WO2015183984A2 - Compositions thérapeutiques contenant un tocophérol et leurs utilisations - Google Patents

Compositions thérapeutiques contenant un tocophérol et leurs utilisations Download PDF

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Publication number
WO2015183984A2
WO2015183984A2 PCT/US2015/032715 US2015032715W WO2015183984A2 WO 2015183984 A2 WO2015183984 A2 WO 2015183984A2 US 2015032715 W US2015032715 W US 2015032715W WO 2015183984 A2 WO2015183984 A2 WO 2015183984A2
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Prior art keywords
phe
arg
lys
tocopherol
aromatic
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WO2015183984A3 (fr
Inventor
D. Travis Wilson
Mark BAMBERGER
Peter OATES
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Stealth Peptides International Inc
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Stealth Peptides International Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • compositions related to the treatment and/or amelioration of diseases and conditions comprising administration of tocopherol and/or naturally or artificially occurring derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide).
  • active agents e.g., an aromatic-cationic peptide
  • the present technology relates generally to aromatic-cationic peptide compositions where the aromatic-cationic peptide is conjugated to a tocopherol and their use in the prevention and treatment of medical diseases and conditions.
  • Biological cells are generally highly selective as to the molecules that are allowed to pass through the cell membrane. As such, the delivery of compounds, such as small molecules and biological molecules into a cell is usually limited by the physical properties of the compound.
  • the small molecules and biological molecules may, for example, be pharmaceutically active compounds.
  • the present technology provides compositions and methods useful in the prevention, treatment and/or amelioration of diseases and conditions.
  • the present disclosure provides a composition comprising tocopherol, derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the composition further comprises one or more additional active agents such as cyclosporine, a cardiac drug, an anti-inflammatory, an anti-hypertensive drug, an antibody, an ophthalmic drug, an antioxidant, a metal complexer, and an
  • the present disclosure provides a method for treating or preventing mitochondrial permeability transition in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method of treating a disease or condition characterized by mitochondrial permeability transition, comprising administering a therapeutically effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 .
  • the disease or condition comprises a neurological or neurodegenerative disease or condition, ischemia, reperfusion, hypoxia, atherosclerosis, ureteral obstruction, diabetes, complications of diabetes, arthritis, liver damage, insulin resistance, diabetic nephropathy, acute renal injury, chronic renal injury, acute or chronic renal injury due to exposure to nephrotoxic agents and/or radiocontrast dyes, hypertension, metabolic syndrome, an ophthalmic disease or condition such as dry eye, diabetic
  • the neurological or neurodegenerative disease or condition comprises Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, Huntington's disease or Multiple Sclerosis.
  • ALS Amyotrophic Lateral Sclerosis
  • Parkinson's disease Huntington's disease or Multiple Sclerosis.
  • the subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue.
  • the present disclosure provides a method for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or
  • the active agents include any one or more of the aromatic- cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing a disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the subject is diagnosed as having, suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy, or obesity.
  • ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy, or obesity.
  • the present disclosure provides a method for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic- cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2 .
  • the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
  • the present disclosure provides a method for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 .
  • the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
  • the present disclosure provides a method of reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, or ALS.
  • the present disclosure provides a method for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or
  • the active agents include any one or more of the aromatic- cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing mechanical ventilation-induced diaphragm dysfunction in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe- D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for preventing
  • norepinephrine uptake in a subject in need of analgesia comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl- Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating atherosclerotic renal vascular disease (ARVD) in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising tocopherol, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 . .
  • the composition comprises tocopherol, derivative, analogue, or pharmaceutically acceptable salts thereof.
  • the composition further comprises one or more of at least one pharmaceutically acceptable pH-lowering agent; and at least one absorption enhancer effective to promote bioavailability of the active agent, and one or more lamination layers.
  • the pH-lowering agent is selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol as well as methods for their use.
  • Such molecules are referred to hereinafter as "peptide conjugates.”
  • At least one tocopherol and at least one aromatic-cationic peptide associate to form a peptide conjugate.
  • the tocopherol and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking.
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-tocopherol
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-tocopherol
  • the type of association between the tocopherol and aromatic-cationic peptides typically depends on, for example, functional groups available on the tocopherol and functional groups available on the aromatic-cationic peptide.
  • the peptide conjugate linker may be nonlabile or labile.
  • the peptide conjugate linker may be enzymatically cleavable.
  • the present technology provides a peptide conjugate comprising tocopherol conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 , or any peptide described in Section II; and wherein the tocopherol is a compound described in Section I.
  • the tocopherol is conjugated to the aromatic-cationic peptide by a linker.
  • the tocopherol and aromatic-cationic peptide are chemically bonded.
  • the tocopherol and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the tocopherol are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the tocopherol.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for delivering an aromatic-cationic peptide and/or tocopherol to a cell, the method comprising contacting the cell with a peptide conjugate, wherein the peptide conjugate comprises the tocopherol conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 , or any peptide described in Section II; and wherein the tocopherol is a compound described in Section I.
  • the tocopherol is conjugated to the aromatic-cationic peptide by a linker.
  • the tocopherol and aromatic-cationic peptide are chemically bonded.
  • the tocopherol and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the tocopherol are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the tocopherol.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for treating, ameliorating or preventing a medical disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol to the subject thereby treating, amelioration or preventing the medical disease or condition.
  • the medical disease or condition is characterized by mitochondrial permeability transition.
  • the medical disease or condition comprises a neurological or neurodegenerative disease or condition, ischemia, reperfusion, hypoxia, atherosclerosis, ureteral obstruction, diabetes, complications of diabetes, arthritis, liver damage, insulin resistance, diabetic nephropathy, acute renal injury, chronic renal injury, acute or chronic renal injury due to exposure to nephrotoxic agents and/or radiocontrast dyes, hypertension, Metabolic Syndrome, an ophthalmic disease or condition such as dry eye, diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, oxygen-induced retinopathy, cardiomyopathy, ischemic heart disease, heart failure, hypertensive cardiomyopathy, vessel occlusion, vessel occlusion injury, myocardial infarction, coronary artery disease, oxidative damage.
  • the neurological or neurodegenerative disease or condition comprises
  • Alzheimer's disease Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease,
  • the subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue.
  • the present technology provides methods for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for treating, ameliorating or preventing a medical disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the subject is diagnosed as having, is suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
  • ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
  • the present technology provides methods for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
  • the present technology provides methods for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
  • the present technology provides methods for reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the neurodegenerative diseases comprise Alzheimer's disease, Parkinson's disease, or ALS.
  • the present technology provides methods for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for treating or preventing mechanical ventilation-induced diaphragm dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for preventing norepinephrine uptake in a subject in need of analgesia, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for treating,
  • ameliorating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the present technology provides methods for treating
  • Atherosclerotic renal vascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • the aromatic-cationic peptide is defined by Formula A.
  • R 1 and R 2 are each independently selected from
  • R 3 and R 4 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from (i) hydrogen;
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • the peptide is defined by Formula B:
  • R 1 and R 2 are each independently selected from
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
  • the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
  • the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
  • Aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), and Trp (W). In some embodiments, the Aromatic residue may be substituted with
  • the Cationic residue is a residue selected from the group consisting of: Arg (R), Lys (K), and His (H).
  • the Cationic residue may be substituted with norleucine (Nle) or 2-amino-heptanoic acid (Ahe).
  • Figure 1 shows an illustrative example of an aromatic-cationic peptide of the present disclosure linked by a labile bond to a tocopherol.
  • Figure 2 shows illustrative examples of aromatic-cationic peptides of the present disclosure linked by covalent attachment to self-immolating moieties.
  • Figure 3 shows an illustrative example of aromatic-cationic peptides of the present disclosure incorporating spacer units to link the additional moieties to the peptide.
  • Figure 4 shows illustrative peptide chemistry to form amide bonds, where the R 2 free amine is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 and Ri is selected from a linker bearing the formula:— (linker)— COOH; or where linker consists of one or more carbon atoms. In some embodiments, the linker consists of two or more carbon atoms.
  • Figures 5A and 5B show exemplary linking chemistry of the present disclosure.
  • R is a tocopherol containing a pendant COOH group and R' is a linker bearing the formula:— (linker)— OH where linker consists of at least one or more carbon atoms.
  • R is a linker bearing the formula:— (linker)— COOH where linker consists of at least one or more carbon atoms; and R' is a tocopherol containing a pendant OH group.
  • Figure 6 shows illustrative examples of tocopherol metabolites.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to a tocopherol.
  • Such molecules are referred to hereinafter as peptide conjugates.
  • At least one tocopherol as described in Section I and at least one aromatic-cationic peptide as described in Section II associate to form a peptide conjugate.
  • the tocopherol and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking.
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-tocopherol
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-tocopherol
  • the type of association between the tocopherol and aromatic-cationic peptides typically depends on, for example, functional groups available on the tocopherol and functional groups available on the aromatic-cationic peptide.
  • the peptide conjugate linker may be nonlabile or labile.
  • the peptide conjugate linker may be enzymatically cleavable.
  • the peptide conjugates described herein can occur and can be used as the neutral (non-salt) peptide conjugate, the description is intended to embrace all salts of the peptide conjugates described herein, as well as methods of using such salts of the peptide conjugates.
  • the salts of the peptide conjugates comprise
  • Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound).
  • the desired salt of a basic peptide conjugate may be prepared by methods known to those of skill in the art by treating the compound with an acid.
  • inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
  • Salts of basic peptide conjugates with amino acids such as aspartate salts and glutamate salts, can also be prepared.
