).

RESULTS:

Patients treated with peramivir did not show an increase in platelet count from the baseline count, regardless of proven influenza (from 263.4 × 109/L to 267.4 × 109/L; 9 = 0.410) or not (from 257.1 × 109/L to 255.4 × 109/L; p = 0.873); wheeras for patients treated with oseltamivir, a significant increase above the baseline was found (from 223.3 × 109/L to 249.9 × 109/L; p = 0.016), although it was transient.

CONCLUSION:

Peramivir and oseltamivir appear to have different effects on patient platelet count when administered at the recommended doses

PMID: 30526812 DOI: 10.5414/CP203366

Keywords: Seasonal Influenza; Antivirals; Oseltamivir; Zanamivir.

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Intravenous #zanamivir for #influenza #myocarditis and enteral malabsorption (Crit Care, abstract)

[Source: Critical Care, full page: (LINK). Summary, edited.]

Intravenous zanamivir for influenza myocarditis and enteral malabsorption

Fritz-Patrick Jahns, Nawfel Ben-Hamouda, Matthias Kirsch, Aurélien Roumy and Lucas Liaudet

Critical Care, 201822:332 / DOI: https://doi.org/10.1186/s13054-018-2263-y

©  The Author(s). 2018

Received: 26 October 2018 – Accepted: 15 November 2018 – Published: 4 December 2018

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Acute myocarditis is an uncommon complication of influenza with a high mortality [1]. Early therapy with neuraminidase inhibitors (NI) is recommended in patients hospitalized for influenza, notably those with myocarditis. Oral oseltamivir is generally used as the first line NI therapy, whereas parenteral zanamivir and peramivir represent alternatives in selected patients who might not respond to oseltamivir, as may occur in conditions of gut failure and defective enteral drug absorption [2, 3]. We present two patients with influenza myocarditis complicated by enteral drug malabsorption, who received early intravenous zanamivir therapy with excellent clinical outcomes.

(…)

Acknowledgements

None.

Funding

None.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

FPJ, data collection and analysis and writing the manuscript. NBH, data collection and analysis, writing the manuscript, and submission. MK, data collection and analysis and writing the manuscript. AR, data collection and analysis and writing the manuscript. LL, data collection and analysis and writing the manuscript and final revision. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Retrospective collection of data. Standard of care.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Keywords: Seasonal Influenza; Myocarditis; Oseltamivir; Zanamivir; Antivirals.

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#Genetic characteristics of #hemagglutinin and #neuraminidase of #avian #influenza A (#H7N9) virus in #Guizhou province, 2014-2017 (Zhonghua Liu Xing Bing Xue Za Zhi, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Zhonghua Liu Xing Bing Xue Za Zhi. 2018 Nov 10;39(11):1465-1471. doi: 10.3760/cma.j.issn.0254-6450.2018.11.009.

[Genetic characteristics of hemagglutinin and neuraminidase of avian influenza A (H7N9) virus in Guizhou province, 2014-2017].

[Article in Chinese; Abstract available in Chinese from the publisher]

Wan YH1, Zhuang L, Zheng QN, Ren LJ, Fu L, Jiang WJ, Tang GP, Zhang DZ, Li SJ.

Author information: 1 Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China.

 

Abstract in English, Chinese

Objective:

To understand the molecular characteristics of hemagglutinin (HA) and neuraminidase (NA) as well as the disease risk of influenza virus A H7N9 in Guizhou province.

Methods:

RNAs were extracted and sequenced from HA and NA genes of H7N9 virus strains obtained from 18 cases of human infection with H7N9 virus and 6 environmental swabs in Guizhou province during 2014-2017. Then the variation and the genetic evolution of the virus were analyzed by using a series of bioinformatics software package.

Results:

Homology analysis of HA and NA genes revealed that 2 strains detected during 2014-2015 shared 98.8%-99.2% and 99.2% similarities with vaccine strains A/Shanghai/2/2013 and A/Anhui/1/2013 recommended by WHO, respectively. Two strains detected in 2016 and 14 strains detected in 2017 shared 98.2%-99.3% and 97.6%-98.8% similarities with vaccine strain A/Hunan/02650/2016, respectively. Other 6 stains detected in 2017 shared 99.1%-99.4% and 98.9%-99.3% similarities with strain A/Guangdong/17SF003/2016, respectively. Phylogenetic analysis showed that all the strains were directly evolved in the Yangtze River Delta evolution branch, but they were derived from different small branch. PEVPKRKRTAR↓GLF was found in 6 of 24 strains cleavage site sequences of HA protein, indicating the characteristic of highly pathogenic avian influenza virus. Mutations A134V, G186V and Q226L at the receptor binding sites were found in the HA. All the strains had a stalk deletion of 5 amino acid residue “QISNT” in NA protein, and drug resistance mutation R294K occurred in strain A/Guizhou-Danzhai/18980/2017. In addition, potential glycosylation motifs mutations NCS42NCT were found in the NA of 9 of 24 strains.

