Quinone derivatives for use in the modulation of redox status of individuals

a technology of redox status and derivatives, which is applied in the direction of peptide/protein ingredients, extracellular fluid disorder, metabolic disorder, etc., can solve the problem of not clear treatment of diseases involving oxidative stress, and achieve the effects of restoring redox balance and metabolic control, reducing glutathione, and increasing the glutathione charge coupl

Inactive Publication Date: 2015-08-06
BIOELECTRON TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The invention provides compounds and methods to address the common glutathione cycle defect associated with several diseases, including mitochondrial and neurodegenerative diseases. Specifically, the compounds and methods regenerate reduced glutathione and increase the glutathione charge couple, resulting in: i) restoration of redox balance and metabolic control; ii) reduction in the generation of reactive oxygen species; and iii) arrest and reversal of disease.

Problems solved by technology

However, the appropriate treatment for diseases involving oxidative stress is by no means clear.

Method used

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  • Quinone derivatives for use in the modulation of redox status of individuals
  • Quinone derivatives for use in the modulation of redox status of individuals
  • Quinone derivatives for use in the modulation of redox status of individuals

Examples

Experimental program
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Effect test

example 1

HPLC Determination of Free GSH, Protein Bound GSH (GS-Pro) and GSSG in Lymphocytes

[0152]The determination of the different forms of GSH obtained from lymphocytes can be performed in a manner similar to the method previously reported by Pastore et al. (Clin. Chem. (Washington, D.C.) 44, 825-832 (1998)). Briefly, 30 μl of 4 M NaBH4, 20 μl of 2 mM EDTA / DTT, 10 μl of 1-octanol and 20 μl of 1.8 M HCl are placed in the derivatization vial containing 30 μl of sample. After the mixture is incubated for three min, 100 μl of 1.5 M N-ethylmorpholine buffer, pH 8.0, 400 μl of distilled water, and 20 μl of 25 mM bromobimane are added. After an additional three-min incubation, 40 μl of acetic acid are added and 20 μl (for free GSH) or 80 μl (for GSSG and GS-Pro) of this mixture are injected into the column. The thiol derivatives are quantified by HPLC (Agilent Technologies 1100 HPLC with a fluorescence detector-excitation at 390 nm and an emission at 478 nm). The analytes are separated for detect...

example 2

Modulation of Glutathione Levels in Treatment of Leigh Disease

[0153]Study Overview:

[0154]A prospective single arm subject-controlled trial of alpha-tocotrienol quinone was performed in children with genetically-confirmed Leigh syndrome (Table 1, FIG. 5). All subjects were treated for three months and evaluated using a battery of disease-relevant functional, neurologic, physiologic and biomarker assessments. This study was conducted at the Ospedale Pediatrico Bambino Gesù in Rome, Italy. Institutional Review Board approval was obtained prior to study initiation.

TABLE 1Baseline patient characteristicsBaselineAge atDefect and % ofNPMDSWeightSubjectenrollmentMutationmutated mtDNAScoreSex(kg)19ND1-G3697ABlood: homoplasmic49.4F2126SUCLA2c.850C > T / c.850C > T62M9.331ETHE1Del Exo4; c.375 + 5G > A38F7.748ND5-G13513AMuscle: 65%36.8F2156EARS2c.502 > G;51.6M16.2c.1279_1280insTCC;c.322C > T613SURF1c.784 delACCC / not found53.1F28.578ND5-G13513ABlood: 61%, Fibroblast: 75%18.7M21.383ND1-G3697AMuscle...

embodiment 1

[0173]A method of treating a subject having a glutathione redox potential disorder, comprising the steps of: a) altering the redox potential of glutathione in the subject by administering a compound to the subject at an initial dosage level that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject; b) subsequent to administering the compound to the subject, measuring the concentration of reduced glutathione and oxidized glutathione in the subject; c) calculating the redox potential of glutathione in the subject; d) adjusting the dosage of the compound administered to the subject; and e) repeating steps b), c), and d) until a ratio of oxidized glutathione concentration to reduced glutathione concentration between about 0.01 and about 0.5 is attained.

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Abstract

Methods of modulating, adjusting, and maintenance of the glutathione redox status of an individual, or cell, tissues, bodily fluids, or body compartments of the individual, are disclosed, as are compositions suitable for such modulating, adjusting, and maintenance. The modulation or adjustment is achieved by altering the amounts of reduced glutathione versus oxidized glutathione in the individual, or cells, tissues, bodily fluids, or body compartments of the individual. Modulation, adjustment, and maintenance of the redox status of an individual enables treatment, prevention or suppression of diseases or symptoms associated with diseases. These methods are achieved by using quinone derivatives.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority benefit of U.S. Provisional Patent Application No. 61 / 698,431 filed Sep. 7, 2012, and of U.S. Provisional Patent Application No. 61 / 792,797 filed Mar. 15, 2013. The entire contents of those applications are hereby incorporated by reference herein.TECHNICAL FIELD OF THE INVENTION[0002]The application discloses compositions and methods useful for modulation of the glutathione redox status and redox potential of an individual, useful in treatment, prevention, or suppression of diseases, by administering redox-active compounds (such as tocotrienol quinones, for example, alpha-tocotrienol quinone).BACKGROUND[0003]A proper balance between oxidation and reduction reactions in cells, tissues, and organisms is vital for health. Maintenance of such a proper redox balance is, for example, critical for proper functioning of processes such as glycolysis, the citric acid cycle, and oxidative phosphorylation, which depen...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/122A61K31/05A61K31/198
CPCA61K31/05C07C66/00A61K31/198A61K31/122A61P1/00A61P3/00A61P3/02A61P3/04A61P3/10A61P7/00A61P9/00A61P9/08A61P9/10A61P11/00A61P13/02A61P13/12A61P21/00A61P21/02A61P21/04A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P27/02A61P27/06A61P27/10A61P27/16A61P35/00A61P39/06A61P43/00
Inventor MILLER, GUY M.SHRADER, WILLIAM D.KHEIFETS, VIKTORIA
Owner BIOELECTRON TECH CORP
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