Ischemia/reperfusion protection compositions and methods of using

Abstract

The invention provides for ischemia/reperfusion protection compositions having one or more ketone bodies and melatonin. The invention also provides for methods of using such compositions to reduce or prevent ischemia/reperfusion injury due to blood loss, stroke or cardiopulmonary arrest or surgery.

1 . A composition comprising about 2 M to about 6 M D-beta-hydroxybutyrate or a pharmaceutically acceptable salt thereof, about 25 mM to about 80 mM melatonin or a metabolite, precursor, or analog thereof, and at least one solvent. 
     
     
         2 . The composition of  claim 1 , wherein the D-beta-hydroxybutyrate or a pharmaceutically acceptable salt thereof is Na-D-beta hydroxybutyrate. 
     
     
         3 . The composition of  claim 1 , wherein the melatonin or a metabolite, precursor, or analog thereof is 5-methyoxy-N-acetyltryptamine. 
     
     
         4 . The composition of  claim 1 , wherein the melatonin or a metabolite, precursor, or analog thereof is selected from the group consisting of 6-hydroxy-melatonin (6-HMEL), 6-sulphatoxy-melatonin (aMT6s), N1-acetyl-N2-formyl-5-methoxy kynuramine (AFMK), N1-acetyl-5-methoxy kynuramine (AMK), and 3-hydroxymelatonin (3-HMEL). 
     
     
         5 . The composition of  claim 1 , wherein the melatonin or a metabolite, precursor, or analog thereof is selected from the group consisting of N-acetylserotonin, 5-hydroxytryptamine, 5-hydroxytryptophan, and L-tryptophan. 
     
     
         6 . The composition of  claim 1 , wherein the melatonin or a metabolite, precursor, or analog thereof is selected from the group consisting of 2-chloromelatonin, 6-fluoromelatonin, 6-chloromelatonin, 6-hydroxymelatonin, N-isobutanoyl 5-methoxytryptamine, N-valeroyl 5-methoxytryptamine, 6-methoxymelatonin, 5-methyl N-acetyltryptamine, 5-benzoyl N-acetyltryptamine, O-acetyl 5-methoxytryptamine, N-acetyltryptamine, N-acetyl 5-hydroxytryptamine, and 5-methoxytryptamine. 
     
     
         7 . The composition of  claim 1 , wherein the solvent is water. 
     
     
         8 . The composition of  claim 1 , wherein the composition comprises about 3 M to about 5 M D-beta-hydroxybutyrate or a pharmaceutically acceptable salt thereof and about 30 mM to about 50 mM melatonin or a metabolite, precursor, or analog thereof. 
     
     
         9 . The composition of  claim 1 , wherein the composition comprises about 3.5 M to about 4.5 M D-beta-hydroxybutyrate or a pharmaceutically acceptable salt thereof and about 40 mM to about 45 mM melatonin or a metabolite, precursor, or analog thereof. 
     
     
         10 . The composition of  claim 1 , wherein the composition comprises about 4 M Na-D-beta-hydroxybutyrate and about 43 mM melatonin. 
     
     
         11 . The composition of  claim 1 , wherein the composition is substantially free of inorganic anions. 
     
     
         12 . The composition of  claim 1 , wherein the composition is substantially free of Cl − . 
     
     
         13 . The composition of  claim 1 , further comprising an antioxidant. 
     
     
         14 . The composition of  claim 13 , wherein the antioxidant is selected from the group consisting of resveratrol, vitamin A, ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), glutathione, beta-carotene, lycopene, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, (R)-2-acetamido-3-mercaptopropanoic acid (N-acetyl-cysteine), and 2-[(2-methyl-2-sulfanylpropanoyl)amino]-3-sulfanylpropanoic acid. 
     
     
         15 . The composition of  claim 1 , further comprising a solubilizer. 
     
     
         16 . The composition of  claim 15 , wherein the solubilizer is selected from the group consisting of DMSO, ethanol, methylsulfonylmethane (MSM or dimethylsulfone) and dimethylformamide (DMF). 
     
     
         17 . The composition of  claim 1 , further comprising a stabilizer. 
     
     
         18 . The composition of  claim 17 , wherein the stabilizer is selected from the group consisting of organic sugars, sugar alcohols, saccharides, amino acids, serum albumin, and immunoglobulins. 
     
     
         19 . The composition of  claim 17 , wherein the stabilizer comprises short, amphiphilic oligomers covalently bound to the D-beta-hydroxybutyrate or a pharmaceutically acceptable salt thereof and/or the melatonin or a metabolite, precursor, or analog thereof. 
     
     
         20 . The composition of  claim 19 , wherein the short, amphiphilic oligomer is selected from the group consisting of polyethylene glycol (PEG) and short chain fatty acid polymers. 
     
     
         21 . The composition of  claim 1 , further comprising a therapeutic compound. 
     
     
         22 . The composition of  claim 21 , wherein the therapeutic compound is selected from the group consisting of a polypeptide, an antisense RNA molecule, a siRNA molecule, a drug, and a small molecule. 
     
     
         23 . The composition of  claim 21 , wherein the therapeutic compound is selected from the group consisting of an antibiotic, an antibacterial, an analgesic, a free fatty acid, a hormone, a metabolite, and a metabolic pathway intermediate. 
     
     
         24 . The composition of  claim 1 , wherein the pH of the composition is from about 7.2 to about 7.6. 
     
     
         25 . The composition of  claim 1 , wherein the pH of the composition is about 7.4. 
     
     
         26 . The composition of  claim 1 , further comprising glucose, acetate, pyruvate, or combinations thereof. 
     
     
         27 . An article of manufacture comprising the composition of  claim 1 . 
     
     
         28 . The article of manufacture of  claim 27 , wherein the composition is comprised within an IV bag or a syringe barrel.