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Article ; Online: Treatments for COVID-19: Lessons from 2020 and new therapeutic options.

Salasc, Fanny / Lahlali, Thomas / Laurent, Emilie / Rosa-Calatrava, Manuel / Pizzorno, Andrés

2021 Volume 62, Page(s) 43–59

Abstract: To face the COVID-19 pandemic, prophylactic vaccines have been developed in record time, but vaccine coverage is still limited, accessibility is not equitable worldwide, and the vaccines are not fully effective against emerging variants. Therefore, ... ...

Abstract	To face the COVID-19 pandemic, prophylactic vaccines have been developed in record time, but vaccine coverage is still limited, accessibility is not equitable worldwide, and the vaccines are not fully effective against emerging variants. Therefore, therapeutic treatments are urgently needed to control the pandemic and treat vulnerable populations, but despite all efforts made, options remain scarce. However, the knowledge gained during 2020 constitutes an invaluable platform from which to build future therapies. In this review, we highlight the main drug repurposing strategies and achievements made over the first 18 months of the pandemic, but also discuss the antivirals, immunomodulators and drug combinations that could be used in the near future to cure COVID-19.
MeSH term(s)	COVID-19 ; Drug Repositioning ; Humans ; Pandemics ; SARS-CoV-2 ; Vaccines
Chemical Substances	Vaccines
Language	English
Publishing date	2021-11-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2021.11.002
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Article ; Online: Drug Repurposing Approaches for the Treatment of Influenza Viral Infection: Reviving Old Drugs to Fight Against a Long-Lived Enemy.

Pizzorno, Andrés / Padey, Blandine / Terrier, Olivier / Rosa-Calatrava, Manuel

Frontiers in immunology

2019 Volume 10, Page(s) 531

Abstract: Influenza viruses still constitute a real public health problem today. To cope with the emergence of new circulating strains, but also the emergence of resistant strains to classic antivirals, it is necessary to develop new antiviral approaches. This ... ...

Abstract	Influenza viruses still constitute a real public health problem today. To cope with the emergence of new circulating strains, but also the emergence of resistant strains to classic antivirals, it is necessary to develop new antiviral approaches. This review summarizes the state-of-the-art of current antiviral options against influenza infection, with a particular focus on the recent advances of anti-influenza drug repurposing strategies and their potential therapeutic, regulatory and economic benefits. The review will illustrate the multiple ways to reposition molecules for the treatment of influenza, from adventitious discovery to
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Drug Repositioning/methods ; Humans ; Influenza, Human/drug therapy ; Orthomyxoviridae/drug effects ; Orthomyxoviridae Infections/drug therapy
Chemical Substances	Antiviral Agents
Keywords	covid19
Language	English
Publishing date	2019-03-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00531
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Article ; Online: Influenza viruses and coronaviruses: Knowns, unknowns, and common research challenges.

Terrier, Olivier / Si-Tahar, Mustapha / Ducatez, Mariette / Chevalier, Christophe / Pizzorno, Andrés / Le Goffic, Ronan / Crépin, Thibaut / Simon, Gaëlle / Naffakh, Nadia

PLoS pathogens

2021 Volume 17, Issue 12, Page(s) e1010106

Abstract: The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in ... ...

Abstract	The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.
MeSH term(s)	Animals ; Antiviral Agents ; COVID-19/therapy ; COVID-19/transmission ; COVID-19/virology ; Drug Development ; Evolution, Molecular ; Humans ; Influenza, Human/therapy ; Influenza, Human/transmission ; Influenza, Human/virology ; Orthomyxoviridae/immunology ; Orthomyxoviridae/physiology ; SARS-CoV-2/immunology ; SARS-CoV-2/physiology ; Selection, Genetic ; Viral Load ; Viral Vaccines
Chemical Substances	Antiviral Agents ; Viral Vaccines
Language	English
Publishing date	2021-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010106
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Article ; Online: The combination of oseltamivir with azithromycin does not show additional benefits over oseltamivir monotherapy in mice infected with influenza A(H1N1)pdm2009 virus.

