Assessing the #susceptibility of highly pathogenic #avian #influenza #H5N1 viruses to #oseltamivir using embryonated chicken #eggs (Indian J Med Res., abstract)

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

Indian J Med Res. 2019 Nov;150(5):486-491. doi: 10.4103/ijmr.IJMR_845_18.

Assessing the susceptibility of highly pathogenic avian influenza H5N1 viruses to oseltamivir using embryonated chicken eggs.

Tare DS1, Kode SS1, Hurt AC2, Pawar SD3.

Author information: 1 Avian Influenza Group, ICMR-National Institute of Virology-Microbial Containment Complex, Pune, Maharashtra, India. 2 WHO Collaborating Centre for Reference & Research on Influenza (VIDRL), Peter Doherty Institute for Infection & Immunity, Melbourne VIC 3000, Australia. 3 ICMR-National Institute of Virology-Mumbai Unit, Mumbai, Maharashtra, India.

 

Abstract

BACKGROUND & OBJECTIVES:

The susceptibility of influenza viruses to neuraminidase inhibitors (NAIs) is studied using enzyme-based assays, sequence analysis and in vitro and in vivo studies. Oseltamivir carboxylate (OC) is the active prodrug of the NAI oseltamivir. There is lack of information on the use of embryonated chicken eggs for studying susceptibility of highly pathogenic avian influenza (HPAI) H5N1 viruses to antiviral drugs. The aim of the present study was to assess the use of 10 day old embryonated chicken eggs for studying antiviral susceptibility of HPAI H5N1 viruses.

METHODS:

Two HPAI H5N1 viruses isolated from India were used in the study. Fluorescence-based NAI assay was performed to determine antiviral susceptibility of these viruses. In ovo antiviral assays were carried out using 10 day old embryonated chicken eggs. The virus dilutions were incubated with 14 μg/ml of OC and inoculated in the allantoic cavity. In the eggs, 50 per cent egg infectious dose (EID50) titres as well as mortality were quantitated.

RESULTS:

The two viruses used were susceptible to OC in the NAI assay. It was found that there was a significant drop in EID50titres; however, no significant protection from mortality after OC treatment was observed.

INTERPRETATION & CONCLUSIONS:

By measuring viral titres, the egg model was suitable to study the susceptibility of HPAI viruses to antiviral drugs along with NAI assay. The present study highlights the use of eggs as a model to study susceptibility of HPAI viruses to OC.

KEYWORDS: Antivirals – embryonated chicken eggs – H5N1 – highly pathogenic avian influenza – oseltamivir

PMID: 31939392 DOI: 10.4103/ijmr.IJMR_845_18

Keywords: Antivirals; Drugs resistance; Avian Influenza; H5N1; Animal models.

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Evaluating the effects of #oseltamivir phosphate on #platelet counts: a retrospective review (Platelets, abstract)

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

Platelets. 2020 Jan 13:1-5. doi: 10.1080/09537104.2020.1714576. [Epub ahead of print]

Evaluating the effects of oseltamivir phosphate on platelet counts: a retrospective review.

Shaim H1, McCaffrey P1, Trieu JA2, DeAnda A3, Yates SG1.

Author information: 1 Department of Pathology, Division of Transfusion Medicine, University of Texas Medical Branch, Galveston, TX, USA. 2 Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA. 3 Department of Surgery, Division of Cardiothoracic Surgery, University of Texas Medical Branch, Galveston, TX, USA.

 

Abstract

Desialylation of platelets results in platelet clearance by the Ashwell-Morrell Receptors (AMR) found on hepatocytes. Studies suggest that oseltamivir phosphate inhibits human sialidases, enzymes responsible for desialylation, extending the lifespan of circulating platelets. We thus evaluated, the effects of oseltamivir on platelet count (PC) following treatment. Of the 385 patients evaluated for influenza, 283 (73.5%) were influenza-infected. Of the 283 infected patients, 241 (85.2%) received oseltamivir (I + O+) while 42 patients did not (I + O-). One hundred two non-infected patients received oseltamivir (I-O+). The two groups receiving oseltamivir (I + O+, I-O+), demonstrated a statistically greater increase in the PC (57.53 ± 93.81, p = .013 and 50.79 ± 70.59, p = .023, respectively) relative to the group that did not (18.45 ± 89.33 × 109/L). The observed increase in PC was statistically similar (p = .61) in both groups receiving oseltamivir (I + O+, I-O+), suggesting that this effect is independent of influenza. Comparing clinical characteristics between responders and non-responders to oseltamivir treatment showed that only duration of oseltamivir treatment (AOR = 1.30, 95% CI 1.05-1.61, p = .015) was associated with a positive PC response. Our findings suggest a correlation between oseltamivir treatment and an increase in PCs. Future studies assessing the possible uses of oseltamivir in medical conditions characterized by diminished or defective thrombopoiesis are warranted.

