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Use Of 5,6-Dimethylxanthenone-4-Acetic Acid as an Antimicrobial Agent

a technology of dimethylxanthenone and acetic acid, which is applied in the field of use of 5,6-dimethylxanthenone4acetic acid as an antimicrobial agent, can solve the problems of antiviral therapy (and prophylaxis), likely to be toxic to the host, and interfere significantly with viral replication

Inactive Publication Date: 2008-05-15
UNIV OF MARYLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to methods and compositions for treating and preventing infections in humans and non-human animals. Specifically, the invention provides methods for stimulating the immune system through the administration of flavone acetic acid analogues, such as DMXAA, and pharmaceutical compositions containing the same. The invention is effective in treating and preventing infections caused by viruses, bacteria, and parasites. The invention is particularly useful for treating and preventing infections in humans caused by rhinoviruses, enteroviruses, influenza viruses, and intracellular bacterial pathogens. The invention provides a therapeutic and prophylactic method for treating and preventing infections in humans and non-human animals."

Problems solved by technology

However, application of the principles of antibacterial therapy to antiviral therapy (and prophylaxis) presents a number of unique problems.
A major challenge is identifying antiviral compounds that are relatively non-toxic to mammalian cells because, unlike bacteria, viruses must replicate intracellularly and often employ host cell biomolecules and organelles for the synthesis of virus particles.
Consequently, antiviral agents are available to treat only a few viral diseases because any drug that interferes significantly with viral replication is likely to be toxic to the host.
However, DMXAA is more effective and 12-fold more potent in vivo against murine colon tumors than FAA, and DMXAA induces cytokine production in both human and murine cell lines, whereas FAA acts on human cells in vitro but does not exert anti-tumor effects in humans in vivo and has undesirable side effects.

Method used

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  • Use Of 5,6-Dimethylxanthenone-4-Acetic Acid as an Antimicrobial Agent
  • Use Of 5,6-Dimethylxanthenone-4-Acetic Acid as an Antimicrobial Agent
  • Use Of 5,6-Dimethylxanthenone-4-Acetic Acid as an Antimicrobial Agent

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

[0077]Methods employed are as described by Roberts, Z. J. et al. (2007) (“The Chemotherapeutic Agent DMXAA Potently And Specifically Activates The TBK1-IRF-3 Signaling Axis,” J. Exp. Med. 204(7):1559-1569), and Vogel, S. N. et al. (1987) (“Macrophages From Endotoxin-Hyporesponsive (Lpsd) C3H / Hej Mice Are Permissive For Vesicular Stomatitis Virus Because Of Reduced Levels Of Endogenous Interferon: Possible Mechanism For Natural Resistance To Virus Infection,” J. Virol. 61(3):812-818), except as indicated below.

Cells and Cell Culture

[0078]Thioglycollate-elicited murine peritoneal macrophages were obtained from 5- to 6-wk-old female C57BL / 6J mice (The Jackson Laboratory, Bar Harbor, Me.), IRF-3+ / + and IRF-3− / − mice (Dr. Tadatsugu Taniguchi, University of Tokyo, Tokyo, Japan) and TLR4+ / + and TRL4− / − mice. Murine macrophage-like RAW 264.7 cells and Madin-Darby canine kidney (MDCK) cells were obtained from the American Type Culture Collection (Manassas, Va.). MEFs fro...

example 2

Antiviral Activity of DMXAA

[0089]FIG. 1 shows that exposure of untreated RAW 264.7 macrophages to increasing titers of VSV results in increasing levels of viral infection and, consequently, increasing CPE (i.e., lysis of macrophages as evidenced by decreasing staining with crystal violet). In contrast, pretreatment of the macrophages for 6 h with 100 μg / ml of DMXAA completely prevents VSV infection and CPE at even the highest level of exposure to VSV (i.e., MOI=10.0).

[0090]TABLE 1 demonstrates that DMXAA inhibits the CPE of influenza virus on MDCK cells. The IC50s for DMXAA's direct and indirect antiviral activities are 5.0 μg / ml and 2.0 μg / ml, respectively.

TABLE 1Inhibition Assay for DMXAA Against Influenza / A / Wuhan[ ] Test Compound per mlDirect (CPE)Indirect (CPE)100 ug DMXAA++++++++25 ug DMXAA++++++++6.25 ug DMXAA++++++++1.56 ug DMXAA+−+−+++−.39 ug DMXAA−−−−−−+−.01 ug DMXAA−−−−−−−−.024 ug DMXAA−−−−−−−−.0006 ug DMXAA−−−−−−−−Tamiflu (0.1 ug)−+++Relenza (0.12 ug)−+++Virus Control−−−−...

example 3

DMXAA Activation of IRF-3-Mediated Gene Expression

[0091]FIGS. 2A, 2B, 2C, 2D and 2E demonstrate that DMXAA is a much more potent inducer of IFN-β protein and IP-10 mRNA in murine macrophages than LPS, while LPS stimulation results in much higher levels of proinflammatory cytokines, e.g., TNF-α and IL-1β. FIG. 2A shows, using real-time PCR to quantify mRNA expression in peritoneal exudate macrophages, that DMXAA induces 10-fold more IFN-β steady-state mRNA than LPS. While LPS stimulation leads to the rapid disappearance of IκBα (FIG. 2B) and NF-κB translocation (FIG. 2C) in primary macrophages and the RAW 264.7 macrophage-like cell line, respectively, treatment with DMXAA at doses 10-fold above those observed to be saturating in FIG. 2A has little effect on either the level of IκBα protein or NF-κB binding activity. Under conditions where LPS activates p38, ERK, and JNK MAPK in C57BL / 6 macrophages, DMXAA has no discernible effect (FIG. 2D). FIG. 2E shows that LPS fails to induce TNF-...

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Abstract

The invention relates to the areas of therapeutics, pharmaceuticals, drug discovery, and immunotherapy. More specifically, the present invention relates to methods of stimulating the immune system through the administration of flavone acetic acid [FAA] analogues, and in particular, the flavone acetic acid analogue, 5,6-dimethylxanthenone-4-acetic acid (DMXAA) so as to comprise an antimicrobial therapeutic agent for the treatment of viral, fungal, bacterial or parasitic infections in humans and non-human animals. The invention is especially suitable for use in a process of treating and preventing infection by viruses (for example, rhinoviruses, enteroviruses, and influenza viruses, etc.) and bacteria (especially intracellular bacterial pathogens such as Francisella tularensis).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 11 / 936,656 (filed on Nov. 8, 2007), which applications claim priority to U.S. Patent Application Ser. No. 60 / 864,991 (filed on Nov. 9, 2006), both of which applications are herein incorporated by reference in their entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with U.S. Government support under Grant No. AI18797, awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention.FIELD OF THE INVENTION[0003]The present invention relates to the areas of therapeutics, pharmaceuticals, drug discovery, and immunotherapy. More specifically, the present invention relates to methods of stimulating the immune system through the administration of flavone acetic acid analogues, and in particular, the flavone acetic acid analogue, 5,6-dimethylxanthenone-4...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/473A61K31/353
CPCA61K31/473A61K31/353A61P31/12
Inventor VOGEL, STEFANIE N.ROBERTS, ZACHARY J.COLE, LEAH E.
Owner UNIV OF MARYLAND
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