Conclusions:

HA and NA genes of avian influenza A (H7N9) virus showed genetic divergence in Guizhou province during 2014-2017. The mutations of key sites might enhance the virulence of the virus, human beings are more susceptible to it. Hence, the risk of infection is increasing.

KEYWORDS: Avian influenza A (H7N9) virus; Hemagglutinin gene; Molecular characteristic; Neuraminidase gene

PMID:  30462955

Keywords: Avian Influenza; H7N9; Human; China; Guizhou; Antivirals; Drugs Resistance; Oseltamivir; Reassortant strain.

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#Combination #treatment with the cap-dependent endonuclease inhibitor #baloxavir marboxil and a #neuraminidase inhibitor in a mouse model of #influenza A virus #infection (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection

Keita Fukao, Takeshi Noshi, Atsuko Yamamoto, Mitsutaka Kitano, Yoshinori Ando, Takahiro Noda, Kaoru Baba, Kazumi Matsumoto, Naoko Higuchi, Minoru Ikeda, Takao Shishido, Akira Naito

Journal of Antimicrobial Chemotherapy, dky462, https://doi.org/10.1093/jac/dky462

Published: 21 November 2018

 

Abstract

Objectives

Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection.

Methods

The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection.

Results

Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung.

Conclusions

Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial.

Topic: cytokine – lung – chemokines – influenza a virus – orthomyxoviridae – infection – endonuclease – influenzavirus a – mice – viruses – oseltamivir – neuraminidase inhibitors – baloxavir marboxil

Issue Section: ORIGINAL RESEARCH

Keywords: Influenza A; Antivirals; Oseltamivir; Baloxavir; Animal models.

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Phase 2b Study of #Pimodivir (JNJ-63623872) as Monotherapy or in Combination With #Oseltamivir for #Treatment of Acute Uncomplicated Seasonal #Influenza A: TOPAZ Trial (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Phase 2b Study of Pimodivir (JNJ-63623872) as Monotherapy or in Combination With Oseltamivir for Treatment of Acute Uncomplicated Seasonal Influenza A: TOPAZ Trial

Robert W Finberg, Riin Lanno, David Anderson, Roman Fleischhackl, Wilbert van Duijnhoven, Robert S Kauffman, Teddy Kosoglou, Johan Vingerhoets, Lorant Leopold

The Journal of Infectious Diseases, jiy547, https://doi.org/10.1093/infdis/jiy547

Published: 14 November 2018

 

Abstract

Background

Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A.

Methods

In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated.

Results

Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription–polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, −3.6 day*log10 copies/mL [95% confidence interval {CI}, −7.1 to −0.1]; 600 mg group, −4.5 [95%CI −8.0 to −1.0]; and combination group, −8.6 [95% CI, −12.0 to −5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea.

Conclusions

Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development.

Clinical Trials Registration NCT02342249, 2014-004068-39, and CR107745.

Antiviral, influenza A, oseltamivir, pimodivir, seasonal influenza

Topic:  polymerase chain reaction – influenza – antiviral agents – influenza a virus – orthomyxoviridae – safety – viral load result – infection – influenzavirus a – oseltamivir

Issue Section:  Major Article

Keywords: Antivirals; Pimovidvir; Oseltamivir; Influenza A; Seasonal Influenza.

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Delayed #oseltamivir plus #sirolimus #treatment attenuates #H1N1 virus-induced severe #lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration

Xuehong Jia , Bo Liu , Linlin Bao , Qi Lv, Fengdi Li, Hui Li, Yunqing An, Xulong Zhang , Bin Cao , Chen Wang

Published: November 13, 2018 / DOI: https://doi.org/10.1371/journal.ppat.1007428 / This is an uncorrected proof.

 

Abstract

Severe influenza A virus infection causes high mortality and morbidity worldwide due to delayed antiviral treatment and inducing overwhelming immune responses, which contribute to immunopathological lung injury. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), was effective in improving clinical outcomes in patients with severe H1N1 infection; however, the mechanisms by which it attenuates acute lung injury have not been elucidated. Here, delayed oseltamivir treatment was used to mimic clinical settings on lethal influenza A (H1N1) pdm09 virus (pH1N1) infection mice model. We revealed that delayed oseltamivir plus sirolimus treatment protects mice against lethal pH1N1 infection by attenuating severe lung damage. Mechanistically, the combined treatment reduced viral titer and pH1N1-induced mTOR activation. Subsequently, it suppressed the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated secretion of interleukin (IL)-1β and IL-18. It was noted that decreased NLRP3 inflammasome activation was associated with inhibited nuclear factor (NF)-κB activation, reduced reactive oxygen species production and increased autophagy. Additionally, the combined treatment reduced the expression of other proinflammatory cytokines and chemokines, and decreased inflammatory cell infiltration in lung tissue and bronchioalveolar lavage fluid. Consistently, it inhibited the mTOR-NF-κB-NLRP3 inflammasome-IL-1β axis in a lung epithelial cell line. These results demonstrated that combined treatment with sirolimus and oseltamivir attenuates pH1N1-induced severe lung injury, which is correlated with suppressed mTOR-NLRP3-IL-1β axis and reduced viral titer. Therefore, treatment with sirolimus as an adjuvant along with oseltamivir may be a promising immunomodulatory strategy for managing severe influenza.

