scholarly journals A universal dual mechanism immunotherapy for the treatment of influenza virus infections

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xin Liu ◽  
Boning Zhang ◽  
Yingcai Wang ◽  
Hanan S. Haymour ◽  
Fenghua Zhang ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza Pandemic ◽  
Intraperitoneal Administration ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Free Virus ◽  
Current Therapies ◽  
Severe Infections ◽  
Infected Cells ◽  
1918 Influenza

Abstract Seasonal influenza epidemics lead to 3–5 million severe infections and 290,000–650,000 annual global deaths. With deaths from the 1918 influenza pandemic estimated at >50,000,000 and future pandemics anticipated, the need for a potent influenza treatment is critical. In this study, we design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which specifically targets the surface of free virus and viral-infected cells. We show that this leads to simultaneous inhibition of virus release, and immune-mediated elimination of both free virus and virus-infected cells. Intranasal or intraperitoneal administration of a single dose of drug to mice infected with 100x MLD50 virus is shown to eradicate advanced infections from representative strains of both influenza A and B viruses. Since treatments of severe infections remain effective up to three days post lethal inoculation, our approach may successfully treat infections refractory to current therapies.

Drug generations that combat influenza A virus infection

2017 ◽  
Vol 13 (1) ◽  
pp. 1-11
Author(s):  
Gabriela Żaroffe ◽  
Jacek Leluk ◽  
Agata Żyźniewska ◽  
Rafał Filip
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Influenza Viruses ◽  
Respiratory Pathogens ◽  
Neuraminidase Inhibitors ◽  
Virus Infections ◽  
Oseltamivir Resistance ◽  
Infected Cells ◽  
New Generation

AbstractInfluenza viruses are significant human respiratory pathogens that cause infections and unpredictable pandemic outbreaks. M2 ion-channel protein, participating in the transmission of viral genetic materials into infected cells, is considered to be the crucial target for old-generation drugs such as rimantadine and amantadine. Neuraminidase protein, which is responsible for the replication of the influenza virus, is affected by the new generation of drugs, including oseltamivir (Tamiflu) and zanamivir (Relenza). The virus mutations that cause oseltamivir resistance are also described. This review presents the details concerning the treatment of influenza neuraminidase inhibitors against the H5N1 strain. It also describes virus mutations that cause resistance to oseltamivir and presents a new drug, peramivir, which is a neuraminidase inhibitor that was introduced against the H1N1 epidemic. This work specifies the details of the pharmacokinetics, dosing, toxicity, side effects, and efficiency of the drugs being used against influenza A virus infections.

scholarly journals In Vivo Influenza Virus-Inhibitory Effects of the Cyclopentane Neuraminidase Inhibitor RWJ-270201

2001 ◽  
Vol 45 (3) ◽  
pp. 749-757 ◽  
Author(s):  
Robert W. Sidwell ◽  
Donald F. Smee ◽  
John H. Huffman ◽  
Dale L. Barnard ◽  
Kevin W. Bailey ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Hong Kong ◽  
Influenza A ◽  
Arterial Oxygen Saturation ◽  
Virus Titer ◽  
Neuraminidase Inhibitor ◽  
Arterial Oxygen ◽  
Virus Infections ◽  
Inhibitory Effects ◽  
Lung Consolidation

ABSTRACT The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was evaluated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victoria/3/75 (H3N2), and B/Hong Kong/05/72 virus infections in mice. Treatment was by oral gavage twice daily for 5 days beginning 4 h pre-virus exposure. The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses. RWJ-270201 was inhibitory to all infections using doses as low as 1 mg/kg/day. Oseltamivir was generally up to 10-fold less effective than RWJ-270201. Ribavirin was also inhibitory but was less tolerated by the mice at the 75-mg/kg/day dose used. Disease-inhibitory effects included prevention of death, lessening of decline of arterial oxygen saturation, inhibition of lung consolidation, and reduction in lung virus titers. RWJ-270201 and oseltamivir, at doses of 10 and 1 mg/kg/day each, were compared with regard to their effects on daily lung parameters in influenza A/Shangdong/09/93 virus-infected mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of >104 cell culture 50% infective doses (CCID50)/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 101.2 CCID50/g, whereas titers from oseltamivir-treated animals were >103CCID50/g. Mean lung consolidation was also higher in the oseltamivir-treated animals on day 8. Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was nontoxic at doses as high as 1,000 mg/kg/day. These data indicate potential for the oral use of RWJ-270201 in the treatment of influenza virus infections in humans.