  • the desired salt of an acidic peptide conjugate can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • inorganic salts of acid conjugates include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
  • organic salts of acid peptide conjugates include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, ⁇ , ⁇ '-dibenzylethylenediamine, and
  • salts of acidic peptide conjugates with amino acids can also be prepared.
  • the present technology also includes all stereoisomers and geometric isomers of the peptide conjugates, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
  • the present technology also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures.
  • the "administration" of an agent, drug, or peptide to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or
  • Administration includes self-administration and the administration by another.
  • alkoxy refers to an alkyl, alkenyl, alkynyl, or hydrocarbon chain linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or i-propoxy), and butoxy (either n-butoxy, i-butoxy, sec-butoxy, or tert- butoxy).
  • the groups listed in the preceding sentence are alkoxy groups; an exemplary alkoxy substituent is methoxy.
  • alkyl refers to a cyclic, branched or straight chain chemical group containing only carbon and hydrogen, such as methyl, butyl and octyl.
  • Alkyl groups can be either unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, or benzyl.
  • Alkyl groups can be saturated or unsaturated at one or several positions.
  • Alkyl groups may comprise the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • Alkyl groups may comprise 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • “Straight-chain alkyl” or “linear alkyl” groups refer to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups.
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.
  • Cycloalkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl.
  • the subset of alkyl groups is C 1 -C 5 alkyl, which is intended to embrace methyl (Me), ethyl (Et), propyl (Pr), n-propyl (nPr), isopropyl (iPr), butyl (Bu), n-butyl (nBu), isobutyl (iBu), sec-butyl (sBu), t-butyl (tBu), cyclopropyl (cyclPr), cyclobutyl (cyclBu), cyclopropyl-methyl (cyclPr-Me), methyl-cyclopropane (Me-cyclPr), pentyl, n- pentyl, isopentyl, neopentyl,
  • Ci-C 6 alkyl is intended to embrace a saturated linear, branched, cyclic, or a combination thereof, hydrocarbon of 1 to 6 carbon atoms.
  • Examples of “Ci-C 6 alkyl” are methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, methyl- cyclopropyl, pentyl where the point of attachment of the pentyl group to the remainder of the molecule can be at any location on the pentyl moiety, cyclopentyl, hexyl where the point of attachment of the hexyl group to the remainder of the molecule can be at any location on the hexyl moiety, and cyclohexyl.
  • Co alkyl when it appears, is intended to mean either a non-existent group, or a hydrogen, which will be understood by the context in which it appears.
  • hydrocarbyl refers to any combination of straight-chain, branched chain, or cyclic alkyl, alkenyl, or alkynyl groups, and any combination thereof.
  • Substituted alkenyl refers to the respective group substituted with one or more substituents, including, but not limited to, groups such as halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the present
  • amino acid includes naturally-occurring amino acids and synthetic amino acids, as well as amino acid analogues and amino acid mimetics that function in a manner similar to the naturally-occurring amino acids.
  • Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
  • Amino acid analogues refer to compounds that have the same basic chemical structure as a naturally-occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g.
  • amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally- occurring amino acid. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • Aryl refers to an aromatic cyclic hydrocarbon group having a single ring (including, but not limited to, groups such as phenyl) or two or more condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups.
  • Aryls unless otherwise specified, contain from 6 to 12 carbon atoms in the ring portion.
  • a range for aryls is from 6 to 10 carbon atoms in the ring portion.
  • Substituted aryls refers to aryls substituted with one or more substituents, including but not limited to, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the present technology, with a protecting group.
  • groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide
  • Alkyl designates an alkyl- substituted aryl group, where any aryl can attach to the alkyl; the alkyl portion is a straight or branched chain of 1 to 6 carbon atoms. In some embodiments, the alkyl chain contains 1 to 3 carbon atoms.
  • the aralkyl group can be connected to the remainder of the molecule at any available valence on either its alkyl moiety or aryl moiety; e.g., the tolyl aralkyl group can be connected to the remainder of the molecule by replacing any of the five hydrogens on the aromatic ring moiety with the remainder of the molecule, or by replacing one of the alpha-hydrogens on the methyl moiety with the remainder of the molecule.
  • the aralkyl group is connected to the remainder of the molecule via the alkyl moiety.
  • the aryl group is phenyl, which can be substituted or unsubstituted.
  • substituents for substituted phenyl groups include, but are not limited to, alkyl, halogen (chlorine (— CI), bromine (— Br), iodine (— I), or fluorine (— F)), hydroxy (— OH), or alkoxy (such as methoxy, ethoxy, n-propoxy or i-propoxy, n-butoxy, i- butoxy, sec-butoxy, or tert-butoxy).
  • substituted phenyl groups have one or two substituents.
  • substituted phenyl groups have one substituent.
  • derivative refers to a compound derived from and thus non-identical to another compound. As used herein, a derivative shares at least one function with the compound from which it is derived, but differs from that compound structurally.
  • the term "effective amount" refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or disorder or one or more signs or symptoms associated with a disease or disorder.
  • the amount of a composition administered to the subject will depend on the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • the compositions can also be administered in combination with one or more additional therapeutic compounds.
  • the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.
  • halo and halogen refer to the Group Vila elements (Group 17 elements in the 1990 IUPAC Periodic Table, IUPAC Nomenclature of Inorganic Chemistry, Recommendations 1990) and include CI, Br, F and I substituents. In some embodiments, halogen substituents are CI and F.
  • haloalkenyl embraces any C 1 -C 5 alkenyl substituent having at least one halogen substituent; the halogen can be attached via any available valence on the C 1 -C 5 alkenyl group.
  • One further subset of C 1 -C 5 haloalkenyl is the subset with exactly one halogen substituent.
  • Another further subset of C 1 -C 5 haloalkenyl is the subset with exactly one chloro substituent.
  • Another further subset of C 1 -C 5 haloalkenyl is the subset with exactly one fluoro substituent.
  • C 1 -C5 haloalkenyl is the subset of C 1 -C 5 perhaloalkenyl; that is, C 1 -C 5 alkenyl with all available valences replaced by halogens.
  • Another further subset of C 1 -C 5 haloalkenyl is the subset of C 1 -C 5
  • perfluoroalkenyl that is, C 1 -C 5 alkenyl with all available valences replaced by fluorines.
  • Another further subset of C 1 -C 5 haloalkenyl is the subset of C 1 -C 5 perchloroalkenyl; that is, C 1 -C5 alkenyl with all available valences replaced by chlorines.
  • haloalkyl embraces any alkyl substituent having at least one halogen substituent.
  • Ci-C 6 haloalkyl is intended to embrace any Ci-C 6 alkyl substituent having at least one halogen substituent; the halogen can be attached via any valence on the Ci-C 6 alkyl group.
  • Ci-C 6 haloalkyl is— CF 3 ,— CC1 3 ,— CHF 2 ,— CHCb,— CHBr 2 ,— CH 2 F,— CH 2 C1.
  • haloalkynyl embraces any C 1 -C 5 alkynyl substituent having at least one halogen substituent; the halogen can be attached via any available valence on the C 1 -C5 alkynyl group.
  • One further subset of C 1 -C5 haloalkynyl is the subset with exactly one halogen substituent.
  • Another further subset of C 1 -C 5 haloalkynyl is the subset with exactly one chloro substituent.
  • Another further subset of C 1 -C 5 haloalkynyl is the subset with exactly one fluoro substituent.
  • C 1 -C 5 haloalkynyl is the subset of C 1 -C 5 perhaloalkynyl; that is, C 1 -C 5 alkynyl with all available valences replaced by halogens.
  • Another further subset of C 1 -C 5 haloalkynyl is the subset of C 1 -C 5
  • C 1 -C 5 alkynyl with all available valences replaced by fluorines.
  • Another further subset of C 1 -C5 haloalkynyl is the subset of C 1 -C5 perchloroalkynyl; that is, C 1 -C 5 alkynyl with all available valences replaced by chlorines.
  • heteroalkyl refers to alkyl, alkenyl, and alkynyl groups, respectively, that contain the number of carbon atoms specified (or if no number is specified, having up to 12 carbon atoms) which contain one or more heteroatoms as part of the main, branched, or cyclic chains in the group.
  • Heteroatoms include, but are not limited to, N, S, O, and P. In some embodiments, the heteroatoms are N or O.
  • Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom.
  • heteroalkyl groups include, but are not limited to, groups such as— O— CH 3 ,— CH 2 — O— CH 3 ,— CH 2 — CH 2 — O— CH 3 ,— S— CH 2 — CH 2 — CH 3 ,— CH 2 — CH(CH 3 )— S— CH 3 ,— CH 2 — CH 2 — NH— CH 2 — CH 2 — , l-ethyl-6-propylpiperidino, and morpholino.
  • heteroalkenyl groups include, but are not limited to, groups such as—
  • Heteroaryl or “HetAr” refers to an aromatic group having a single ring (including, but not limited to, examples such as pyridyl, imidazolyl, thiophene, or furyl) or two or more condensed rings (including, but not limited to, examples such as indolizinyl or benzothienyl) and having at least one hetero atom, including, but not limited to, heteroatoms such as N, O, P, or S, within the ring.
  • heteroaryl examples include pyridine, pyrazine, imidazoline, thiazole, isothiazole, pyrazine, triazine, pyrimidine, pyridazine, pyrazole, thiophene, pyrrole, pyran, furan, indole, quinoline, quinazoline, benzimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, benzotriazole, imidazo-pyridines, pyrazolo-pyridines, pyrazolo-pyrazine, acridine, carbazole, and the like.
  • heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups have between one and five heteroatoms and between one and twelve carbon atoms.
  • Substituted heteroalkyl refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups substituted with one or more substituents, including, but not limited to, groups such as alkyl, alkenyl, alkynyl, benzyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the present technology, with a protecting group.
  • groups such as alkyl, alkenyl, alkynyl, benzyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl,
  • the heteroatom(s) and/or the carbon atoms of the group can be substituted.
  • the heteroatom(s) can also be in oxidized form, if chemically possible.
  • the substituent moiety can be attached to the remainder of the molecule at any point on the moiety where chemically possible ⁇ i.e., by using any available valence at a given point of the moiety, such as a valence made available by removing one or more hydrogen atoms from the moiety) unless otherwise specified.
  • Co-Cg alkyl-C6-Cio aryl-Co-Cg alkyl if the leftmost Co-Cg alkyl group is a C 3 alkyl group, it can be attached to the sp 2 carbon of the carbonyl group at any of the three carbon atoms in the chain, unless otherwise specified.
  • the C 6 -Cio aryl group can be attached to the alkyl groups at any carbons in the aryl group, unless otherwise specified.
  • heterocycle is intended to encompass a monovalent, saturated, or partially unsaturated, carbocyclic radical having one or more rings incorporating one, two, three or four heteroatoms within the ring ⁇ e.g., nitrogen, oxygen, sulfur).
  • heterocycles include morpholine, piperidine, piperazine, thiazolidine, pyrazolidine, pyrazoline, imidazolidine, pyrrolidine,
  • an "isolated” or “purified” polypeptide or peptide is substantially free of cellular material or other contaminating polypeptides from the cell or tissue source from which the agent is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.
  • an isolated aromatic-cationic peptide would be free of materials that would interfere with diagnostic or therapeutic uses of the agent.
  • interfering materials may include enzymes, hormones and other proteinaceous and nonproteinaceous solutes.
  • non-naturally-occurring refers to a composition which is not found in this form in nature.
  • a non-naturally-occurring composition can be derived from a naturally-occurring composition, e.g., as non-limiting examples, via purification, isolation, concentration, chemical modification (e.g., addition or removal of a chemical group), and/or, in the case of mixtures, addition or removal of ingredients or compounds.
  • a non-naturally-occurring composition can comprise or be derived from a non-naturally- occurring combination of naturally-occurring compositions.
  • a non-naturally-occurring composition can comprise a mixture of purified, isolated, modified and/or concentrated naturally-occurring compositions, and/or can comprise a mixture of naturally-occurring compositions in forms, concentrations, ratios and/or levels of purity not found in nature.
  • net charge refers to the balance of the number of positive charges and the number of negative charges carried by the amino acids present in the aromatic-cationic peptides of the present technology.
  • net charges are measured at physiological pH.
  • the naturally occurring amino acids that are positively charged at physiological pH include L-lysine, L-arginine, and L-histidine.
  • the naturally occurring amino acids that are negatively charged at physiological pH include L- aspartic acid and L-glutamic acid.
  • polypeptide As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
  • Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art.
  • prevention or “preventing” of a disorder or condition refers to one or more compounds that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic
  • Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBz or Z), t- butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS), 9- fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, ⁇ -, ⁇ -dimethyldimethoxybenzyloxycarbonyl (DDZ), 5- bromo-7-nitroindolinyl, and the like. Hydroxyl protecting groups include, but are not limited to, Fmoc
  • the term “separate” therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes.
  • sequential therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.
  • the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
  • the terms "subject,” “individual,” or “patient” can be an individual organism, a vertebrate, a mammal, or a human.
  • substituted alkyl refers to alkyl groups substituted with one or more substituents including, but not limited to, groups such as halogen (fluoro, chloro, bromo, and iodo), alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the present technology, with a protecting group.
  • groups such as halogen (fluoro, chloro, bromo, and iodo), alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that
  • substituted alkyl groups include, but are not limited to, groups such as— CH 2 — OH;— CH 2 CH 2 CH(NH 2 )CH 3 , etc.
  • the substituent(s) on the substituted alkyl group may be at any available location on the group.
  • Substituted alkyl embraces the a subset of C 1 -C 5 haloalkyl, which is intended to embrace any C 1 -C 5 alkyl substituent having at least one halogen substituent; the halogen can be attached via any available valence on the C 1 -C 5 alkyl group.
  • C 1 -C 5 haloalkyl is— CF 3 , — CC1 3 ,— CBr 3 , and— CI 3 .
  • Another further subset of C 1 -C 5 haloalkyl is the subset with exactly one halogen substituent.
  • Another further subset of C 1 -C 5 haloalkyl is the subset with exactly one chloro substituent.
  • Another further subset of C 1 -C5 haloalkyl is the subset with exactly one fluoro substituent.
  • Another further subset of C 1 -C 5 haloalkyl is the subset of Ci- C 5 perhaloalkyl; that is, C 1 -C 5 alkyl with all available valences replaced by halogens.
  • C 1 -C 5 haloalkyl is the subset of C 1 -C 5 perfluoroalkyl; that is, C 1 -C 5 alkyl with all available valences replaced by fluorines, such as— CF 3 and— CF 2 -CF 3 .
  • C 1 -C 5 haloalkyl is the subset of C 1 -C 5 perchloroalkyl; that is, C 1 -C 5 alkyl with all available valences replaced by chlorines.
  • a "synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of agents. For example, lower doses of one or more agents may be used in treating a disease or disorder, resulting in increased therapeutic efficacy and decreased side-effects.
  • a "therapeutically effective amount" of a compound refers to compound levels in which the physiological effects of a disease or disorder are, at a minimum, ameliorated.
  • a therapeutically effective amount can be given in one or more administrations.
  • the amount of a compound which constitutes a therapeutically effective amount will vary depending on the compound, the disorder and its severity, and the general health, age, sex, body weight and tolerance to drugs of the subject to be treated, but can be determined routinely by one of ordinary skill in the art.
  • Treating covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • the various modes of treatment or prevention of medical diseases and conditions as described are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
  • the treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition.
  • the tocopherol compounds described herein are useful in compositions of the present technology.
  • the tocopherol compounds of the present technology are selected from the group consisting of alpha-tocopherols, beta-tocopherols, gamma-tocopherols, delta-tocopherols, epsilon-tocopherols, zetai-tocopherols, zeta 2 - tocopherols, eta-tocopherols, xii-tocopherols, xi 2 -tocopherols, sigma-tocopherols and/or metabolites or derivatives thereof.
  • tocopherol is meant any of a family of molecules (including both tocopherols and tocotrienols and derivatives thereof) which are characterized by a 6-chromanol ring structure and a side chain at the 2 position. Tocopherols possess a 4',8',12'-trimethyltridecyl phytol side chain, and the tocotrienols differ by the presence of double bonds at the 3', 7' and 11 ' positions of the side chain.
  • tocopherol encompasses, but is not limited to: alpha-tocopherol (vitamin E), [2R-2R*(4R*,8R*)]-3,4-dihydro- 2, 5, 7, 8- tetramethyl- 2- ( 4, 8, 12-trimethyltridecyl)-2H-l-benzopyran-6-ol; 2,5,7,8-tetramethyl-2- (4',8',12'-trimethyltridecyl)-6-chromanol; 5,7,8-trimethyltocol (see Fernholz (1937) Am. Chem. Soc.
  • beta-tocopherol 3,4-dihydro-2,5,8-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-l- benzopyran-6-ol; 2,5,8-trimethyl-2-(4,8, 12-trimethyltridecyl)-6-chromanol; 5-8- dimethyltocol; cumotocopherol; neotocopherol; p-xylotocopherol; gamma-tocopherol, 3,4-dihydro-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-l- benzyopyran-6-ol; 2,7,8-trimethyl-2-(4,8, 12-trimethyltridecyl)-6-chromanol; 7,8- dimethyltocol; o-xylotocopherol; delta-tocopherol, [2R-[2R*(4R !i: ,8R !i:
  • tocopherols include xii-, xi 2 -, and sigma-tocopherols.
  • Prototypical tocopherols include alpha-, beta-, gamma-, and delta-tocopherol.
  • alkyl groups can vary by the number and position of alkyl groups, double bonds and other substituents and variations on the ring and side chain.
  • An "alkyl” is a cyclic, branched or straight chain chemical group containing only carbon and hydrogen, such as methyl, butyl and octyl.
  • Alkyl groups can be either unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, or benzyl.
  • Alkyl groups can be saturated or unsaturated at one or several positions.
  • alkyl groups will comprise 1 to 8 carbons, or 1 to 6, or 1 to 4 carbon atoms.
  • Additional tocopherols can be constructed by conjugation to the ring structure or side chain of various other moieties, such as those containing oxygen, nitrogen, sulfur and/or phosphorus.
  • Tocopherol derivatives can also be made, as known in the art, by modifying the length of the side chain from that found in prototypical tocopherols such as alpha-, beta-, delta-, and gamma-tocopherol. Tocopherols can also vary in stereochemistry and saturation of bonds in the ring structure and side chain.
  • Additional tocopherol derivatives can be made by conjugation of sugars or other moieties to the side chain or ring structure; these can serve any of a number of functions, including increasing solubility and increasing functional activity of the tocopherol.
  • the present technology encompasses the use of tocopherol derivatives in which substitutions, additions and other alterations have been made in the 6-chromanol ring and/or side chain, with the proviso that the derivatives maintain at least one functional activity of a tocopherol, such as antioxidant activity or ability to counteract sterility in animals.