 

Author summary

The severity and lethality of influenza A virus infection are frequently aggravated by virus-induced tissue destruction and overwhelming immune responses. Combined therapy with antiviral medications and immunomodulators, which not only inhibit viral replication, but also reduce the damaging consequences of host immune responses, will be beneficial in the treatment of severe influenza. In the present study, we revealed that pH1N1-induced activation of mTOR promotes lung immunopathological injury, which is correlated with upregulated NF-κB activity and increased reactive oxygen species production. Subsequently, it induces NLRP3 inflammasome activation and the secretion of IL-1β and IL-18. Combined treatment with oseltamivir and the mTOR inhibitor sirolimus (as an adjuvant) not only blocks viral replication, but also suppresses mTOR-NLRP3-IL-1β axis-mediated immune damage, thus protecting mice against lethal pH1N1 infection. Our findings provide the theoretical and experimental basis for the clinical investigation of sirolimus as an adjunct treatment for severe influenza.

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Citation: Jia X, Liu B, Bao L, Lv Q, Li F, Li H, et al. (2018) Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration. PLoS Pathog 14(11): e1007428. https://doi.org/10.1371/journal.ppat.1007428

Editor: Paul G. Thomas, St. Jude Children’s Research Hospital, UNITED STATES

Received: April 10, 2018; Accepted: October 22, 2018; Published: November 13, 2018

Copyright: © 2018 Jia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This work was supported by grants from National Natural Science Foundation of China (81373114) (http://www.nsfc.gov.cn/) and Beijing Municipal Natural Science Foundation (7182013) (http://bjnsf.bjkw.gov.cn/) to XZ, National Science Grant for Distinguished Young Scholars (81425001/H0104) (http://www.nsfc.gov.cn/) and National Key Technology Support Program from Ministry of Science and Technology (2015BAI12B11) (http://www.most.gov.cn/) to BC, and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-014, 2016-12M-006) (www.pumc.edu.cn/) to LB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Influenza A; H1N1pdm09; Antivirals; Oseltamivir; Sirolimus; Animal Models.

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#Risk of #neuropsychiatric adverse events associated with the use of #oseltamivir: a nationwide population-based case-crossover study (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Risk of neuropsychiatric adverse events associated with the use of oseltamivir: a nationwide population-based case-crossover study

Hye-Rim Kang, Eui-Kyung Lee, Woo Jung Kim, Ju-Young Shin

Journal of Antimicrobial Chemotherapy, dky445, https://doi.org/10.1093/jac/dky445

Published: 12 November 2018

 

Abstract

Background

Although the potential risk of neuropsychiatric adverse events (NPAEs) upon administration of oseltamivir has been raised in case reports, the association between the use of oseltamivir and the risk of NPAEs is unclear.

Objectives

We aimed to evaluate whether the use of oseltamivir triggers NPAEs.

Patients and methods

We conducted a population-based case-crossover study using the National Sample Cohort data from the National Health Insurance Service in South Korea. From a total of 236 348 incident patients with NPAEs as either a primary or secondary diagnosis, our final case series included 5322 patients with a prior prescription for oseltamivir between 2009 and 2013. Exposure to oseltamivir was assessed during 2, 7, 14, 28 and 56 day hazard periods prior to each patient’s NPAE. Three pre-consecutive control periods were matched using the same time windows. Conditional logistic regression analysis was used to estimate adjusted ORs (aORs), adjusting for time-variant diagnosis of influenza and concomitant medications.

Results

Matched analyses found a consistently increased risk of NPAEs associated with the use of oseltamivir in the 2 day (aOR 1.90, 95% CI 1.29–2.81), 7 day (aOR 1.32, 95% CI 1.00–1.74), 14 day (aOR 1.28, 95% CI 1.03–1.60), 28 day (aOR 1.25, 95% CI 1.06–1.47) and 56 day (aOR 1.13, 95% CI 0.99–1.29) hazard periods compared with use in the three control periods.

Conclusions

This study found that the short-term use of oseltamivir triggers the incidence of NPAEs. Early monitoring of NPAEs may be required when prescribing oseltamivir with careful consideration of the risk–benefit balance of oseltamivir.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antivirals; Drugs Safety; Oseltamivir; Neurology; Psychiatry.

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