Immune-mediated #Drug-induced #Liver #Injury Caused by #Laninamivir Octanoate Hydrate: A Case Report (Intern Med., abstract)

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

Intern Med. 2019 May 22. doi: 10.2169/internalmedicine.2740-19. [Epub ahead of print]

Immune-mediated Drug-induced Liver Injury Caused by Laninamivir Octanoate Hydrate: A Case Report.

Kawaguchi T1, Arinaga-Hino T1, Shimizu M2, Tanikawa K3, Tokushige T4, Hirai S4, Nagamatsu H2, Tateishi H4, Takata A5, Ide T1, Torimura T1.

Author information: 1 Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Japan. 2 Department of Gastroenterology, Juntendo University School of Medicine, Japan. 3 Department of Diagnostic Pathology, Yame General Hospital, Japan. 4 Department of Gastroenterology, Yame General Hospital, Japan. 5 Department of Gastroenterology, Asakura Medical Association Hospital, Japan.

 

Abstract

We herein report the first case of immune-mediated drug-induced liver injury that may have been caused by laninamivir. A 15-year-old girl was diagnosed with influenza and prescribed 40 mg laninamivir. Six weeks later, she was admitted to our hospital because of jaundice and fatigue. Laboratory examinations revealed elevated levels of hepatobiliary enzymes, and acute liver injury was suspected. Laboratory examinations and histological findings were characteristic of autoimmune hepatitis. Steroid treatment was ineffective, and azathioprine was added to the treatment. Twenty-two months after the onset, a second biopsy revealed the absence of inflammatory infiltrations, and the drugs were withdrawn. Liver function tests remained normal nine months after withdrawal.

KEYWORDS: autoimmune hepatitis; drug-induced autoimmune hepatitis; drug-induced liver injury; immune-mediated drug-induced liver injury; laninamivir

PMID: 31118398 DOI: 10.2169/internalmedicine.2740-19

Keywords: Antivirals; Drugs Safety; Laninamivir.

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One hundred years after the 1918 #pandemic: new concepts for #preparing for #influenza pandemics (Curr Opin Infect Dis., abstract)

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

Curr Opin Infect Dis. 2019 May 20. doi: 10.1097/QCO.0000000000000564. [Epub ahead of print]

One hundred years after the 1918 pandemic: new concepts for preparing for influenza pandemics.

Pavia A1.

Author information: 1 Division of Pediatric Infectious Diseases, University of Utah, Salt Lake City, Utah, USA.

 

Abstract

PURPOSE OF REVIEW:

In the 100 years since the influenza pandemic of 1918-1919, the most deadly event in human history, we have made substantial progress yet we remain vulnerable to influenza pandemics This article provides a brief overview of important advances in preparing for an influenza pandemic, viewed largely from the perspective of the healthcare system.

RECENT FINDINGS:

We have gained insights into influenza pathogenicity, the animal reservoir and have improved global surveillance for new strains and tools for assessing the pandemic risk posed by novel strains. Public health has refined plans for severity assessment, distribution of countermeasures and nonpharmaceutical approaches. Modest improvements in vaccine technology include cell culture-based vaccines, adjuvanted vaccine and recombinant technology. Conventional infection control tools will be critical in healthcare settings. New evidence suggests that influenza virus may be present in aerosols; the contribution of airborne transmission and role of N95 respirators remains unknown. Baloxavir and pimodivir are new antivirals that may improve treatment, especially for severely ill patients. Optimal use and the risk of resistance require further study.

SUMMARY:

Despite the progress in pandemic preparedness, gaps remain including important scientific questions, adequate resources and most importantly, the ability to rapidly deliver highly effective vaccines.

PMID: 31116135 DOI: 10.1097/QCO.0000000000000564

Keywords: Pandemic Influenza; Spanish flu; Pandemic Preparedness; Antivirals; Vaccines.

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#Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses #influenza virus #replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models (PLoS One, abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models

Keita Fukao, Yoshinori Ando, Takeshi Noshi, Mitsutaka Kitano, Takahiro Noda, Makoto Kawai, Ryu Yoshida, Akihiko Sato, Takao Shishido , Akira Naito

Published: May 20, 2019 / DOI: https://doi.org/10.1371/journal.pone.0217307

 

Abstract

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.