  • a "tocopherol" for use in the present technology can alternatively be a mixture of tocopherols.
  • mixtures include without limitation mixtures of stereoisomers of a single tocopherol (e.g., + and - stereoisomers of alpha-tocopherol; (+/-) indicates a racemic mixture) or mixtures of structurally distinct tocopherols (e.g., alpha- plus gamma-tocopherol).
  • Derivatives of these compounds include, but are not limited to, salts, including but not limited to succinate, nicotinate, allophanate, acetate, and phosphate salts of the tocopherols described herein. Salts also include pharmaceutically acceptable salts.
  • Derivatives include halogenated derivatives. Derivatives also include quinone derivatives and prodrug forms of tocopherols, such as those described in U.S. Pat. No. 5,114,957.
  • tocopherols and derivatives thereof are described in, e.g., U.S. Pat. Nos. 5,606,080 50 and 5,235,073. Preparations of various tocopherols are described in, e.g., U.S. Pat. Nos. 5,504,220, 4,978,617, and 4,977,282. Various tocopherols are available from Sigma
  • ⁇ -CEHC refers to the 2,7,8-trimethyl-2-(P-carboxy-ethyl)-6-hydroxy chroman, having a molecular weight of 264. This compound is a metabolite of ⁇ -tocopherol and its synthesis and properties are described in U.S. Patent 6,083,982, herein incorporated by reference in its entirety (where it is also referred to as "LLU-alpha"). ⁇ -CEHC may be in the racemic form or as the S enantiomer. A general discussion of the isolation and characterization of ⁇ -CEHC is provided by Wechter et al. (U.S. Patent 6,150,402).
  • ⁇ -CEBC refers to the compound 2,7,8-trimethyl-2-([3-carboxybutyl)-6- hydroxy chroman, having a molecular weight of about 278. It may also be present in racemic form or as pure isomer(s).
  • gamma-tocopherol derivative is meant gamma-tocopherol metabolites and synthetic chroman derivatives including, but not limited to, ⁇ -CEHC, ⁇ -CEBC, racemic chromans, chroman methyl esters, chroman esters, chroman amides, R 4 chroman esters, oxidized chroman derivatives, racemic 2,5,7,8-tetramethyl-2-(P-carboxyethyl)-6-hydroxy chroman, and the like. Additional derivatives were defined by Wechter (U.S. Patent
  • Tocopherol metabolites and derivatives include, for example, 2,5,7,8-tetramethyl- 2-(P-carboxyethyl)-chroman, 2,7,8-trimethyl-2-(P-carboxyethyl) chroman, racemic 4-methyl- 6-(5 ,6-dimethylbenzohinoyl)-4-hexanolid, 4-Methyl-6-(3 ,5 ,6-trimethylbenzochinoyl)4- hexanolid, (S)-4-Methyl-6-(5,6-dimethylbenzochinoyl)-4-hexanolid, 2,7,8-Trimethyl-2-(P- carboxyethyl)-6-acetyl chroman, 2,7,8-Trimethyl-2-(P-carboxyethyl)-6-acetyl chroman methyl ester, and benzodipyran methyl ester, as well as ⁇ -CE
  • gamma-tocopherol, beta-tocopherol, and delta-tocopherol break down into metabolites, including, for example, the metabolites described in Wechter et al. United States Patent Nos. 6,150,402; 6,083,982; 6,048,891 and 6,242,479.
  • the present technology encompasses the use of gamma-tocopherol enriched tocopherol compositions that further comprise gamma-tocopherol metabolites such as gamma-CEHC, racemic gamma-CEHC and (S) gamma-CEHC.
  • the general structures of other tocopherol metabolites are shown in Figure 6.
  • the present technology also encompasses the use of tocopherol metabolite enriched compositions and such compositions that further comprise a tocopherol.
  • non-alpha tocopherol-enriched tocopherol composition a composition that is enriched in (i.e., comprises 50% or greater) a tocopherol other than alpha- tocopherol.
  • non-alpha tocopherol enriched tocopherol compositions include without limitation, beta-tocopherol enriched tocopherol compositions, beta-tocopherol metabolite enriched compositions, delta-tocopherol enriched tocopherol compositions, delta- tocopherol metabolite enriched compositions, gamma-tocopherol enriched tocopherol compositions, gamma-tocopherol metabolite enriched compositions, epsilon-tocopherol enriched tocopherol compositions, zeta-tocopherol enriched tocopherol compositions, etc.
  • non-gamma tocopherol enriched composition a composition that is enriched in a tocopherol other than gamma-tocopherol.
  • non-gamma tocopherol enriched tocopherol compositions include without limitation, beta-tocopherol enriched tocopherol compositions, beta-tocopherol metabolite enriched compositions, delta-tocopherol enriched tocopherol compositions, delta-tocopherol metabolite enriched compositions, epsilon- tocopherol enriched tocopherol compositions, zeta-tocopherol enriched tocopherol compositions, etc.
  • a non-alpha, non-gamma-tocopherol enriched tocopherol composition refers to a composition that is enriched in a tocopherol other than alpha-tocopherol and gamma-tocopherol.
  • Examples of non-alpha, non-gamma-tocopherol enriched tocopherol compositions include without limitation, beta-tocopherol enriched tocopherol compositions, beta-tocopherol metabolite enriched compositions, delta-tocopherol enriched tocopherol compositions, delta-tocopherol metabolite enriched compositions, epsilon-tocopherol enriched tocopherol compositions, zeta-tocopherol enriched tocopherol compositions, etc.
  • non-tocopherol any compound which is not a tocopherol, tocotrienol, or derivative thereof, or the like.
  • the present technology relates to tocopherol compounds of general Formula (S):
  • Ri CH 3 with S or R configuration
  • R ⁇ CH 3 with S or R configuration
  • R 7 CH 3 with S or R configuration
  • R 5 H, CH 3 , acetate, or succinate
  • Ri CH 3 with S or R configuration
  • R ⁇ CH 3 with S or R configuration
  • R 7 CH 3 with S or R configuration
  • R 5 H, CH 3 , acetate, or succinate
  • tocopherols in the compositions of the present technology are metabolites and derivatives (including substituted chromans) of the Formula (U) (substituted chromans):
  • R is O, S, SO, S0 2 , a secondary or tertiary amine group, a phosphate group, a phosphoester group, or an unsubstituted or substituted methylene group;
  • R 1 and R 2 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6- membered aliphatic or aromatic ring;
  • R 3 and R 4 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6- membered aliphatic, aromatic or heterocyclic ring;
  • R 5 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ester or unsubstituted or substituted amine;
  • R 6 is COOH, COOR 7 , CONH 2 , CONHR 7 , CONR 7 R 8 , NH 2 , NHR 7 , NRV, or a carboxylate salt;
  • R 7 and R 8 independently are unsubstituted or substituted alkyl, aryl, alkaryl, aralkyl, alkenyl or alkynyl;
  • n 0 to 3;
  • n l
  • m 2
  • R 6 is COOH
  • R 3 is H or OH
  • R 4 is H or CH 3 .
  • R 1 , R 2 and R 5 are CH 3 .
  • Exemplary compounds include:
  • R is O
  • R 1 , R 2 , and R 5 are CH 3
  • R 3 is H
  • R 4 is H or CH 3
  • R 6 is COOH
  • R 7 is a Ci_ 6 alkyl group, in particular CH 3 .
  • R 3 is OH.
  • gamma-tocopherol metabolites include for example, gamma- CEHC (synonyms: 6-hydroxy-2,7,8-trimethylchroman-2 -propanoic acid and 2,7,8-trimethyl- 2-( P-carboxyethyl)-6-hydroxy chroman).
  • the gamma-tocopherol metabolites have the formula:
  • compositions of the present technology are compounds selected from the group consisting of: (S)-gamma-CEHC
  • R 1 and R 2 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6- membered aliphatic or aromatic ring;
  • R 3 and R 4 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6- membered aliphatic, aromatic or heterocyclic ring;
  • R 5 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ester or unsubstituted or substituted amine;
  • R 6 is COOH, COOR 7 , CONH 2 , CONHR 7 , CONR 7 R 8 , NH 2 , NHR 7 , NRV, or a carboxylate salt;
  • R 7 and R 8 independently are unsubstituted or substituted alkyl, aryl, alkaryl, aralkyl, alkenyl or alkynyl;
  • n 0 to 3;
  • m 0 to 5.
  • R 1 , R 2 and R 5 are CH 3 .
  • R 3 is OH and additionally R 4 is H.
  • R 6 is COOCH 2 CH 3 and R 9 is OH.
  • R 6 is COOH and R 9 is CH 3 CH 2 0.
  • R 1 and R 2 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6- membered aliphatic or aromatic ring;
  • R 3 and R 4 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6-membered aliphatic, aromatic or heterocyclic ring;
  • R 5 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ester or unsubstituted or substituted amine;
  • Specific exemplary compounds of Formula (X) include:
  • R 1 and R 2 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6-membered aliphatic or aromatic ring;
  • R 4 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl;
  • R 5 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ester or unsubstituted or substituted amine;
  • R 6 is COOH, COOR 7 , CONH 2 , CONHR 7 , CONR 7 R 8 , NH 2 , NHR 7 , NRV, or a carboxylate salt;
  • R 7 and R 8 independently are unsubstituted or substituted alkyl, aryl, alkaryl, aralkyl, alkenyl or alkynyl;
  • R 9 is hydroxyl or unsubstituted or substituted alkoxyl
  • n 0 to 3;
  • m 0 to 5.
