QUINONE DERIVATIVES FOR USE IN THE MODULATION OF REDOX STATUS OF INDIVIDUALS
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.
1 . 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.
2 . 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 the redox potential of glutathione in the subject is at least an absolute value of about 10 mV more negative than the redox potential of glutathione in the subject prior to treatment.
3 . The method of claim 1 , wherein the subject having a glutathione redox potential disorder has a ratio of oxidized glutathione concentration to reduced glutathione concentration of about 2 or greater prior to administering the compound.
4 . The method of claim 1 , wherein the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione comprises an HPLC measurement.
5 . The method of claim 1 , wherein the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject comprises measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the blood plasma, blood serum, or cerebrospinal fluid of the subject.
6 . The method of claim 1 , wherein the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject comprises measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the lymphocytes of the subject.
7 . The method of claim 1 , wherein step a) and step d) additionally comprise measuring the concentration of total glutathione in the subject, or calculating the concentration of total glutathione in the subject from the measured concentration of reduced glutathione and concentration of oxidized glutathione in the subject, and step a) additionally comprises administering a therapeutically effective amount of N-acetyl cysteine to the subject if the concentration of total glutathione in the subject is below about 30 nmol/mg cell protein.
8 . The method of claim 7 , wherein sufficient N-acetyl cysteine is administered to the subject to adjust the concentration of total glutathione in the subject above about 30 nmol/mg cell protein.
9 . The method of claim 2 , wherein step a) and step d) additionally comprise measuring the concentration of total glutathione in the subject, or calculating the concentration of total glutathione in the subject from the measured concentration of reduced glutathione and concentration of oxidized glutathione in the subject, and step a) additionally comprises administering a therapeutically effective amount of N-acetyl cysteine to the subject if the concentration of total glutathione in the subject is below about 1 micromolar.
10 . The method of claim 9 , wherein the amount of N-acetyl cysteine administered to the subject is about 50 mg to about 1000 mg.
11 . The method of claim 1 , wherein the compound administered to the subject 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 is selected from the group consisting of pharmaceutically acceptable two-electron redox-active molecules having a reduction potential between about −350 millivolts and about +150 millivolts versus the standard hydrogen electrode.
12 . The method of claim 1 , wherein the compound administered to the subject 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 is selected from the group consisting of pharmaceutically acceptable two-electron redox-active molecules having a reduction potential between about 20 millivolts more reductive than Coenzyme Q and about 250 millivolts more reductive than Coenzyme Q.
13 . The method of claim 1 , wherein the compound administered to the subject 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 is selected from the group consisting of compounds of Formula I:
where R is selected from:
where the asterisk * indicates the attachment of R in Formula I;
where R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl,
m is an integer from 0 to 9 inclusive,
and the bonds indicated by a dashed line can be either double or single bonds.
14 . The method of claim 13 , wherein the compound administered to the subject is selected from the group consisting of compounds of Formula I-ox or Formula I-red:
where R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl;
m is an integer from 0 to 9 inclusive;
and the bonds indicated by a dashed line can be either double or single bonds.
15 . The method of claim 14 , wherein the compound administered to the subject 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 is selected from the group consisting of: alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone, and delta-tocopherol quinone, or any combination thereof.