Alleviating oxidative stress disorders with pufa derivatives

Abstract

Some aspects of the invention provide for essential fatty acids which are substituted in specific positions to slow down oxidative damage by Reactive Oxygen Species (ROS), and to suppress the rate of consequent formation of reactive products, for the purpose of preventing or reducing the damage associated with oxidative stress associated diseases such as neurological diseases and age-related macular degeneration (AMD).

1 . A method of treating or preventing the progression of a neurodegenerative disease comprising
 selecting a subject that has a neurodegenerative disease or is susceptible to a neurodegenerative disease,   administering an effective amount of isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof to the subject;   wherein upon administration, the isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof is incorporated in brain and/or neuronal tissue of the subject.   
     
     
         2 . The method of  claim 1 , wherein the subject has Alzheimer's disease or is susceptible to Alzheimer's disease. 
     
     
         3 . The method of  claim 1 , wherein the subject has mild cognitive impairment or is susceptible to mild cognitive impairment. 
     
     
         4 . The method of  claim 1 , wherein the subject has Parkinson's disease or is susceptible to Parkinson's disease. 
     
     
         5 . The method of  claim 1 , wherein the subject has schizophrenia or is susceptible to schizophrenia. 
     
     
         6 . The method of  claim 1 , wherein the subject has a bipolar disorder or is susceptible to a bipolar disorder. 
     
     
         7 . The method of  claim 1 , wherein the subject has amyotrophic lateral sclerosis or is susceptible to amyotrophic lateral sclerosis. 
     
     
         8 . A method of treating or preventing the progression of an oxidative disease of the eye comprising
 selecting a subject that has an oxidative disease of the eye or is susceptible to an oxidative disease of the eye,   administering an effective amount of at least one isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof to the subject;   wherein upon administration, the isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof is incorporated in eye tissue of the subject.   
     
     
         9 . The method of  claim 8 , wherein the subject has a retinal disease or is susceptible to a retinal disease. 
     
     
         10 . The method of  claim 8 , wherein the subject has age related macular degeneration or is susceptible to age related macular degeneration. 
     
     
         11 . The method of  claim 8 , wherein the subject has diabetic retinopathy or is susceptible to diabetic retinopathy. 
     
     
         12 . The method of  claim 8 , wherein the subject has retinitis pigmentosa or is susceptible to retinitis pigmentosa; or wherein the subject has cataracts or is susceptible to cataracts. 
     
     
         13 . A method comprising
 selecting a subject in need of increased levels of high-density lipoprotein and/or decreased levels of low-density lipoprotein,   administering an effective amount of isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof to the subject; and   wherein upon administration, the level of high-density lipoprotein is increased and/or the level of low-density lipoprotein is decreased.   
     
     
         14 . The method of  claim 13 , wherein the subject has atherosclerotic vascular disease or is susceptible to atherosclerotic vascular disease. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method of treating an inborn error of metabolism comprising
 selecting a subject that has an inborn error of metabolism,   administering an effective amount of isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof to the subject;   wherein upon administration, the isotopically modified polyunsaturated fatty acid, mimetic or ester pro-drug thereof is incorporated in brain and/or neuronal tissue of the subject.   
     
     
         19 . The method of  claim 18  wherein the inborn error of metabolism is Down's syndrome. 
     
     
         20 . A polyunsaturated fatty acid composition comprising
 a pharmaceutically acceptable excipient; and   an isotopically modified polyunsaturated fatty acid or ester thereof comprising at least one  13 C or at least one deuterium atoms at a bis-allylic position;   wherein the composition has an isotopic purity in the range of 5% to 99%.   
     
     
         21 . The composition of  claim 20  wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises 11, 11, 14, 14, D4-linolenic acid, 11, 11, D2-linolenic acid, 14, 14, D2-linolenic acid, or an ester of any of the foregoing. 
     
     
         22 . The composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises deuterium at a pro-bis-allylic position. 
     
     
         23 . (canceled) 
     
     
         24 . The composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof has an isotopic purity of from about 50%-99%. 
     
     
         25 . A polyunsaturated fatty acid composition comprising
 naturally occurring polyunsaturated fatty acid, or ester thereof, that are modified chemically to be effective at preventing specific disease mechanisms;   wherein the chemical modification does not change the elemental composition of the naturally occurring polyunsaturated fatty acid, or ester thereof;   with the proviso wherein the isotopically modified polyunsaturated fatty acid is not 11, 11, 14, 14, D4-linolenic acid or 11, 11, D2-linoleic acid.   
     
     
         26 . The polyunsaturated fatty acid composition of  claim 25 ,
 wherein the naturally occurring polyunsaturated fatty acid, or ester thereof is stabilized against oxidation.   
     
     
         27 . The polyunsaturated fatty acid composition of  claim 25 ,
 wherein the naturally occurring polyunsaturated fatty acid, or ester thereof is stabilized against oxidation at oxidation sensitive loci.   
     
     
         28 . The polyunsaturated fatty acid composition of  claim 27 ,
 wherein the naturally occurring polyunsaturated fatty acid, or ester thereof is stabilized against oxidation at oxidation sensitive loci with heavy isotope substitution.   
     
     
         29 . The polyunsaturated fatty acid composition of  claim 28 ,
 wherein the naturally occurring polyunsaturated fatty acid, or ester thereof is stabilized against oxidation at oxidation sensitive loci at the bis-allylic carbon hydrogen atoms.   
     
     
         30 . A method comprising
 administering to a subject a sufficient amount of an isotopically modified PUFA, wherein a cell or tissue of the subject maintains a sufficient concentration of isotopically modified PUFAs to maintain autooxidation of the PUFA.   
     
     
         31 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid ester comprises an ethyl or glyceryl ester of 11,11-D2-linoleic acid; 11-D-linoleic acid; 11,11,14,14-D4-linolenic acid; 11,14-D2-linolenic acid; 11,11-D2-linolenic acid; 11-D-linolenic acid; 14-D-linolenic acid; or 14,14-D2-linolenic acid. 
     
     
         32 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid ester comprises an ethyl ester of 11,11-D2-linoleic acid; 11-D-linoleic acid; 11,11,14,14-D4-linolenic acid; 11,14-D2-linolenic acid; 11,11-D2-linolenic acid; 11-D-linolenic acid; 14-D-linolenic acid; or 14,14-D2-linolenic acid. 
     
     
         33 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid ester comprises an ethyl ester of 11,11-D2-linoleic acid or 11-D-linoleic acid. 
     
     
         34 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises a ω-6 polyunsaturated fatty acid or ester thereof. 
     
     
         35 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises an arachidonic acid or ester thereof. 
     
     
         36 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises an eicosapentaenoic acid or ester thereof. 
     
     
         37 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises a docosahexaenoic acid or ester thereof. 
     
     
         38 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof comprises a combination of two or more of an arachidonic acid, an eicosapentaenoic acid, a docosahexaenoic acid, or an ester of any of the foregoing. 
     
     
         39 . The polyunsaturated fatty acid composition of  claim 20 , wherein the isotopically modified polyunsaturated fatty acid or ester thereof has the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R is H or C 3 H 7 , 
         R 1  is H or alkyl, 
         each Y is independently H or Deuterium, with at least one Y being deuterium, 
         each X is independently H or Deuterium, with at least one Y being deuterium, 
         m=1-10, 
         n=1-5, and 
         p=1-10. 
       
     
     
         40 . The polyunsaturated fatty acid composition of  claim 20 , wherein the composition has an isotopic purity in the range of 10% to 95%. 
     
     
         41 . The polyunsaturated fatty acid composition of  claim 20 , wherein the composition is in a form suitable for oral administration.