Fage, Clément / Pizzorno, Andrés / Rhéaume, Chantal / Abed, Yacine / Boivin, Guy

Journal of medical virology

2017 Volume 89, Issue 12, Page(s) 2239–2243

Abstract: The combination of azithromycin, an immunomodulator, with oseltamivir was compared to oseltamivir monotherapy in a lethal BALB/c model of influenza A(H1N1)pdm09 infection. Groups of 14-16 mice received oral oseltamivir (10 mg/kg once daily for 5 days, ... ...

Abstract	The combination of azithromycin, an immunomodulator, with oseltamivir was compared to oseltamivir monotherapy in a lethal BALB/c model of influenza A(H1N1)pdm09 infection. Groups of 14-16 mice received oral oseltamivir (10 mg/kg once daily for 5 days, starting at day 2 post-inoculation) alone or combined to azithromycin (a single 100 mg/kg dose, injected intraperitoneally at day 3 post-inoculation). Based on survival rates, lung viral titers, and pro-inflammatory cytokine levels, the combination therapy did not provide obvious additional clinical/virological benefits over oseltamivir monotherapy. Additional studies are still needed to better define the potential role of adjunctive immunomodulatory therapy for severe influenza infections.
MeSH term(s)	Animals ; Antiviral Agents/administration & dosage ; Antiviral Agents/adverse effects ; Antiviral Agents/therapeutic use ; Azithromycin/administration & dosage ; Azithromycin/adverse effects ; Drug Therapy, Combination ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects ; Influenza, Human/drug therapy ; Influenza, Human/virology ; Injections, Intraperitoneal ; Lung/drug effects ; Lung/virology ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/drug therapy ; Orthomyxoviridae Infections/virology ; Oseltamivir/administration & dosage ; Oseltamivir/adverse effects ; Viral Load
Chemical Substances	Antiviral Agents ; Oseltamivir (20O93L6F9H) ; Azithromycin (83905-01-5)
Language	English
Publishing date	2017-08-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.24911
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Article ; Online: Interactions between Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Major Respiratory Viruses in Human nasal Epithelium.

Andrés, Pizzorno / Blandine, Padey / Victoria, Dulière / William, Mouton / Justine, Oliva / Laurent, Emilie / Cedrine, Milesi / Bruno, Lina / Aurelien, Traversier / Thomas, Julien / Sophie, Trouillet Assant / Manuel, Rosa Calatrava / Olivier, Terrier

The Journal of infectious diseases

2022

Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with extensive non-pharmacological interventions, have profoundly altered the epidemiology of major respiratory viruses. Some studies have described virus-virus ... ...

Abstract	The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with extensive non-pharmacological interventions, have profoundly altered the epidemiology of major respiratory viruses. Some studies have described virus-virus interactions, particularly manifested by viral interference mechanisms at different scales. Still, our knowledge of the mutual interactions between SARS-CoV-2 and other respiratory viruses remains incomplete. Here, we studied the interactions between SARS-CoV-2 and several respiratory viruses (influenza, RSV, hMPV, and hRV) in a reconstituted human epithelial airway model, exploring different scenarios affecting the sequence and timing of co-infections. We show that the virus type and the sequence of infections are key parameters of virus-virus interactions, having the impact of primary infections on the regulation of the immune response a determinant role in the outcome of secondary infections.
Language	English
Publishing date	2022-08-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiac357
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Article ; Online: Influenza viruses and coronaviruses

Olivier Terrier / Mustapha Si-Tahar / Mariette Ducatez / Christophe Chevalier / Andrés Pizzorno / Ronan Le Goffic / Thibaut Crépin / Gaëlle Simon / Nadia Naffakh

PLoS Pathogens, Vol 17, Iss 12, p e

Knowns, unknowns, and common research challenges.

2021 Volume 1010106

Abstract	The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Permissive changes in the neuraminidase play a dominant role in improving the viral fitness of oseltamivir-resistant seasonal influenza A(H1N1) strains.