  • Specific exemplary compounds of Formula (Y) include:
  • R 1 and R 2 independently are H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6-membered aliphatic or aromatic ring;
  • R 4 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl;
  • R 5 is H, OH, alkyl, aryl, alkenyl, alkynyl, aromatic, ester or unsubstituted or substituted amine;
  • n 0 to 3;
  • R 4 is H
  • R 5 is not CH 3 .
  • gamma-tocopherol is metabolized in vivo to form, for example, gamma-CEHC and gamma-CEBC, among other metabolites.
  • this metabolite is thought to be the result of sequential oxidation of its phytyl sidechain by enzymes that catalyze omega and beta oxidation. Therefore, a further aspect of the present technology includes methods of treatment in which the patient is treated with agents effective to induce such oxidation, such as, for example, inducers of the enzyme cytochrome P450. Such inducers and methods are known in the art.
  • compositions of the present technology are tocopherol enriched tocopherol compositions comprising a tocopherol and that may further comprise a tocopherol metabolite, and/or tocopherol derivative and/or other tocopherols for use as an active agent against damage, injury(ies) and/or symptoms associated with a medical disease or condition.
  • tocopherol enriched tocopherol compositions useful as tocopherols in the compositions of the present technology include, for example: gamma-tocopherol enriched composition comprising greater than 90% gamma-tocopherol or greater than 95% gamma-tocopherol; gamma-CEHC enriched composition comprising greater than 90% gamma- CEHC or greater than 95% gamma-CEHC; gamma-tocopherol enriched composition comprising gamma-CEHC; gamma-tocopherol enriched composition for intravenous injection comprising at least 50% gamma-tocopherol and delta-tocopherol; gamma-tocopherol enriched composition for gavage administration comprising at least 50% gamma-tocopherol and beta-tocopherol; beta-tocopherol compositions comprising greater than 90% beta-tocopherol or greater than 95% beta-tocopherol; and delta-tocopherol composition
  • tocopherols useful in the compositions of the present technology are ingredients in gamma-tocopherol enriched tocopherol compositions comprising gamma- tocopherol that may further comprise gamma-tocopherol metabolites, and/or derivatives thereof, and/or other tocopherols (or metabolites or derivatives thereof), for use as active agents against damage, injury(ies) and/or symptoms associated with a medical disease or condition which includes, but is not limited to, e.g., mitochondrial disease.
  • tocopherols useful in the compositions of the present technology are ingredients in gamma-tocopherol metabolite enriched compositions comprising gamma- tocopherol metabolite(s) that may further comprise gamma-tocopherol, and/or derivatives thereof, and/or other tocopherols (or metabolites or derivatives thereof), for use as active agents against damage, injury(ies) and/or symptoms associated with a medical disease or condition.
  • tocopherols useful in the compositions of the present technology are ingredients in beta-tocopherol enriched tocopherol compositions comprising beta- tocopherol that may further comprise beta-tocopherol metabolites, and/or beta-tocopherol derivatives, and/or other tocopherols (or metabolites or derivatives thereof), for use as active agents against damage, injury(ies) and/or symptoms associated with a medical disease or condition.
  • tocopherols useful in the compositions of the present technology are ingredients in beta-tocopherol metabolite enriched compositions comprising beta- tocopherol metabolite(s) that may further comprise beta-tocopherol, and/or derivatives thereof, and/or other tocopherols (or metabolites or derivatives thereof), for use as active agents against damage, injury(ies) and/or symptoms associated with a medical disease or condition.
  • tocopherols useful in the compositions of the present technology are ingredients in delta-tocopherol enriched tocopherol compositions comprising delta- tocopherol that may further comprise delta-tocopherol metabolites, and/or delta-tocopherol derivatives, and/or other tocopherols (or metabolites or derivatives thereof), for use as active agents against damage, injury(ies) and/or symptoms associated with a medical disease or condition.
  • tocopherols useful in the compositions of the present technology are ingredients in delta-tocopherol metabolite enriched compositions comprising delta- tocopherol metabolite(s) that may further comprise delta-tocopherol, and/or derivatives thereof, and/or other tocopherols (or metabolites or derivatives thereof), for use as active agents against damage, injury(ies) and/or symptoms associated with a medical disease or condition.
  • tocopherols useful in the compositions of the present technology are ingredients in gamma-tocopherol enriched compositions that comprise at least 50% gamma-tocopherol, at least 55% gamma-tocopherol, at least 60% gamma-tocopherol, at least 65% gamma-tocopherol, at least 70% gamma-tocopherol, at least 75% gamma- tocopherol, at least 80% gamma-tocopherol, at least 85% gamma-tocopherol, at least 90% gamma-tocopherol, at least 95% gamma-tocopherol, or at least 98% gamma-tocopherol.
  • Gamma-tocopherol enriched tocopherol compositions may also comprise gamma-tocopherol derivative(s) and/or gamma-tocopherol metabolite(s), and/or other tocopherol(s) and/or mixtures thereof.
  • a gamma-tocopherol "enriched" tocopherol composition comprises gamma-tocopherol as the sole active ingredient.
  • tocopherols useful in the compositions of the present technology are ingredients in gamma-tocopherol enriched tocopherol compositions that comprise less than 50%) alpha-tocopherol, less than 45% alpha-tocopherol, less than 40%> alpha-tocopherol, less than 35% alpha-tocopherol, less than 30% alpha-tocopherol, less than 25% alpha-tocopherol, less than 20 % alpha-tocopherol, less than 15% alpha-tocopherol, less than 10% alpha- tocopherol or less than 5% alpha-tocopherol.
  • tocopherols useful in the compositions of the present technology are ingredients in beta-tocopherol enriched compositions that comprise at least 50% beta-tocopherol, at least 55% beta-tocopherol, at least 60%> beta-tocopherol, at least 65%> beta-tocopherol, at least 70%> beta-tocopherol, at least 75% beta-tocopherol, at least 80%> beta-tocopherol, at least 85% beta-tocopherol, at least 90%> beta-tocopherol, at least 95% beta-tocopherol, or at least 98% beta-tocopherol.
  • Beta-tocopherol enriched tocopherol compositions may also comprise beta-tocopherol derivative(s) and/or beta-tocopherol metabolite(s), and/or other tocopherol(s) and/or mixtures thereof.
  • a beta-tocopherol "enriched" tocopherol composition comprises beta-tocopherol as the sole active ingredient.
  • tocopherols useful in the compositions of the present technology are ingredients in beta-tocopherol enriched tocopherol compositions that comprise less than 50% alpha-tocopherol, less than 45% alpha-tocopherol, less than 40% alpha-tocopherol, less than 35% alpha-tocopherol, less than 30% alpha-tocopherol, less than 25%) alpha-tocopherol, less than 20 % alpha-tocopherol, less than 15% alpha-tocopherol, less than 10% alpha-tocopherol or less than 5% alpha-tocopherol.
  • tocopherols useful in the compositions of the present technology are ingredients in delta-tocopherol enriched compositions that comprise at least 50%) delta-tocopherol, at least 55% delta-tocopherol, at least 60% delta-tocopherol, at least 65%) delta-tocopherol, at least 70% delta-tocopherol, at least 75% delta-tocopherol, at least 80%) delta-tocopherol, at least 85% delta-tocopherol, at least 90% delta-tocopherol, at least 95% delta-tocopherol, or at least 98% delta-tocopherol.
  • Delta-tocopherol enriched tocopherol compositions may also comprise delta-tocopherol derivative(s) and/or delta- tocopherol metabolite(s), and/or other tocopherol(s) and/or mixtures thereof.
  • a delta-tocopherol "enriched" tocopherol composition comprises delta- tocopherol as the sole active ingredient.
  • tocopherols useful in the compositions of the present technology are ingredients in delta-tocopherol enriched tocopherol compositions that comprise less than 50% alpha-tocopherol, less than 45% alpha- tocopherol, less than 40% alpha-tocopherol, less than 35% alpha-tocopherol, less than 30% alpha-tocopherol, less than 25% alpha-tocopherol, less than 20 % alpha-tocopherol, less than 15% alpha-tocopherol, less than 10% alpha-tocopherol or less than 5% alpha-tocopherol.
  • tocopherols useful in the compositions of the present technology are ingredients in gamma-tocopherol metabolite or derivative enriched
  • compositions that comprise at least 50% gamma-tocopherol metabolite or derivative, at least 55% gamma-tocopherol metabolite or derivative, at least 60% gamma-tocopherol metabolite or derivative, at least 65% gamma-tocopherol metabolite or derivative, at least 70% gamma- tocopherol metabolite or derivative, at least 75% gamma-tocopherol metabolite or derivative, at least 80% gamma-tocopherol metabolite or derivative, at least 85% gamma-tocopherol metabolite or derivative, at least 90% gamma-tocopherol metabolite or derivative, at least 95% gamma-tocopherol metabolite or derivative, or at least 98% gamma-tocopherol metabolite or derivative.
  • tocopherols useful in compositions of the present technology are ingredients in gamma-tocopherol metabolite or derivative enriched compositions that comprise less than 50% alpha-tocopherol, less than 45% alpha-tocopherol, less than 40% alpha-tocopherol, less than 35% alpha-tocopherol, less than 30% alpha- tocopherol, less than 25% alpha-tocopherol, less than 20 % alpha-tocopherol, less than 15% alpha-tocopherol, less than 10% alpha-tocopherol or less than 5% alpha-tocopherol.
