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Combination therapy for the treatment of influenza

A technology for influenza, subjects, applied in the field of compositions for the treatment of viral infections, capable of solving the problems of high case fatality rate, harmful patient survival, impact, etc.

Inactive Publication Date: 2011-04-27
THE UNIVERSITY OF HONG KONG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, if the patient received the antiviral treatment 48 hours after the onset of the disease, the mortality rate of the patient was more than 70%
Although oseltamivir is highly effective in mouse models, case fatality rates in humans remain high, and delays in initiation of treatment appear to have deleterious effects on patient survival

Method used

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  • Combination therapy for the treatment of influenza
  • Combination therapy for the treatment of influenza
  • Combination therapy for the treatment of influenza

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: Treatment of Mice with Antiviral Drugs in Combination with Immunomodulators

[0074] Methods and Materials

[0075] Animal models and virus challenge.

[0076] BALB / c female mice aged 5-7 weeks were purchased from the Experimental Animal Unit of the University of Hong Kong. Mice were housed in biosafety level 3 housing with standard pelleted feed and water available ad libitum. Aliquots of influenza A strain A / Vietnam / 1194 / 04 stocks were grown in embryonated eggs. Allantoic fluid containing virus was collected and stored in aliquots at -70°C. The median lethal dose (LD) was determined in mice after serial dilution of virus stock 50 ). All experimental virus attacks used 1000LD 50 . Influenza virus infection was established by intranasal inoculation of isoflurane-anesthetized mice.

[0077] Antiviral and Immunomodulatory Therapy

[0078] Antiviral drugs and immunomodulators were administered by intraperitoneal injection (i.p.) using 0.5ml 29-gauge u...

Embodiment 2

[0093] Example 2: Reduction of virus titer

[0094] Materials and methods

[0095] Virology test.

[0096] Virus titers released in tracheo-lung lavage fluid by TCID 50 Assay, viral RNA in lung tissue cells was quantified by real-time RT-PCR (Li, B.J. et al. Nat Med 11: 944-951 (2005); Zheng, B.J. et al. Antivir Ther 10: 393-403 (2005); Wang, M . et al. Emerg Infect Dis 12: 1773-1775 (2006)). Briefly, the total RNA of the lysed lung tissue was extracted using the RNeasy Mini kit (Qiagen, Germany), and the applied SuperScript II Reverse Transcriptase TM (Invitrogen, USA) to reverse transcribe it into cDNA. The NP gene of the virus and the internal control actin gene were measured by SYBR green Mx3000 Real-Time PCR System (real-time PCR system) (Stratagene, USA), wherein the primer NP-forward: 5'-GAC CAG GAG TGG AGG AAA CA- 3' (SEQ ID NO: 1), NP-reverse: 5'-CGG CCA TAA TGG TCA CTC TT-3' (SEQ ID NO: 2); - Actin-forward: 5'-CGT ACC ACT GGC ATC GTGAT-5' (SEQ ID NO: 3), -act...

Embodiment 3

[0103] Example 3: Histology

[0104] Materials and methods

[0105] Histopathological analysis

[0106] Lung, brain, spleen, kidney and liver tissues from challenged mice were immediately fixed in 10% buffered formalin and embedded in paraffin. Sections 4-6 μm thick were mounted on glass slides. According to the method described by Zheng, B.J. et al. Eur J Immun 32:3294-3304 (2002); Zheng, B.J. et al. Int J Cancer 92:421-425 (2001), hematoxylin Determination by sperm and eosin (H&E) staining.

[0107] Immunohistochemical assay

[0108] Lung sections were stained with the following reagents as previously described (28, 30): 1:5000 dilution of anti-influenza nucleoprotein monoclonal antibody (HB65, ATCC, USA), 1:2000 dilution of goat anti-mouse IgG H and L Strept-specific biotin conjugate (Calbiochem, USA) and streptavidin / peroxidase complex reagent (Vector Laboratories, USA).

[0109] Flow Cytometry

[0110] Blood cells from mice were stained with fluorescein-labeled m...

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Abstract

Compositions and methods for treating one or more symptoms of influenza, preferably influenza due to infection with influenza A (H5N1) are provided. It has been discovered that administration of a combination of a neuraminidase inhibitor with two immunomodulators increases survivability in subjects 24, 48, or even 72 hours post infection compared to administration of the neuraminidase inhibitor alone. A preferred neuraminidase inhibitor includes, but is not limited to zanamivir. Preferred immunomodulators include, but are not limited to celecoxib and mesalazine. Another embodiment provides a method for treating influenza, preferably, influenza due to infection with avian influenza A (H5N1) by administering to subject infected with the influenza virus, an effective amount of a neuraminidase inhibitor to inhibit or reduce budding of the influenza virus from infected cells of the subject, and an effective amount of at least two immunomodulators effective to reduce or inhibit one or more symptoms of inflammation in the subject.

Description

[0001] Cross References to Related Applications [0002] This application claims priority and benefit to US Provisional Patent Application No. 61 / 055,573 filed May 23, 2008 by Bojian Zheng and Kwok-Yung Yuen, which application is incorporated by reference in its entirety where permitted. field of invention [0003] The present invention relates generally to compositions and methods for the treatment of viral infections, particularly influenza virus infections, especially avian influenza. Background of the invention [0004] Mortality in patients with pneumonia caused by influenza A / H5N1 virus and multiple organ involvement has varied from 45% to 81% since first reported in 1997 (Yuen, K.Y. et al. , Lancet 351:467-471 (1998); Beigel et al., N Engl J Med 353:1374-1385 (2005)). The subsequently available neuraminidase inhibitor oseltamivir did not reduce mortality. Oseltamivir is an antiviral drug used in the treatment and prevention of both influenza A and B viruses. Oselta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/155A61K31/196A61K31/415A61K31/606A61P31/16
CPCA61K45/06A61K31/415A61K31/196A61K31/606A61K31/155A61P31/16A61K2300/00
Inventor 郑伯建袁国勇
Owner THE UNIVERSITY OF HONG KONG
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