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Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Inactive Publication Date: 2012-11-22
ROMARK LAB L C
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]In one specific embodiment, the invention provides a method of treating or preventing a viral infection in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a thiazolide compound. In a preferred embodiment the thiazolide agent is nitazoxanide. In another preferred embodiment, the thiazolide agent is tizoxanide. In yet another preferred embodiment, the thiazolide agent is RM-4848 or a pharmaceutically acceptable prodrug thereof. In one aspect of the invention, the viral infection is influenza. The influenza may be caused by a virus selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7. In another aspect of the invention, the viral infection is Hepatitis B. In another aspect of the invention, the viral infection is diarrhea or gastroenteritis caused by rotavirus or norovirus. In a preferred embodiment, the thiazolide compound is administered alone. In other preferred embodiments, the thiazolide compound is administered in combination with a neuraminidase inhibitor, such as Laninamivir, Oseltamivir, Zanamivir or Peramivir, or an immunostimulant, such as Imiquimod or Resiquimod, or an adamantine analogue, or a recombinant sialidase fusion protein, or an anti-hepatitis B drug. In yet another preferred embodiment, the thiazolide compound is administered in combination with a vaccine.
[0020]In another specific embodiment, the invention provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a thiazolide compound. In a preferred embodiment the thiazolide agent is nitazoxanide. In another preferred embodiment, the thiazolide agent is tizoxanide. In yet another preferred embodiment, the thiazolide agent is RM-4848. In a particular aspect of the invention, the cancer is leukemia. Preferably, the leukemia is hairy cell leukemia or chronic myeloid leukemia. In a different aspect of the invention, the cancer is melanoma. In yet another aspect of the invention, the cancer is non-Hodgkin lymphoma. In a further aspect of the invention, the cancer is renal cell carcinoma. In one preferred embodiment, the thiazolide compound is administered alone. In another preferred embodiment of the invention, the thiazolide compound is administered in combination with a vaccine, or an immunostimulant, or an anticancer drug. The anticancer drug may include, but is not limited to, STI571, CGP 74588, 1-β-D-Arabinofuranosylcytosine (Ara-C), doxorbicin, dacarbazine, cisplatin, bleomyc

Problems solved by technology

Chronic hepatitis B may eventually cause liver cirrhosis and liver cancer-a fatal disease with very poor response to current chemotherapy.
Without early treatment the cancer can advance, spread and be fatal.
Prevention and treatment, however, are hampered by the ability of pathogens to escape the host immune response.

Method used

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  • Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
  • Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
  • Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cell Preparation

[0056]Mononuclear blood cells have an important role in the immune response system, as they produce different cytokines in response to pathogen infections. Accordingly, the immunomodulatory effects of tizoxanide (TIZ) in peripheral mononuclear blood cells (PMBCs) obtained from ten (10) healthy donors and isolated by centrifugation on Ficoll-Paque. The PMBCs were cultured in RPMI-1640 media supplemented with 10% human serum in the presence or absence of three different doses of TIZ (0.5, 1.0 and 10 mg / ml) in both unstimulated and flu-stimulated conditions.

example 2

Immunological Analyses

[0057]The unstimulated and stimulated PMBCs were analyzed for T helper and CTL activity as well as for TLR7 and TLR8 expression and type I IFN responses in the absence or presence of different doses of tizoxanide. The immunological analyses were as follows:

[0058]T helper functions were detected by determining the amount of IFNγ- and IL-2-secreting CD4+ T cells. CTL activity was detected by determining the amount of perforin-, granzyme- and Fas-expressing CD8+ T cells.

[0059]TLR expression was detected by measuring TLR8-, TLR7- and TLR3-expressing CD14+ monocytes. Tizoxanide modulation of the TLR pathway was detected by PCR array analysis of Human Type I Interferon (IFN).

[0060]Specifically, TIZ immunomodulating effects were determined in unstimulated and flu-stimulated PMBCs by analysis of the following:

[0061]Human Type I Interferon (IFN) and TLR Pathway (PCR Array):

Interferons: Ligands for Interferon-alpha and Interferon-beta Receptors: IFNA1, IFNA4, IFNB1, IFNK...

example 3

The Immunomodulatory Effects of Tizoxanide

[0070]TIZ showed potent immunomodulatory effects inducing an increase in: 1) IFNγ- and IL2-secreting CD4+ T cells (FIGS. 4A and 4B); 2) CTL degranulation (FIG. 5B); 3) Fas-expressing CD8+ T cells (FIG. 5C); 4) TLR3-, TLR8- and TLR7- expression on monocytes (FIGS. 1A-C); 5) IFNα- and IFNβ- mRNA expression (FIG. 3A), 6) mRNA specific for type I IFN inducible genes (MXA, PRKCZ, ADAR, CXCL10, IRF1, PRKRA) (FIG. 3B); and 7) mRNA specific for gene involved in MHC class I presentation (HLA-A, HLA-B, TAP1) (FIG. 3C).

[0071]These results clearly demonstrate that TIZ has remarkable immumodulatory activity and stimulates a strong immune response, which is mediated by both the innate and the acquired immune systems.

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Abstract

The invention provides for the use of pharmaceutical compositions comprising a thiazolide in the stimulation of the immune system in a subject in need thereof, thereby preventing and / or treating viral diseases, cancer and diseases caused by intracellular protozoan infections

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS[0001]This application claims priority from U.S. Provisional Application 61 / 486,728, filed May 16, 2011, incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention is directed to compositions and methods for immunomodulation, including preventing or treating viral diseases, cancer and diseases caused by intracellular protozoan infections.BACKGROUND OF THE INVENTION[0003]Influenza is a highly contagious acute respiratory illness that affects all age groups and causes about 36,000 deaths and over 226,000 hospitalizations per year in the United States alone. Classified (as types A, B, and C), according to antigenic differences in their nucleoprotein and matrix protein, the influenza viruses are enveloped, negative-stranded RNA viruses. The many subtypes of influenza A virus differ in their two surface glycoproteins, hemagglutinin (“HA”) and neuraminidase (“NA”), which are the main targets of the prote...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61P37/04A61K31/4745A61K38/47A61P31/12A61P31/16A61P31/20A61P35/00A61P35/02A61K31/7068A61K33/24A61K38/14A61K31/475A61K31/704A61K31/44A61K38/21A61P33/02A61K31/506A61K31/7056A61K31/473A61P31/04A61P31/06A61K39/39
CPCA61K39/39A61K2039/55511A61K45/06A61K31/426A61K38/47A61K38/212A61K2300/00A61P1/16A61P13/12A61P31/04A61P31/06A61P31/12A61P31/16A61P31/20A61P33/00A61P33/02A61P35/00A61P35/02A61P37/04A61P43/00Y02A50/30A61K31/425B41F7/025B41F7/06B41F7/08B41F9/021B41F11/00B41F13/18B41F13/193
Inventor ROSSIGNOL, JEAN-FRANCOIS
Owner ROMARK LAB L C
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