Isotopically modified components and therapeutic uses thereof

Abstract

Methods are provided of identifying a subject having impaired aldehyde dehydrogenase activity; and administering to the subject a compound comprising an isotopicaliy-modified polyunsaturated fatty acid, an isotopicaliy-modified polyunsaturated fatty acid ester, an isotopicaliy-modified polyunsaturated fatty acid thioester, an isotopicaliy-modified polyunsaturated fatty acid amide, a polyunsaturated fatty acid mimetic, or an isotopicaliy-modified polyunsaturated fatty acid pro-drug, the compound having an isotopic modification that reduces oxidation of the compound, thereby reducing production in the subject of substrate for aldehyde dehydrogenase. Some aspects provide coadministering an isotopicaliy-modified polyunsaturated fatty acid and an oxylipin.

1 .- 91 . (canceled) 
     
     
         92 . A method for treating a disease or condition in a patient which disease or condition is mediated by cytotoxic levels of aldehydes and/or defects in an aldehyde dehydrogenase enzyme which method comprises:
 identifying a subject having cytotoxic levels of aldehydes and/or defects in said aldehyde dehydrogenase enzyme(s); and   administering to the subject an effective amount of a compound comprising a polyunsaturated fatty acid, a polyunsaturated fatty acid ester, a polyunsaturated fatty acid thioester, a polyunsaturated fatty acid amide,   wherein the polyunsaturated fatty acid, the polyunsaturated fatty acid ester, the polyunsaturated fatty acid thioester, or the polyunsaturated fatty acid amide is deuterated at one or more bis-allylic positions.   
     
     
         93 . The method of  claim 92 , wherein the aldehyde dehydrogenase is ALDH1, ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH1L2, ALDH2, ALDH3, ALDH3B1, ALDH3B2, ALDH4, ALDH4A1, ALDH5, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDH16A1, ALDH18A1, or AKR1b1. 
     
     
         94 . The method of  claim 92 , wherein the compound is an isotopically modified polyunsaturated fatty acid or ester thereof. 
     
     
         95 . The method of  claim 92 , wherein compound is an isotopically modified polyunsaturated fatty acid amide, an isotopically modified polyunsaturated fatty acid thioester, or an isotopically modified polyunsaturated fatty acid prodrug. 
     
     
         96 . The method of  claim 94 , wherein the polyunsaturated fatty acid ester is triglyceride, diglyceride, or monoglyceride. 
     
     
         97 . The method of  claim 94 , wherein the polyunsaturated fatty acid ester is an ethyl ester. 
     
     
         98 . The method of  claim 94 , wherein the compound is a ω-3 or ω-6 fatty acid, ω-3 or ω-6 fatty acid ester, ω-3 or ω-6 fatty acid amide, ω-3 or ω-6 fatty acid thioester, or prodrug thereof. 
     
     
         99 . The method of  claim 98 , wherein the compound is a linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, or an ester, amide, thioester, or prodrug thereof. 
     
     
         100 . The method of  claim 94 , wherein the compound comprises between about 1% and 100% of the total amount of polyunsaturated fatty acids or polyunsaturated fatty acid esters administered to the patient. 
     
     
         101 . The method of  claim 94 , wherein the compound is selected from the group consisting of 11,11, D2-linolenic acid, 14,14, D2-linolenic acid, 11,11,14,14, D4-linolenic acid, 11,11, D2-linoleic acid, 14,14, D2-linoleic acid, and 11,11,14,14, D4-linoleic acid or an ester of any of said compounds. 
     
     
         102 . The method of  claim 94 , wherein the compound is an omega-3 fatty acid. 
     
     
         103 . The method of  claim 94 , wherein the compound is an omega-6 fatty acid. 
     
     
         104 . The method of  claim 92 , wherein the compound is administered with an antioxidant. 
     
     
         105 . The method of  claim 104 , wherein the antioxidant is selected from Coenzyme Q, idebenone, mitoquinone, mitoquinol, vitamin E, vitamin C, or any combination thereof. 
     
     
         106 . The method of  claim 92 , wherein the compound is administered with one or more oxylipin. 
     
     
         107 . The method of claim  1060 , wherein the oxylipin is a prostaglandin.