KEYWORDS: Ashwell-Morell Receptor; glycans; oseltamivir; thrombocytopenia

PMID: 31931672 DOI: 10.1080/09537104.2020.1714576

Keywords: Antivirals; Oseltamivir; Platelets; Hematology.

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Early Administration of #Oseltamivir Within 48 Hours After Onset of Flulike Symptoms Can Reduce the #Risk of Influenza B Virus-Associated #Pneumonia in Hospitalized #Pediatric Patients with Influenza B Virus Infection (Pediatr Infect Dis J., abstract)

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

Pediatr Infect Dis J. 2020 Feb;39(2):e20-e22. doi: 10.1097/INF.0000000000002528.

Early Administration of Oseltamivir Within 48 Hours After Onset of Flulike Symptoms Can Reduce the Risk of Influenza B Virus-Associated Pneumonia in Hospitalized Pediatric Patients with Influenza B Virus Infection.

Dai Z1, Zhang L, Yu Q, Liu L, Yang M, Fan K.

Author information: 1 From the Department of Accident and Emergency, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.

 

Abstract

We conducted a retrospective study to identify the risk factors for pneumonia in hospitalized pediatric patients with influenza B infection. Receiving oseltamivir within the first 48 hours of onset and frequent cough was respectively considered as a protective factor and a risk factor for the influenza B virus-associated pneumonia in hospitalized pediatric patients. Early administration of oseltamivir can reduce the risk of influenza B virus-associated pneumonia.

PMID: 31929434 DOI: 10.1097/INF.0000000000002528

Keywords: Seasonal Influenza; Influenza B; Antivirals; Oseltamivir; Pneumonia; Pediatrics.

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#Drug #development against #smallpox: present and future (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Drug development against smallpox: present and future.

Déborah Delaune, Frederic Iseni

DOI: 10.1128/AAC.01683-19

 

ABSTRACT

Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus de novo, implying that VARV could, in theory, be resurrected. Because of this new perspective the WHO Advisory Committee on VARV Research released new recommendations concerning research on poxviruses that strongly encourages pursuing the development of new antiviral drugs against orthopoxviruses. In 2018, the US FDA advised in favor of two molecules for smallpox treatment: Tecovirimat and Brincidofovir. This review highlights the difficulties to develop new drugs targeting an eradicated disease, especially as it requires working under the FDA “animal efficacy rule” with the few, and imperfect, animal models available.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: Antivirals; Orthopoxvirus; Smallpox; Brincidofovir.

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A molecularly engineered #antiviral banana #lectin inhibits #fusion and is efficacious against #influenza virus infection in vivo (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo

Evelyn M. Covés-Datson, Steven R. King, Maureen Legendre, Auroni Gupta, Susana M. Chan, Emily Gitlin, Vikram V. Kulkarni, Jezreel Pantaleón García, Donald F. Smee, Elke Lipka, Scott E. Evans, E. Bart Tarbet, Akira Ono, and David M. Markovitz

PNAS first published January 13, 2020 / DOI: https://doi.org/10.1073/pnas.1915152117

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved December 19, 2019 (received for review September 8, 2019)

 

Significance

There is a pressing need for new antiinfluenza therapeutic agents. We show that a molecularly engineered banana lectin (carbohydrate-binding protein) has broad-spectrum activity against all influenza strains tested, including drug-resistant and currently circulating strains; is safe upon repeated administration in mice; and, moreover, is efficacious at treating lethal influenza infection via clinically pertinent routes of administration. We demonstrate that the lectin binds to the viral hemagglutinin glycoprotein and exerts its primary antiviral effect via inhibition of an early stage of the viral life cycle, viral membrane fusion to the host endosomal membrane. Our findings indicate that this engineered lectin, which has a mechanism of action quite distinct from the presently available agents, has potential as an antiinfluenza agent.