Abed, Yacine / Pizzorno, Andrés / Bouhy, Xavier / Boivin, Guy

Antiviral research

2015 Volume 114, Page(s) 57–61

Abstract: Permissive neuraminidase (NA) substitutions such as R222Q, V234M and D344N have facilitated the emergence and worldwide spread of oseltamivir-resistant influenza A/Brisbane/59/2007 (H1N1)-H275Y viruses. However, the potential contribution of genetic ... ...

Abstract	Permissive neuraminidase (NA) substitutions such as R222Q, V234M and D344N have facilitated the emergence and worldwide spread of oseltamivir-resistant influenza A/Brisbane/59/2007 (H1N1)-H275Y viruses. However, the potential contribution of genetic changes in other viral segments on viral fitness remains poorly investigated. A series of recombinant A(H1N1)pdm09 and A/WSN/33 7:1 reassortants containing the wild-type (WT) A/Brisbane/59/2007 NA gene or its single (H275Y) and double (H275Y/Q222R, H275Y/M234V and H275Y/N344D) variants were generated and their replicative properties were assessed in vitro. The Q222R reversion substitution significantly reduced viral titers when evaluated in both A(H1N1)pdm09 and A/WSN/33 backgrounds. The permissive role of the R222Q was further confirmed using A/WSN/33 7:1 reassortants containing the NA gene of the oseltamivir-susceptible or oseltamivir-resistant influenza A/Mississippi/03/2001 strains. Therefore, NA permissive substitutions play a dominant role for improving viral replication of oseltamivir-resistant A (H1N1)-H275Y viruses in vitro.
MeSH term(s)	Antiviral Agents/pharmacology ; Drug Resistance, Viral/genetics ; Genetic Fitness ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects ; Influenza A Virus, H1N1 Subtype/genetics ; Influenza A Virus, H1N1 Subtype/physiology ; Influenza, Human/virology ; Mutation, Missense ; Neuraminidase/genetics ; Neuraminidase/metabolism ; Oseltamivir/pharmacology ; Seasons ; Viral Load ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Replication
Chemical Substances	Antiviral Agents ; Viral Proteins ; Oseltamivir (20O93L6F9H) ; NA protein, influenza A virus (EC 3.2.1.18) ; Neuraminidase (EC 3.2.1.18)
Language	English
Publishing date	2015-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2014.12.006
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Article ; Online: Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro.

Jonsdottir, Hulda R / Siegrist, Denise / Julien, Thomas / Padey, Blandine / Bouveret, Mendy / Terrier, Olivier / Pizzorno, Andres / Huang, Song / Samby, Kirandeep / Wells, Timothy N C / Boda, Bernadett / Rosa-Calatrava, Manuel / Engler, Olivier B / Constant, Samuel

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 150, Page(s) 113058

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available and multitudes of antiviral treatments have been proposed and ... ...

Abstract	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available and multitudes of antiviral treatments have been proposed and tested. Although many of the vaccines show clinical efficacy, they are not equally accessible worldwide. Additionally, due to the continuous emergence of new variants and generally short duration of immunity, the development of effective antiviral treatments remains of the utmost importance. Since the emergence of SARS-CoV-2, substantial efforts have been undertaken to repurpose existing drugs for accelerated clinical testing and emergency use authorizations. However, drug-repurposing studies using cellular assays often identify hits that later prove ineffective clinically, highlighting the need for more complex screening models. To this end, we evaluated the activity of single compounds that have either been tested clinically or already undergone extensive preclinical profiling, using a standardized in vitro model of human nasal epithelium. Furthermore, we also evaluated drug combinations based on a sub-maximal concentration of molnupiravir. We report the antiviral activity of 95 single compounds and 30 combinations. We show that only a few single agents are highly effective in inhibiting SARS-CoV-2 replication while selected drug combinations containing 10 µM molnupiravir boosted antiviral activity compared to single compound treatment. These data indicate that molnupiravir-based combinations are worthy of further consideration as potential treatment strategies against coronavirus disease 2019 (COVID-19).
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Cytidine/analogs & derivatives ; Humans ; Hydroxylamines ; Nasal Mucosa ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Hydroxylamines ; Cytidine (5CSZ8459RP) ; molnupiravir (YA84KI1VEW)
Language	English
Publishing date	2022-05-02
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.113058
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Article ; Online: In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses.

