scholarly journals Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus

2017 ◽  
Vol 217 (6) ◽  
pp. 887-896 ◽  
Author(s):  
Maki Kiso ◽  
Tiago J S Lopes ◽  
Seiya Yamayoshi ◽  
Mutsumi Ito ◽  
Makoto Yamashita ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Combination Therapy ◽  
Nude Mice ◽  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Drug Resistant ◽  
Neuraminidase Inhibitors ◽  
Combination Therapies ◽  
Survival Times ◽  
Immunocompromised Hosts

Abstract Background Treatment of immunocompromised, influenza virus–infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants. Methods Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof. Results Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor–resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors. Conclusions Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor–resistant variants.

scholarly journals Baloxavir Marboxil Treatment of Nude Mice Infected With Influenza A Virus

2019 ◽  
Vol 221 (10) ◽  
pp. 1699-1702 ◽  
Author(s):  
Maki Kiso ◽  
Seiya Yamayoshi ◽  
Jurika Murakami ◽  
Yoshihiro Kawaoka
Keyword(s):  
Nude Mice ◽  
Influenza A ◽  
Body Weight Loss ◽  
Resistant Mutant ◽  
Prolonged Treatment ◽  
Drug Resistant ◽  
Neuraminidase Inhibitors ◽  
Drug Resistant Mutant ◽  
Suboptimal Dose ◽  
Resistant Mutants

Abstract Background Immunocompromised patients infected with influenza virus require prolonged treatment with neuraminidase inhibitors, because these patients are not able to eradicate the virus from the respiratory tract, leading to the emergence of drug-resistant mutant viruses. Methods In this study, we examined the efficacy of baloxavir marboxil in nude mice that were immunologically deficient. Results Daily treatment with a suboptimal dose of baloxavir marboxil increased the survival time of the virus-infected nude mice but did not clear the virus from their respiratory organs, resulting in gradual body weight loss after termination of treatment. Conclusions Despite the prolonged baloxavir marboxil treatment, few resistant mutants were detected.

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.

scholarly journals Large-Scale Sequence Analysis of M Gene of Influenza A Viruses from Different Species: Mechanisms for Emergence and Spread of Amantadine Resistance

2009 ◽  
Vol 53 (10) ◽  
pp. 4457-4463 ◽  
Author(s):  
Yuki Furuse ◽  
Akira Suzuki ◽  
Hitoshi Oshitani
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Drug Resistant ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
M Gene ◽  
Drug Pressure ◽  
Human Influenza Virus ◽  
Selective Pressures ◽  
Amantadine Resistance

ABSTRACT Influenza A virus infects many species, and amantadine is used as an antiviral agent. Recently, a substantial increase in amantadine-resistant strains has been reported, most of which have a substitution at amino acid position 31 in the M2 gene. Understanding the mechanism responsible for the emergence and spread of antiviral resistance is important for developing a treatment protocol for seasonal influenza and for deciding on a policy for antiviral stockpiling for pandemic influenza. The present study was conducted to identify the existence of drug pressure on the emergence and spread of amantadine-resistant influenza A viruses. We analyzed data on more than 5,000 virus sequences and constructed a phylogenetic tree to calculate selective pressures on sites in the M2 gene associated with amantadine resistance (positions 26, 27, 30, and 31) among different hosts. The phylogenetic tree revealed that the emergence and spread of the drug-resistant M gene in different hosts and subtypes were independent and not through reassortment. For human influenza virus, positive selection was detected only at position 27. Selective pressures on the sites were not always higher for human influenza virus than for viruses of other hosts. Additionally, selective pressure on position 31 did not increase after the introduction of amantadine. Although there is a possibility of drug pressure on human influenza virus, we could not find positive pressure on position 31. Because the recent rapid increase in drug-resistant virus is associated with the substitution at position 31, the resistance may not be related to drug use.

scholarly journals Laninamivir-Interferon Lambda 1 Combination Treatment Promotes Resistance by Influenza A Virus More Rapidly than Laninamivir Alone

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Simone E. Adams ◽  
Vladimir Y. Lugovtsev ◽  
Anastasia Kan ◽  
Nicolai V. Bovin ◽  
Raymond P. Donnelly ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Combination Treatment ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
The United States ◽  
Epithelial Cell Line ◽  
Drug Resistant ◽  
Interferon Lambda

ABSTRACT Each year, 5% to 20% of the population of the United States becomes infected with influenza A virus. Combination therapy with two or more antiviral agents has been considered a potential treatment option for influenza virus infection. However, the clinical results derived from combination treatment with two or more antiviral drugs have been variable. We examined the effectiveness of cotreatment with two distinct classes of anti-influenza drugs, i.e., neuraminidase (NA) inhibitor, laninamivir, and interferon lambda 1 (IFN-λ1), against the emergence of drug-resistant virus variants in vitro. We serially passaged pandemic A/California/04/09 [A(H1N1)pdm09] influenza virus in a human lung epithelial cell line (Calu-3) in the presence or absence of increasing concentrations of laninamivir or laninamivir plus IFN-λ1. Surprisingly, laninamivir used in combination with IFN-λ1 promoted the emergence of the E119G NA mutation five passages earlier than laninamivir alone (passage 2 versus passage 7, respectively). Acquisition of this mutation resulted in significantly reduced sensitivity to the NA inhibitors laninamivir (∼284-fold) and zanamivir (∼1,024-fold) and decreased NA enzyme catalytic activity (∼5-fold) compared to the parental virus. Moreover, the E119G NA mutation emerged together with concomitant hemagglutinin (HA) mutations (T197A and D222G), which were selected more rapidly by combination treatment with laninamivir plus IFN-λ1 (passages 2 and 3, respectively) than by laninamivir alone (passage 10). Our results show that treatment with laninamivir alone or in combination with IFN-λ1 can lead to the emergence of drug-resistant influenza virus variants. The addition of IFN-λ1 in combination with laninamivir may promote acquisition of drug resistance more rapidly than treatment with laninamivir alone.