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Citation: Fukao K, Ando Y, Noshi T, Kitano M, Noda T, Kawai M, et al. (2019) Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models. PLoS ONE 14(5): e0217307. https://doi.org/10.1371/journal.pone.0217307

Editor: Stefan Pöhlmann, Deutsches Primatenzentrum GmbH – Leibniz-Institut fur Primatenforschung, GERMANY

Received: February 8, 2019; Accepted: May 8, 2019; Published: May 20, 2019

Copyright: © 2019 Fukao 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 manuscript and its Supporting Information files.

Funding: This study was sponsored by Shionogi and Co., Ltd (Osaka, Japan), manufacturer/licensee of baloxavir marboxil. The sponsor provided support in the form of salaries for authors [KF, YA, TN, MK, TN, MK, RY, AS, TS and AN], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: All authors are employees of Shionogi and Co., Ltd or Shionogi TechnoAdvance Research, Co., Ltd, an affiliation of Shionogi. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Keywords: Influenza A; Antivirals; Baloxavir Marboxil; Animal Models.

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#Effectiveness of the #Neuraminidase #Inhibitors: The Supporting #Evidence Increases (J Infect Dis., summary)

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

Effectiveness of the Neuraminidase Inhibitors: The Supporting Evidence Increases

Arnold S Monto

The Journal of Infectious Diseases, jiz157, https://doi.org/10.1093/infdis/jiz157

Published: 20 May 2019

Issue Section: Editorial Commentary

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The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir were the first in that class of influenza antivirals to receive approval by the Food and Drug Administration, with both approved at the turn of the last century [1, 2] The regulatory approvals, for both prophylaxis and treatment of uncomplicated influenza, occurred after standard review of studies. The 2 drugs target nearby sites in the enzymatically active pocket of the virus but are very different in their route of administration and pharmacokinetics [1, 2]. Despite these differences, the results of the clinical trials of both were remarkably similar in terms of the characteristics of prophylactic efficacy and of treatment effects. Recruitment of cases to the treatment studies was based on clinical criteria but was limited to the influenza season; these cases were the intent-to-treat population [3–5]. The studies were done before use of polymerase chain reaction analysis had become accepted for influenza diagnosis, so the standard method of detecting the infecting virus was by cell culture.

(…)

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Notes

Potential conflicts of interest.

A. S. M. reports personal fees from Roche outside the submitted work. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Keywords: Antivirals; Oseltamivir; Zanamivir; Peramivir; Influenza A; Pandemic Influenza.

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In vitro #neuraminidase inhibitory concentration (#IC50) of four neuraminidase inhibitors in the #Japanese 2017-18 #season: Comparison with the 2010-11 to 2016-17 seasons (J Infect Chemother., abstract)

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

J Infect Chemother. 2019 May 14. pii: S1341-321X(19)30099-6. doi: 10.1016/j.jiac.2019.04.007. [Epub ahead of print]

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2017-18 season: Comparison with the 2010-11 to 2016-17 seasons.

Ikematsu H1, Kawai N2, Chong Y3, Bando T2, Iwaki N2, Kashiwagi S2.

Author information: 1 Japan Physicians Association, Tokyo, Japan; Ricerca Clinica Co., Fukuoka, Japan. Electronic address: ikematsu@gray.plala.or.jp. 2 Japan Physicians Association, Tokyo, Japan. 3 Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

 

Abstract

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the viruses epidemic in the 2017-18 Japanese influenza season, we measured the 50% inhibitory concentration (IC50) for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2016-17 seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype 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 237 virus isolates, 50 A(H1N1)pdm09, 92 A(H3N2), and 95 B were measured. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2017-18 season. No isolates with highly reduced sensitivity to the four NAIs have been found for A(H3N2) or B from the 2010-11 to 2017-18 seasons. The geometric mean IC50s of the four NAIs were quite consistent during the eight studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained.

Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: 50% inhibitory concentration; Influenza virus; Neuraminidase inhibitor; Resistance; Surveillance

PMID: 31101530 DOI: 10.1016/j.jiac.2019.04.007

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir; Laninamivir; Japan; Seasonal Influenza; H1N1pdm09; H3N2; Influenza B.