  • Gamma- tocopherol metabolite enriched compositions may also comprise gamma-tocopherol and/or a gamma-tocopherol derivative(s), and/or other tocopherol(s) and/or mixtures thereof.
  • the gamma-tocopherol metabolite is gamma-CEHC.
  • a gamma-tocopherol metabolite or derivative "enriched" tocopherol composition comprises gamma-tocopherol metabolite or derivative as the sole active ingredient.
  • tocopherols useful in the compositions of the present technology are ingredients in beta-tocopherol metabolite or derivative enriched compositions that comprise at least 50% beta-tocopherol metabolite or derivative, at least 55% beta- tocopherol metabolite or derivative, at least 60% beta-tocopherol metabolite or derivative, at least 65% beta-tocopherol metabolite or derivative, at least 70% beta-tocopherol metabolite or derivative, at least 75% beta-tocopherol metabolite or derivative, at least 80% beta- tocopherol metabolite or derivative, at least 85% beta-tocopherol metabolite or derivative, at least 90% beta-tocopherol metabolite or derivative, at least 95% beta-tocopherol metabolite or derivative, or at least 98% beta-tocopherol metabolite or derivative.
  • beta-tocopherol metabolite or derivative enriched compositions that comprise at least 50% beta-tocopherol metabolite or derivative
  • tocopherols useful in the compositions of the present technology are ingredients in beta-tocopherol metabolite or derivative enriched compositions that comprise less than 50% alpha-tocopherol, less than 45% alpha-tocopherol, less than 40% alpha- tocopherol, less than 35% alpha-tocopherol, less than 30% alpha-tocopherol, less than 25% alpha-tocopherol, less than 20 % alpha-tocopherol, less than 15% alpha-tocopherol, less than 10% alpha-tocopherol or less than 5% alpha-tocopherol.
  • Beta-tocopherol metabolite enriched compositions may also comprise beta-tocopherol and/or a beta-tocopherol derivative(s), and/or other tocopherol(s) and/or mixtures thereof.
  • a beta-tocopherol metabolite or derivative "enriched" tocopherol composition comprises beta- tocopherol metabolite or derivative as the sole active ingredient.
  • tocopherols useful in the compositions of the present technology are ingredients in delta-tocopherol metabolite or derivative enriched compositions that comprise at least 50% delta-tocopherol metabolite or derivative, at least 55% delta- tocopherol metabolite or derivative, at least 60% delta-tocopherol metabolite or derivative, at least 65% delta-tocopherol metabolite or derivative, at least 70% delta-tocopherol metabolite or derivative, at least 75% delta-tocopherol metabolite or derivative, at least 80% delta- tocopherol metabolite or derivative, at least 85% delta-tocopherol metabolite or derivative, at least 90% delta-tocopherol metabolite or derivative, at least 95% delta-tocopherol metabolite or derivative, or at least 98% delta-tocopherol metabolite or derivative.
  • delta-tocopherol metabolite or derivative enriched compositions that comprise at least 50% delta-tocopherol metabolite or derivative
  • tocopherols useful in the compositions of the present technology are ingredients in delta-tocopherol metabolite or derivative enriched compositions that comprise less than 50% alpha-tocopherol, less than 45% alpha-tocopherol, less than 40% alpha- tocopherol, less than 35% alpha-tocopherol, less than 30%> alpha-tocopherol, less than 25% alpha-tocopherol, less than 20 % alpha-tocopherol, less than 15% alpha-tocopherol, less than 10% alpha-tocopherol or less than 5% alpha-tocopherol.
  • Delta-tocopherol metabolite enriched compositions may also comprise delta-tocopherol and/or a delta-tocopherol derivative(s), and/or other tocopherol(s) and/or mixtures thereof.
  • a delta-tocopherol metabolite or derivative "enriched" tocopherol composition comprises delta- tocopherol metabolite or derivative as the sole active ingredient.
  • tocopherols useful in the compositions of the present technology are ingredients in non-alpha tocopherol enriched tocopherol compositions.
  • the non-alpha tocopherol enriched tocopherol composition is a gamma- tocopherol enriched tocopherol composition or a gamma-tocopherol metabolite enriched composition.
  • the non-alpha tocopherol enriched tocopherol composition is a beta-tocopherol enriched tocopherol composition or a beta-tocopherol metabolite enriched composition.
  • the non-alpha tocopherol enriched tocopherol composition is a delta-tocopherol enriched tocopherol composition or a delta- tocopherol metabolite enriched composition.
  • a non-alpha tocopherol composition comprises a non-alpha tocopherol in a range of about 10 to about 1000 mg per kg body weight of a mammalian subject. In some embodiments, a non-alpha tocopherol composition comprises a non-alpha tocopherol in a range of about 5 to about 50 mg per kg body weight of a mammalian subject.
  • tocopherols useful in the compositions of the present technology are ingredients in non-alpha, non-gamma tocopherol enriched tocopherol compositions.
  • the non-alpha, non-gamma tocopherol enriched tocopherol composition is a non-alpha, non-gamma tocopherol metabolite or derivative enriched composition.
  • the non-alpha, non-gamma tocopherol enriched tocopherol composition is a beta- tocopherol enriched tocopherol composition or a beta-tocopherol metabolite enriched composition.
  • the non-alpha, non-gamma tocopherol enriched tocopherol composition is a delta-tocopherol enriched tocopherol composition or a delta-tocopherol metabolite enriched composition.
  • a non-alpha, non-gamma tocopherol composition comprises a non-alpha, non-gamma tocopherol in a range of about 1 to about 1000 mg per kg body weight of a mammalian subject.
  • a non-alpha, non-gamma tocopherol composition comprises a non- alpha, non-gamma tocopherol in a range of about 1 to about 50 mg per kg body weight of a mammalian subject.
  • a non-alpha, non-gamma tocopherol composition comprises a non-alpha, non-gamma tocopherol in a range of about 10 to about 100 mg per kg body weight of a mammalian subject.
  • tocopherols useful in the compositions of the present technology are ingredients in compositions comprising a tocopherol and a non-tocopherol.
  • the non-tocopherol is a lactoferrin or lactoferrin derivative.
  • Lactoferrin is the major iron-binding glycoprotein found in milk and other secretions and body fluids, including saliva, tears and mucosal secretions. Suitable lactoferrins include those derived from various mammals including humans, and derivatives thereof. Lactoferrin sequences known in the art include without limitation those which are human, (Metz-Boutigue et al. (1984) Eur. J. Biochem. 1451 :659-676; Rado et al. (1987) Blood 70:989-993; Rey et al.
  • tocopherols useful in the compositions of the present technology are ingredients in a composition comprising a tocopherol or derivative and a lactoferrin or a lactoferrin derivative wherein the lactoferrin or lactoferrin derivative is human.
  • Derivatives of lactoferrin can differ from any of the known lactoferrin sequences by sequence differences, including substitution, deletion, addition, or insertion of amino acids. Sequence determination can be performed by any method known in the art, including, for example, that described in Sanger et al. (1977) Proc. Natl Acad. Sci. U.S.A. 74:5463-5467 or use of SEQUENASETM kit (U. S. Biochemical Corp., Cleveland, Ohio).
  • compositions of the present technology are ingredients in a composition comprising a tocopherol (or a metabolite or derivative thereof) and lactoferrin (or a derivative thereof) in the following ratios (w/v) or tocopheroklactoferrin: at least about 1 : 10,000, at least about 1 : 1000, at least about 1 : 100, at least about 1 :10, at least about 1 :3, at least about 1 : 1, at least about 3: 1, at least about 10: 1, at least about 100: 1, at least about 1000: 1, or at least about 10,000: 1.
  • tocopherols useful in the compositions of the present technology are ingredients in a composition comprising a tocopherol (or a metabolite or derivative thereof) and lactoferrin (or a derivative thereof) in the following ratios (w/v) or tocopheroklactoferrin: no more than about 1 : 10,000, no more than about 1 : 1000, no more than about 1 : 100, no more than about 1 : 10, no more than about 1 : 3 , no more than about 1 : 1 , no more than about 3 : 1 , no more than about 10 : 1 , no more than about 100: 1, no more than about 1000: 1, or no more than about 10,000: 1.
  • tocopherols useful in the compositions of the present technology are ingredients in a composition comprising a tocopherol (or a metabolite or derivative thereof) and lactoferrin (or a derivative thereof) in the following ratios (w/v) or tocopheroklactoferrin: at least about 1 : 1, at least about 1 :3, or at least about 1 : 10.
  • suitable ratios and amounts of various tocopherols and lactoferrin can be determined based on laboratory experiments to determine efficacy, as described in U.S. Pat. No. 6,426,362.
  • the ratio of tocopherol: lactoferrin will be such that the composition allows an amelioration of at least one stress-induced alteration in energy metabolism, which is defined and which can be measured as described in U.S. Pat. No. 6,426,362.
  • compositions of the present technology are ingredients in a composition comprising a tocopherol (or a metabolite or derivative thereof) and lactoferrin (or a derivative thereof).
  • the composition can comprise at least about 0.3, at least about 1, at least about 3, at least about 10, at least about 25, at least about 50, at least about 100, at least about 200, at least about 400, at least about 500, at least about 1000, at least about 2000, at least about 4000, at least about 5000, or at least about 10,000 ⁇ / ⁇ . of tocopherol (or a metabolite or derivative thereof).
  • the composition can comprise no more than about 0.3, no more than about 1, no more than about 3, no more than about 10, no more than about 25, no more than about 50, no more than about 100, no more than about 200, no more than about 400, no more than about 500, no more than about 1000, no more than about 2000, no more than about 4000, no more than about 5000, or no more than about 10,000 ⁇ g/mL of tocopherol (or a metabolite or derivative thereof).