The Osteopathic Approach During the 1918 Influenza Pandemic, Featuring Newly Analyzed Case Reports

2021 ◽  
Vol 31 (2) ◽  
pp. 9-16
Author(s):  
Leslie M. Ching ◽  
Ashley Watson ◽  
Tyler Watson ◽  
Philip Ridgway
Keyword(s):  
Mortality Rate ◽  
Influenza A ◽  
Case Reports ◽  
Influenza Pandemic ◽  
Geographic Location ◽  
H1n1 Influenza ◽  
Patient Treatment ◽  
Osteopathic Medicine ◽  
1918 Influenza ◽  
Osteopathic Physicians

Abstract Osteopathic physicians played a pivotal role in treating patients suffering from the H1N1 influenza A virus of the 1918 Influenza Pandemic. This article focuses on case reports and questionnaire answers from the Journal of the American Osteopathic Association (JAOA), now the Journal of Osteopathic Medicine (JOM), and Osteopathic Physician concerning the modalities, techniques, and efficacy of osteopathic treatments of the 1918 pandemic. There are 19,565 patients who are represented in this analysis. The results are compared to the often-cited 110,120 patient cases reported by the JOM in 1920. Several different approaches, including lymphatic and visceral techniques, were widely used at the time, and their historic incorporation into patient treatment is explored. There is a discussion of the geographic location and characteristics of the practices. Statistical breakdown of mortality rate, the most commonly used approaches, somatic dysfunctions commonly treated, physician anecdotes, and other common remedies used by osteopathic physicians, are noted additionally. A comparison is done of the literature regarding the osteopathic approach for COVID-19. The newly analyzed case reports in this article demonstrate a similar mortality rate as in the 1920 JAOA article and illustrate the geographical distribution, treatment approaches, and personal stories of osteopaths during the pandemic.

Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104.

1997 ◽  
Vol 41 (9) ◽  
pp. 1949-1952 ◽  
Author(s):  
E J Eisenberg ◽  
A Bidgood ◽  
K C Cundy
Keyword(s):  
Oral Administration ◽  
Oral Bioavailability ◽  
Influenza A ◽  
Area Under The Curve ◽  
Parent Drug ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Important Indicator ◽  
Potential Efficacy ◽  
Plasma Peak

GS4071 is a novel potent inhibitor of influenza neuraminidase (Ki < 1 nM) with low (< 5%) oral bioavailability in animals. An ethyl ester prodrug of GS4071, GS4104, has exhibited good oral bioavailability in rat, mouse, and dog models and is currently being developed for the treatment of influenza A and B virus infections. Since influenza virus replicates primarily in the surface epithelial cells of the respiratory tract, the ability of the prodrug to deliver GS4071 to the bronchoalveolar lining fluid (BALF) following an oral dose of GS4104 should be an important indicator of its potential efficacy. In the present study, we determined the concentration-time profiles of GS4071 in the BALF and plasma of rats following oral administration of GS4104. The BALF was sampled by bronchoalveolar lavage with endogenous urea as a dilution marker. The concentration of GS4071 in BALF reached a peak at 2 h (1 h after the plasma peak) and declined at a slower rate than plasma levels, suggesting slow clearance of drug from the lung acini. The ratios of the area-under-the-curve (AUC) values of GS4071 in BALF to those in plasma were 1.05 for AUC from 0 to 6 h (AUC(0-6)) and 1.51 for AUC(0-infinity), indicating significant penetration of the parent drug into the lower respiratory tracts of rats following oral administration of the prodrug. No unchanged GS4104 was detected in BALF.

scholarly journals Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

1998 ◽  
Vol 42 (3) ◽  
pp. 647-653 ◽  
Author(s):  
Weixing Li ◽  
Paul A. Escarpe ◽  
Eugene J. Eisenberg ◽  
Kenneth C. Cundy ◽  
Clive Sweet ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Ethyl Ester ◽  
Oral Bioavailability ◽  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Neuraminidase Activity ◽  
Orally Bioavailable ◽  
Influenza Virus Neuraminidase