 

Abstract

There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.

influenza virus – hemagglutinin – membrane fusion – lectin – antiviral

Keywords: Antivirals; Banana lectin; Influenza A; Animal models.

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#Ribavirin and #Interferon #Therapy for Critically Ill Patients With #MERS: A Multicenter Observational Study (Clin Infect Dis., abstract)

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

Clin Infect Dis. 2019 Jun 25. pii: ciz544. doi: 10.1093/cid/ciz544. [Epub ahead of print]

Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study.

Arabi YM1, Shalhoub S2,3, Mandourah Y4, Al-Hameed F5, Al-Omari A6, Al Qasim E1, Jose J1, Alraddadi B7,8, Almotairi A9, Al Khatib K10, Abdulmomen A11, Qushmaq I7, Sindi AA12, Mady A13,14, Solaiman O15, Al-Raddadi R16, Maghrabi K15, Ragab A17, Al Mekhlafi GA18, Balkhy HH19, Al Harthy A13, Kharaba A20, Gramish JA21, Al-Aithan AM22, Al-Dawood A1, Merson L23, Hayden FG23,24, Fowler R25.

Author information: 1 Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia. 2 Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada. 3 King Fahad Armed Forces Hospital, Jeddah. 4 Military Medical Services, Ministry of Defense, Prince Sultan Military Medical City, Riyadh. 5 Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Jeddah. 6 Department of Intensive Care, College of Medicine, Alfaisal University, Dr Sulaiman Al-Habib Group Hospitals, Riyadh. 7 Department of Medicine, King Faisal Specialist Hospital and Research Center, Jeddah. 8 Department of Medicine, University of Jeddah. 9 Department of Critical Care Medicine, King Fahad Medical City, Riyadh. 10 Intensive Care Department, Al-Noor Specialist Hospital, Makkah. 11 Department of Critical Care Medicine, King Saud University, Riyadh. 12 Department of Anesthesia and Critical Care, Faculty of Medicine, King Abdulaziz University, Jeddah. 13 Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia. 14 Tanta University Hospitals, Egypt. 15 Intensive Care Department, King Faisal Specialist Hospital and Research Center, Riyadh. 16 Department of Community Medicine, Faculty of Medicine, King Abdulaziz University. 17 Intensive Care Department, King Fahd Hospital, Jeddah. 18 Department of Intensive Care Services, Prince Sultan Military Medical City. 19 Department of Infection Prevention and Control, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh. 20 Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah. 21 Pharmaceutical Care Department, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh. 22 Department of Medicine, Critical Care Division, King Abdulaziz Hospital, Al Ahsa, Saudi Arabia. 23 International Severe Acute Respiratory and Emerging Infection Consortium, Infectious Diseases Data Observatory, Oxford University, United Kingdom. 24 Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville. 25 Institute of Health Policy Management and Evaluation, University of Toronto, Department of Critical Care Medicine and Department of Medicine, Sunnybrook Hospital, Ontario, Canada.

 

Abstract

BACKGROUND:

The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders.

METHODS:

This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders.

RESULTS:

Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a; none received rIFN-β1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73-1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30-1.44]; P = .29).

CONCLUSIONS:

In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

KEYWORDS: Middle East respiratory syndrome; coronavirus; interferon; pneumonia; ribavirin

PMID: 31925415 DOI: 10.1093/cid/ciz544

Keywords: Antivirals; Ribavirin; Interferons; MERS-CoV.

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Comparative #therapeutic efficacy of #remdesivir and combination #lopinavir#, ritonavir, and #interferon beta against #MERS-CoV (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Timothy P. Sheahan, Amy C. Sims, Sarah R. Leist, Alexandra Schäfer, John Won, Ariane J. Brown, Stephanie A. Montgomery, Alison Hogg, Darius Babusis, Michael O. Clarke, Jamie E. Spahn, Laura Bauer, Scott Sellers, Danielle Porter, Joy Y. Feng, Tomas Cihlar, Robert Jordan, Mark R. Denison & Ralph S. Baric

Nature Communications, volume 11, Article number: 222 (2020)

 

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.

Keywords: Antivirals; Remdesivir; Lopinavir; Ritonavir; Interferons; MERS-CoV; Animal models.

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