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#Antiviral #resistant #cytomegalovirus infections in solid organ #transplantation in the #Netherlands (J Antimicrob Chemother., abstract)

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

Antiviral-resistant cytomegalovirus infections in solid organ transplantation in the Netherlands

Coretta C Van Leer Buter, Danielle W K de Voogd, Hans Blokzijl, Anoek A E de Joode, Stefan P Berger, Erik A M Verschuuren, Hubert G M Niesters

Journal of Antimicrobial Chemotherapy, dkz196, https://doi.org/10.1093/jac/dkz196

Published: 15 May 2019

 

Abstract

Objectives

Antiviral resistance in cytomegalovirus (CMV) may result from mutations in the molecular targets of antiviral agents. The aim of this study was to investigate both the prevalence of resistance-associated mutations and the factors associated with antiviral resistance in solid organ transplant (SOT) patients with repeated high CMV loads during antiviral treatment.

Methods

SOT patients were selected retrospectively, based on CMV loads of >30 000 IU/mL at least twice in a period during which treatment was given. Patient samples were tested for antiviral resistance by Sanger sequencing the UL97 and UL54 genes of CMV, which code for the viral kinase and polymerase. Factors predisposing to and resulting from the development of antiviral resistance mutations were analysed.

Results

Multiple samples from 113 SOT patients were tested, showing resistance-associated mutations in 25 patients (22%). A further 20 (18%) patients showed mutations that were not known to be associated with antiviral resistance. Several factors were associated with development of resistance-associated mutations in UL97 as well as UL54, including human leucocyte antigen (HLA) mismatch, which occurred more frequently in the group of patients with resistance mutations. High-level resistance mutations were most frequently seen in UL97.

Conclusions

This study shows that by selecting patients solely on the basis of virological response to treatment, more patients with antiviral resistance mutations are identified. In this study we confirm findings by other groups that primary infections are associated with resistance development. Moreover, we show that HLA mismatch is associated with the development of antiviral resistance, which suggests a role for host immunity in the development of resistance.

Topic: mutation – human leukocyte antigens – antiviral agents – drug resistance, viral – genes – immunity – netherlands – organ transplantation – phosphotransferases – infection – cytomegalovirus infections – cytomegalovirus – virology – transplanted organ – dideoxy chain termination dna sequencing – host (organism) – mismatch

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. 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 Resistance; CMV; Organ transplantation.

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Identification of #Ebola Virus #Inhibitors Targeting GP2 using Principles of Molecular Mimicry (J Virol., abstract)

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

Identification of Ebola Virus Inhibitors Targeting GP2 using Principles of Molecular Mimicry

Courtney D. Singleton, Monica S. Humby, Hyun Ah Yi, Robert C. Rizzo, Amy Jacobs

DOI: 10.1128/JVI.00676-19

 

ABSTRACT

A key step in the Ebola virus (EBOV) replication cycle involves conformational changes in the viral glycoprotein 2 (GP2) which facilitate host-viral membrane fusion and subsequent release of the viral genome. Ebola GP2 plays a critical role in viral entry and has similarities in mechanism and structure to the HIV gp41 protein for which inhibitors have been successfully developed. In this work, a putative binding pocket for the C-terminal heptad repeat in the N-terminal heptad repeat trimer was targeted for identification of small molecules that arrest EBOV-host membrane fusion. Two computational structure-based virtual screens of ∼1.7M compounds were performed (DOCK program), against a GP2 five-helix bundle, resulting in 165 commercially available compounds purchased for experimental testing. Based on assessment of inhibitory activity, cytotoxicity, and target specificity, four promising candidates emerged with IC50 values in the 3-26 μM range. Molecular dynamics simulations of the two most potent candidates in their DOCK-predicted binding poses indicate that the majority of favorable interactions involve seven highly conserved residues which can be used to guide further inhibitor development and refinement targeting EBOV.

 

IMPORTANCE

The most recent Ebola Virus Disease outbreak from 2014 – 2016, resulted in approximately 28,000 individuals becoming infected, which led to over 12,000 causalities worldwide. The particularly high pathogenicity of the virus makes identification and development of promising lead compounds to serve as inhibitors of Ebola infection paramount. To limit viral load, the viral-host membrane fusion event can be targeted through the inhibition of the class I fusion glycoprotein of Ebolavirus. In the current work, several promising small molecule inhibitors that target the glycoprotein GP2 were identified through systematic application of structure-based computational and experimental drug design procedures.

Copyright © 2019 Singleton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Ebola; Antivirals.

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