ABSTRACT GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (C maxs; C max<0.06 μg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high C maxs of GS 4071 (Cmax = 0.47 μg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

scholarly journals Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice

2009 ◽  
Vol 83 (8) ◽  
pp. 3754-3761 ◽  
Author(s):  
Li Qi ◽  
John C. Kash ◽  
Vivien G. Dugan ◽  
Ruixue Wang ◽  
Guozhong Jin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Binding Specificity ◽  
Influenza Viruses ◽  
Virulence Determinants ◽  
Sialic Acid Binding ◽  
1918 Influenza

ABSTRACT The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via α2-3 glycosidic bonds, while human-adapted hemagglutinins bind α2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with α2-6 or mixed α2-6/α2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either α2-6, α2-3, or α2-3/α2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing α2-3 to α2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity.

scholarly journals Protective Role of Combined Polyphenols and Micronutrients against Influenza A Virus and SARS-CoV-2 Infection In Vitro

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1721
Author(s):  
Marta De Angelis ◽  
David Della-Morte ◽  
Gabriele Buttinelli ◽  
Angela Di Martino ◽  
Francesca Pacifici ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Viral Proteins ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Virus Infections ◽  
Infected Cells ◽  
Respiratory Virus Infections

Polyphenols have been widely studied for their antiviral effect against respiratory virus infections. Among these, resveratrol (RV) has been demonstrated to inhibit influenza virus replication and more recently, it has been tested together with pterostilbene against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present work, we evaluated the antiviral activity of polydatin, an RV precursor, and a mixture of polyphenols and other micronutrients, named A5+, against influenza virus and SARS-CoV-2 infections. To this end, we infected Vero E6 cells and analyzed the replication of both respiratory viruses in terms of viral proteins synthesis and viral titration. We demonstrated that A5+ showed a higher efficacy in inhibiting both influenza virus and SARS-CoV-2 infections compared to polydatin treatment alone. Indeed, post infection treatment significantly decreased viral proteins expression and viral release, probably by interfering with any step of virus replicative cycle. Intriguingly, A5+ treatment strongly reduced IL-6 cytokine production in influenza virus-infected cells, suggesting its potential anti-inflammatory properties during the infection. Overall, these results demonstrate the synergic and innovative antiviral efficacy of A5+ mixture, although further studies are needed to clarify the mechanisms underlying its inhibitory effect.

scholarly journals Efficacy and Safety of the Neuraminidase Inhibitor Zanamivirin the Treatment of Influenza A and B Virus Infections

1999 ◽  
Vol 180 (2) ◽  
pp. 254-261 ◽  
Author(s):  
A. S. Monto ◽  
D. M. Fleming ◽  
D. Henry ◽  
R. de Groot ◽  
M. Makela ◽  
...  
Keyword(s):  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Efficacy And Safety ◽  
Virus Infections ◽  
B Virus

scholarly journals Fifty Years of Influenza A(H3N2) Following the Pandemic of 1968

2020 ◽  
Vol 110 (5) ◽  
pp. 669-676 ◽  
Author(s):  
Barbara J. Jester ◽  
Timothy M. Uyeki ◽  
Daniel B. Jernigan
Keyword(s):  
Influenza A ◽  
50Th Anniversary ◽  
H3n2 Virus ◽  
Virus Infections ◽  
Influenza A H1n1 ◽  
Short And Long Term ◽  
Influenza Prevention ◽  
1918 Influenza ◽  
Long Term Impact

In 2018, the world commemorated the centennial of the 1918 influenza A(H1N1) pandemic, the deadliest pandemic in recorded history; however, little mention was made of the 50th anniversary of the 1968 A(H3N2) pandemic. Although pandemic morbidity and mortality were much lower in 1968 than in 1918, influenza A(H3N2) virus infections have become the leading cause of seasonal influenza illness and death over the last 50 years, with more than twice the number of hospitalizations from A(H3N2) as from A(H1N1) during the past six seasons. We review the emergence, progression, clinical course, etiology, epidemiology, and treatment of the 1968 pandemic and highlight the short- and long-term impact associated with A(H3N2) viruses. The 1968 H3N2 pandemic and its ongoing sequelae underscore the need for improved seasonal and pandemic influenza prevention, control, preparedness, and response efforts.

Sign in / Sign up

Export Citation Format

Share Document