Checkmahomed, Liva / Padey, Blandine / Pizzorno, Andrés / Terrier, Olivier / Rosa-Calatrava, Manuel / Abed, Yacine / Baz, Mariana / Boivin, Guy

Viruses

2020 Volume 12, Issue 10

Abstract: Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead ...

Abstract	Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations.
MeSH term(s)	Acids, Carbocyclic/pharmacology ; Amides/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Cell Line ; Dibenzothiepins/pharmacology ; Dogs ; Drug Combinations ; Drug Resistance, Viral/drug effects ; Drug Synergism ; Guanidines/pharmacology ; Influenza A Virus, H1N1 Subtype/drug effects ; Influenza A Virus, H3N2 Subtype/drug effects ; Madin Darby Canine Kidney Cells ; Morpholines/pharmacology ; Neuraminidase/antagonists & inhibitors ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Orthomyxoviridae Infections/drug therapy ; Oseltamivir/pharmacology ; Pyrazines/pharmacology ; Pyridones/pharmacology ; Ribavirin/pharmacology ; Triazines/pharmacology ; Viral Proteins/antagonists & inhibitors ; Virus Replication/drug effects ; Zanamivir/pharmacology
Chemical Substances	Acids, Carbocyclic ; Amides ; Antiviral Agents ; Dibenzothiepins ; Drug Combinations ; Guanidines ; Morpholines ; Nucleic Acid Synthesis Inhibitors ; Pyrazines ; Pyridones ; Triazines ; Viral Proteins ; Oseltamivir (20O93L6F9H) ; Ribavirin (49717AWG6K) ; baloxavir (4G86Y4JT3F) ; Neuraminidase (EC 3.2.1.18) ; favipiravir (EW5GL2X7E0) ; Zanamivir (L6O3XI777I) ; peramivir (QW7Y7ZR15U)
Language	English
Publishing date	2020-10-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12101139
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Article ; Online: Oseltamivir-zanamivir combination therapy is not superior to zanamivir monotherapy in mice infected with influenza A(H3N2) and A(H1N1)pdm09 viruses.

Pizzorno, Andrés / Abed, Yacine / Rhéaume, Chantal / Boivin, Guy

Antiviral research

2014 Volume 105, Page(s) 54–58

Abstract: The efficacy of oseltamivir-zanamivir combination therapy compared to that of monotherapy was evaluated in mice infected with influenza A(H3N2) or A(H1N1)pdm09 viruses. For A(H3N2) virus, zanamivir monotherapy and oseltamivir-zanamivir combination showed ...

Abstract	The efficacy of oseltamivir-zanamivir combination therapy compared to that of monotherapy was evaluated in mice infected with influenza A(H3N2) or A(H1N1)pdm09 viruses. For A(H3N2) virus, zanamivir monotherapy and oseltamivir-zanamivir combination showed significant reduction of mean weight loss compared to oseltamivir. Zanamivir monotherapy also conferred decreased mortality, weight loss and lung viral titers (LVT) compared to oseltamivir for A(H1N1)pdm09 wild-type virus. Intermediate benefits were observed for the oseltamivir-zanamivir combination. For the oseltamivir-resistant A(H1N1)pdm09 H275Y virus, the efficacy of oseltamivir-zanamivir was comparable to that of zanamivir and significantly higher than that of oseltamivir in terms of survival, weight loss and LVT.
MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Body Weight ; Disease Models, Animal ; Drug Therapy, Combination/methods ; Influenza A Virus, H1N1 Subtype/isolation & purification ; Influenza A Virus, H3N2 Subtype/isolation & purification ; Lung/virology ; Mice, Inbred C57BL ; Orthomyxoviridae Infections/drug therapy ; Orthomyxoviridae Infections/virology ; Oseltamivir/therapeutic use ; Survival Analysis ; Treatment Outcome ; Viral Load ; Zanamivir/therapeutic use
Chemical Substances	Antiviral Agents ; Oseltamivir (20O93L6F9H) ; Zanamivir (L6O3XI777I)
Language	English
Publishing date	2014-05
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2014.02.017
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