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 Oseltamivir-zanamivir combination therapy suppresses drug-resistant H1N1 influenza A viruses in the hollow fiber infection model (HFIM) system

2018 ◽  
Vol 111 ◽  
pp. 443-449 ◽  
Author(s):  
Camilly P. Pires de Mello ◽  
George L. Drusano ◽  
Jonathan R. Adams ◽  
Matthew Shudt ◽  
Robert Kulawy ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Hollow Fiber ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Infection Model ◽  
Drug Resistant ◽  
Influenza A Viruses

scholarly journals Overexpression of the α-2,6-Sialyltransferase in MDCK Cells Increases Influenza Virus Sensitivity to Neuraminidase Inhibitors

2003 ◽  
Vol 77 (15) ◽  
pp. 8418-8425 ◽  
Author(s):  
Mikhail Matrosovich ◽  
Tatyana Matrosovich ◽  
Jackie Carr ◽  
Noel A. Roberts ◽  
Hans-Dieter Klenk
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Cultured Cells ◽  
Mdck Cells ◽  
Sialic Acids ◽  
Neuraminidase Inhibitors ◽  
Human Influenza ◽  
Oseltamivir Carboxylate ◽  
Human Influenza Virus ◽  
Human Virus

ABSTRACT No reliable cell culture assay is currently available for monitoring human influenza virus sensitivity to neuraminidase inhibitors (NAI). This can be explained by the observation that because of a low concentration of sialyl-α2,6-galactose (Sia[α2,6]Gal)-containing virus receptors in conventional cell lines, replication of human virus isolates shows little dependency on viral neuraminidase. To test whether overexpression of Sia(α2,6)Gal moieties in cultured cells could make them suitable for testing human influenza virus sensitivity to NAI, we stably transfected MDCK cells with cDNA of human 2,6-sialyltransferase (SIAT1). Transfected cells expressed twofold-higher amounts of 6-linked sialic acids and twofold-lower amounts of 3-linked sialic acids than parent MDCK cells as judged by staining with Sambucus nigra agglutinin and Maackia amurensis agglutinin, respectively. After transfection, binding of a clinical human influenza virus isolate was increased, whereas binding of its egg-adapted variant which preferentially bound 3-linked receptors was decreased. The sensitivity of human influenza A and B viruses to the neuraminidase inhibitor oseltamivir carboxylate was substantially improved in the SIAT1-transfected cell line and was consistent with their sensitivity in neuraminidase enzyme assay and with the hemagglutinin (HA) receptor-binding phenotype. MDCK cells stably transfected with SIAT1 may therefore be a suitable system for testing influenza virus sensitivity to NAI.

scholarly journals Synergistic Antiviral Activity of S-033188/S-033447, a Novel Inhibitor of Influenza Virus Cap-Dependent Endonuclease, in Combination with Neuraminidase Inhibitors In Vitro

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S371-S371 ◽  
Author(s):  
Mitsutaka Kitano ◽  
Atsuko Yamamoto ◽  
Takeshi Noshi ◽  
Makoto Kawai ◽  
Ryu Yoshida ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Cultured Cells ◽  
H1n1 Virus ◽  
Mdck Cells ◽  
Active Form ◽  
Neuraminidase Inhibitors ◽  
Dependent Endonuclease ◽  
Influenza A H1n1

Abstract Background S-033447, an active form of orally available prodrug S-033188, is a novel small molecule inhibitor of cap-dependent endonuclease that is essential for influenza virus transcription and replication. In this study, we evaluated the inhibitory effect of S-033188 in combination with neuraminidase inhibitors on the replication of influenza A/H1N1 virus in cultured cells. Methods The inhibitory effects of S-033447 in combination with NA inhibitors on the cytopathic effect of A/PR/8/34 strain in Madin–Darby canine kidney cells cultured for 2 days were tested and EC50 were determined. The combination index (CI), which were obtained when S-033188 and NA inhibitor were added at the closest ratio of each EC50 value, were used for the evaluation of these combinational effects (Table 1). CI values were calculated by the Chou and Talalay method, in which combinational effect were determined according to the criteria as follows: synergistic if CI ≤ 0.8, additive if 0.8 &lt; CI &lt; 1.2, and antagonistic if CI ≥ 1.2. CI = (DA/A + B)/DA + (DB/A + B)/DB + (DA/A + B × DB/A + B)/(DA × DB) DA: the EC50 of S-033447 DB: the EC50 of NA inhibitor DA/A + B: the concentration of S-033447 giving 50% inhibition in combination with NA inhibitor at the closest ratio of each EC50 value DB/A + B: the concentration of NA inhibitor giving 50% inhibition in combination with S-033447 at the closest ratio of each EC50 value Results All CI values were lower than 0.8, under the condition that both S-033447 and NA inhibitor (oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate) were added at the closest ratio of each EC50 value (Table 1). Conclusion S-033447 in combination with oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate synergistically inhibited the replication of influenza A/H1N1 virus in MDCK cells. Disclosures All authors: No reported disclosures.

scholarly journals Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 483 ◽  
Author(s):  
Meghan Leary ◽  
Sarah Heerboth ◽  
Karolina Lapinska ◽  
Sibaji Sarkar
Keyword(s):  
Drug Resistance ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Progenitor Cells ◽  
Rational Design ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Combination Therapies ◽  
Cancer Drug Resistance ◽  
Rational Development

Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals.

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