  • the composition comprises at least about 0.3, at least about 1, at least about 5, or at least about 10 ⁇ g/mL tocopherol (or a metabolite or derivative thereof).
  • the composition can comprise at least about 0.3, at least about 1 , at least about 3, at least about 10, at least about 25, at least about 50, at least about 100, at least about 200, at least about 400, at least about 500, at least about 1000, at least about 2000, at least about 4000, at least about 5000, or at least about 10,000 ⁇ g/mL of lactoferrin (or a derivative thereof).
  • the composition can comprise no more than about 0.3, no more than about 1, no more than about 3, no more than about 10, no more than about 25, no more than about 50, no more than about 100, no more than about 200, no more than about 400, no more than about 500, no more than about 1000, no more than about 2000, no more than about 4000, no more than about 5000, or no more than about 10,000 ⁇ g/mL of lactoferrin (or a derivative thereof).
  • the composition comprises at least about 0.3, at least about 1, at least about 5, or at least about 10 ⁇ g/mL of lactoferrin (or a derivative thereof).
  • the composition comprises at least about 0.3, at least about 1, at least about 5, or at least about 10 ⁇ g/mL of lactoferrin (or a derivative thereof).
  • Exemplary ratios include, but are not limited to, a ratio of 33: 1, 10: 1, 3.3:1 or 1.1 : 1 (w/v) lactoferrin to alpha-tocopherol.
  • tocopherols useful in the compositions of the present technology are ingredients in a nutritional composition comprising a tocopherol to be administered in a range of about 1 to about 50 mg per kg body weight of a mammalian subject.
  • the nutritional composition comprises a tocopherol to be administered at a lower limit of at least about 1.00, 1.50, 2.00, 2.50, 5.00, 7.50, 10.00, 12.50, 15.00, 17.50, 20.00, 22.25, and 25.00 mg per kg body weight of a mammalian subject and at an upper limit of not greater than about 27.25, 30.00, 32.50, 35.00, 37.25, 40.00, 42.25, 45.00, 47.25, and 50.00 mg per kg body weight of a mammalian subject, with the lower limit and upper limit to be selected independently.
  • tocopherols useful in the compositions of the present technology are ingredients in a pharmaceutical composition comprising a tocopherol to be administered in a range of about 1 to about 1000 mg per kg body weight of a mammalian subject.
  • the pharmaceutical composition will comprise a tocopherol to be administered at a lower limit of at least about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, and 500 mg per kg body weight of a mammalian subject and at an upper limit of not greater than about 60, 70, 100, 200, 300, 400, 500, 600, 700, 800, 900, and 1000 mg per kg body weight of a mammalian subject, with the lower limit and upper limit to be selected independently.
  • the pharmaceutical composition will comprise a tocopherol to be administered in a range of about 10 to about 100 mg per kg body weight of a mammalian subject.
  • aromatic-cationic peptides of the present technology are water-soluble, highly polar, and can readily penetrate cell membranes.
  • aromatic-cationic peptides of the present technology include a minimum of three amino acids, covalently joined by peptide bonds.
  • the maximum number of amino acids present in the aromatic-cationic peptides of the present technology is about twenty amino acids covalently joined by peptide bonds. In some embodiments, the maximum number of amino acids is about twelve. In some embodiments, the maximum number of amino acids is about nine. In some embodiments, the maximum number of amino acids is about six. In some embodiments, the maximum number of amino acids is four.
  • the present technology provides an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof such as acetate salt or trifluoroacetate salt.
  • the peptide comprises at least one net positive charge; a minimum of three amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1 ; and a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a is the largest number that is less than or equal to p t + 1 , except that when a is 1 , p t may also be 1.
  • the peptide comprises the amino acid sequence 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 .
  • the peptide comprises one or more of the peptides of Table A:
  • the aromatic-cationic peptide is defined by Formula A:
  • R 1 and R 2 are each independently selected from
  • R and R 4 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from (i) hydrogen;
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • the peptide is defined by Formula B:
  • R 1 and R 2 are each independently selected from
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
  • the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
  • the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
  • Aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), and Trp (W). In some embodiments, the Aromatic residue may be substituted with
  • the Cationic residue is a residue selected from the group consisting of: Arg (R), Lys (K), and His (H).
  • the Cationic residue may be substituted with norleucine (Nle) or 2-amino-heptanoic acid (Ahe).
  • amino acids of the aromatic-cationic peptides of the present technology can be any amino acid.
  • amino acid is used to refer to any organic molecule that contains at least one amino group and at least one carboxyl group. In some embodiments, at least one amino group is at the a position relative to the carboxyl group.
  • the amino acids may be naturally occurring.
  • Naturally occurring amino acids include, for example, the twenty most common levorotatory (L,) amino acids normally found in mammalian proteins, i.e., alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (He), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan, (Trp), tyrosine (Tyr), and valine (Val).
  • L levorotatory amino acids normally found in mammalian proteins
  • alanine (Ala) amino acids normally found in mammalian proteins i.e., alanine (Ala), arginine (Arg), asparag
  • amino acids include, for example, amino acids that are synthesized in metabolic processes not associated with protein synthesis.
  • amino acids ornithine and citrulline are synthesized in mammalian metabolism during the production of urea.
  • the peptides useful in the present technology can contain one or more non-naturally occurring amino acids.
  • the non-naturally occurring amino acids may be (L-), dextrorotatory (D-), or mixtures thereof.
  • the peptide has no amino acids that are naturally occurring.
  • Non-naturally occurring amino acids are those amino acids that typically are not synthesized in normal metabolic processes in living organisms, and do not naturally occur in proteins.
  • the non-naturally occurring amino acids useful in the present technology are also not recognized by common proteases.
  • the non-naturally occurring amino acid can be present at any position in the peptide.
  • the non-naturally occurring amino acid can be at the N terminus, the C-terminus, or at any position between the N-terminus and the C-terminus.
  • the non-natural amino acids may, for example, comprise alkyl, aryl, or alkylaryl groups.
  • alkyl amino acids include a-aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminovaleric acid, and ⁇ -aminocaproic acid.
  • aryl amino acids include ortho-, meta, and para-aminobenzoic acid.
  • alkylaryl amino acids include ortho-, meta-, and para-aminophenyl acetic acid, and ⁇ -phenyl- ⁇ -aminobutyric acid.
  • Non-naturally occurring amino acids also include derivatives of naturally occurring amino acids.
  • the derivatives of naturally occurring amino acids may, for example, include the addition of one or more chemical groups to the naturally occurring amino acid.
  • one or more chemical groups can be added to one or more of the 2', 3', 4', 5', or 6' position of the aromatic ring of a phenylalanine or tyrosine residue, or the 4', 5', 6', or 7' position of the benzo ring of a tryptophan residue.
  • the group can be any chemical group that can be added to an aromatic ring.
  • Some examples of such groups include branched or unbranched C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, or t-butyl, C 1 -C 4 alkyloxy (i.e., alkoxy), amino, C 1 -C 4 alkylamino and C 1 -C 4 dialkylamino (e.g., methylamino, dimethylamino), nitro, hydroxyl, halo (i.e., fluoro, chloro, bromo, or iodo).
  • Some specific examples of non-naturally occurring derivatives of naturally occurring amino acids include norvaline (Nva), norleucine (Nle), and hydroxyproline (Hyp).
  • Another example of a modification of an amino acid in a peptide useful in the present methods is the derivatization of a carboxyl group of an aspartic acid or a glutamic acid residue of the peptide.
  • derivatization is amidation with ammonia or with a primary or secondary amine, e.g., methylamine, ethylamine, dimethylamine or diethylamine.
  • Another example of derivatization includes esterification with, for example, methyl or ethyl alcohol.
  • Another such modification includes derivatization of an amino group of a lysine, arginine, or histidine residue.
  • amino groups can be acylated.
  • suitable acyl groups include, for example, a benzoyl group or an alkanoyl group comprising any of the C 1 -C4 alkyl groups mentioned above, such as an acetyl or propionyl group.
  • the non-naturally occurring amino acids are resistant, and in some embodiments insensitive, to common proteases.
  • non-naturally occurring amino acids that are resistant or insensitive to proteases include the dextrorotatory (D-) form of any of the above-mentioned naturally occurring L-amino acids, as well as L- and/or D non- naturally occurring amino acids.
  • D-amino acids do not normally occur in proteins, although they are found in certain peptide antibiotics that are synthesized by means other than the normal ribosomal protein synthetic machinery of the cell, as used herein, the D-amino acids are considered to be non-naturally occurring amino acids.
  • the peptides useful in the methods of the present technology should have less than five, less than four, less than three, or less than two contiguous L-amino acids recognized by common proteases, irrespective of whether the amino acids are naturally or non-naturally occurring.
  • the peptide has only D-amino acids, and no L-amino acids.
  • the peptide contains protease sensitive sequences of amino acids, at least one of the amino acids is a non-naturally-occurring D-amino acid, thereby conferring protease resistance.
  • An example of a protease sensitive sequence includes two or more contiguous basic amino acids that are readily cleaved by common proteases, such as endopeptidases and trypsin. Examples of basic amino acids include arginine, lysine and histidine.
  • the aromatic-cationic peptides have a minimum number of net positive charges at physiological pH in comparison to the total number of amino acid residues in the peptide.
  • the minimum number of net positive charges at physiological pH is referred to below as (p m ).
  • the total number of amino acid residues in the peptide is referred to below as (r).
  • physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
  • physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
  • physiological pH of a human is normally approximately 7.4, but normal physiological pH in mammals may be any pH from about 7.0 to about 7.8.
  • a peptide has a positively charged N-terminal amino group and a negatively charged C-terminal carboxyl group. The charges cancel each other out at physiological pH.
  • the peptide Tyr-Arg-Phe-Lys- Glu-His-Trp-Arg has one negatively charged amino acid (i.e., Glu) and four positively charged amino acids (i.e., two Arg residues, one Lys, and one His). Therefore, the above peptide has a net positive charge of three.
  • the aromatic-cationic peptides have a relationship between the minimum number of net positive charges at physiological pH (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1.
  • the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
  • the aromatic-cationic peptides have a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 2p m is the largest number that is less than or equal to r + 1.
  • the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
  • the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) are equal.
  • the peptides have three or four amino acid residues and a minimum of one net positive charge, or a minimum of two net positive charges, or a minimum of three net positive charges.
  • aromatic-cationic peptides have a minimum number of aromatic groups in comparison to the total number of net positive charges (p t ).
  • the minimum number of aromatic groups will be referred to below as (a).
  • Naturally-occurring amino acids that have an aromatic group include the amino acids histidine, tryptophan, tyrosine, and phenylalanine.
  • the hexapeptide Lys-Gln-Tyr-D-Arg-Phe-Trp has a net positive charge of two (contributed by the lysine and arginine residues) and three aromatic groups (contributed by tyrosine, phenylalanine and tryptophan residues).
  • the aromatic-cationic peptides should also have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges at physiological pH (p t ) wherein 3 a is the largest number that is less than or equal to p t + 1, except that when p t is 1 , a may also be 1.
  • the relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) is as follows:
  • the aromatic-cationic peptides have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a is the largest number that is less than or equal to p t + 1.
  • the number of aromatic groups (a) and the total number of net positive charges (pt) are equal.
  • carboxyl groups are amidated with, for example, ammonia to form the C-terminal amide.
  • the terminal carboxyl group of the C-terminal amino acid may be amidated with any primary or secondary amine.
  • the primary or secondary amine may, for example, be an alkyl, especially a branched or unbranched C1-C4 alkyl, or an aryl amine.
  • amino acid at the C-terminus of the peptide may be converted to an amido, N-methylamido, N-ethylamido, N,N-dimethylamido, ⁇ , ⁇ -diethyl amido, N-methyl-N- ethylamido, N-phenylamido or N-phenyl-N-ethylamido group.
  • the free carboxylate groups of the asparagine, glutamine, aspartic acid, and glutamic acid residues not occurring at the C-terminus of the aromatic-cationic peptides of the present technology may also be amidated wherever they occur within the peptide.
  • the amidation at these internal positions may be with ammonia or any of the primary or secondary amines described herein.
  • the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and at least one aromatic amino acid.
  • the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and two aromatic amino acids.
  • Aromatic-cationic peptides useful in the methods of the present technology include, but are not limited to, the following peptide examples:
  • the aromatic-cationic peptide is a peptide having:
  • 2p m is the largest number that is less than or equal to r+1, and a may be equal to p t .
  • the aromatic-cationic peptide may be a water-soluble peptide having a minimum of two or a minimum of three positive charges.
  • the peptide comprises one or more non-naturally occurring amino acids, for example, one or more D-amino acids.
  • the C-terminal carboxyl group of the amino acid at the C-terminus is amidated.
  • the peptide has a minimum of four amino acids. The peptide may have a maximum of about 6, a maximum of about 9, or a maximum of about 12 amino acids.
  • the peptides have a tyrosine residue or a tyrosine derivative at the N-terminus (i.e., the first amino acid position).
  • Suitable derivatives of tyrosine include 2'- methyltyrosine (Mmt); 2',6'-dimethyltyrosine (2'6'-Dmt); 3 ',5 '-dimethyltyrosine (3'5'Dmt); N,2',6'-trimethyltyrosine (Tmt); and 2'-hydroxy-6'-methyltyrosine (Hmt).
  • a peptide has the formula Tyr-D-Arg-Phe-Lys-NH 2 .
  • Tyr-D- Arg-Phe-Lys-NH 2 has a net positive charge of three, contributed by the amino acids tyrosine, arginine, and lysine and has two aromatic groups contributed by the amino acids phenylalanine and tyrosine.
  • the tyrosine of Tyr-D-Arg-Phe-Lys-NH 2 can be a modified derivative of tyrosine such as in 2',6'-dimethyltyrosine to produce the compound having the formula 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 .
  • 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 has a molecular weight of 640 and carries a net three positive charge at physiological pH. 2',6'-Dmt-D-Arg- Phe-Lys-NH 2 readily penetrates the plasma membrane of several mammalian cell types in an energy-independent manner (Zhao et ah, J. Pharmacol Exp Ther., 304:425-432, 2003).
  • the aromatic-cationic peptide does not have a tyrosine residue or a derivative of tyrosine at the N-terminus (i.e., amino acid position 1).
  • the amino acid at the N-terminus can be any naturally-occurring or non-naturally-occurring amino acid other than tyrosine.
  • the amino acid at the N-terminus is phenylalanine or its derivative.
  • Exemplary derivatives of phenylalanine include 2'- methylphenylalanine (Mmp), 2',6'-dimethylphenylalanine (2',6'-Dmp), N,2',6'- trimethylphenylalanine (Tmp), and 2'-hydroxy-6'-methylphenylalanine (Hmp).
  • an aromatic-cationic peptide that does not have a tyrosine residue or a derivative of tyrosine at the N-terminus is a peptide with the formula Phe-D-Arg-Phe-Lys- NH 2 .
  • the N-terminal phenylalanine can be a derivative of phenylalanine such as 2',6'-dimethylphenylalanine (2'6'-Dmp).
  • the amino acid sequence of 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 is rearranged such that Dmt is not at the N-terminus.
  • An example of such an aromatic-cationic peptide is a peptide having the formula of D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • Suitable substitution variants of the peptides listed herein include conservative amino acid substitutions.
  • Amino acids may be grouped according to their physicochemical characteristics as follows:
  • Non-polar amino acids Ala(A) Ser(S) Thr(T) Pro(P) Gly(G) Cys (C);
  • Aromatic amino acids Phe(F) Tyr(Y) Trp(W) His (H).
  • substitutions of an amino acid in a peptide by another amino acid in the same group are referred to as a conservative substitution and may preserve the physicochemical characteristics of the original peptide.
  • substitutions of an amino acid in a peptide by another amino acid in a different group are generally more likely to alter the
  • Examples of peptides that have a tyrosine residue or a tyrosine derivative at the N- terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 6.
  • Tmt N, 2',6'-trimethyltyrosine
  • dnsDap P-dansyl-L- ⁇ , ⁇ -diaminopropionic acid
  • Examples of peptides that do not have a tyrosine residue or a tyrosine derivative at the N-terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 7.
  • amino acids of the peptides shown in Table 6 and 7 may be in either
  • the methods disclosed herein provide therapies for the treatment of medical disease or conditions and/or side effects associated with existing therapeutics against medical diseases or conditions comprising administering an effective amount of tocopherol alone or in combination with one or more aromatic-cationic peptides or pharmaceutically acceptable salts thereof, such as acetate, tartrate or trifluoroacetate.
  • the present technology provides methods for treating,
  • one or more peptide conjugate(s) may be: (1) co-formulated and administered or delivered alone or simultaneously in a combined formulation with other tocopherols or aromatic-cationic peptides; (2) delivered by alternation or in parallel as separate
  • the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • Administering combinations of aromatic peptides and tocopherols can result in synergistic biological effect when administered in a therapeutically effective amount to a subject suffering from a medical disease or condition and in need of treatment.
  • An advantage of such an approach is that lower doses of aromatic-cationic peptide and/or tocopherol may be needed to prevent, ameliorate or treat a medical disease or condition in a subject. Further, potential side-effects of treatment may be avoided by use of lower dosages of aromatic- cationic peptide and/or tocopherol.
  • the combination therapy comprises administering to a subject in need thereof an aromatic-cationic peptide
  • composition combined with one or more tocopherols.
  • the tocopherol and the aromatic-cationic peptide are chemically linked.
  • the tocopherol and the aromatic-cationic peptide are physically linked.
  • the tocopherol and the aromatic-cationic peptide are not linked.
  • Ischemia in a tissue or organ of a mammal is a multifaceted pathological condition which is caused by oxygen deprivation (hypoxia) and/or glucose (e.g., substrate) deprivation.
  • Oxygen and/or glucose deprivation in cells of a tissue or organ leads to a reduction or total loss of energy generating capacity and consequent loss of function of active ion transport across the cell membranes.
  • Oxygen and/or glucose deprivation also leads to pathological changes in other cell membranes, including permeability transition in the mitochondrial membranes.
  • other molecules, such as apoptotic proteins normally
  • Ischemia or hypoxia in a particular tissue or organ may be caused by a loss or severe reduction in blood supply to the tissue or organ.
  • the loss or severe reduction in blood supply may, for example, be due to thromboembolic stroke, coronary atherosclerosis, or peripheral vascular disease.
  • the tissue affected by ischemia or hypoxia is typically muscle, such as cardiac, skeletal, or smooth muscle.
  • the organ affected by ischemia or hypoxia may be any organ that is subject to ischemia or hypoxia.
  • organs affected by ischemia or hypoxia include brain, heart, kidney, and prostate.
  • cardiac muscle ischemia or hypoxia is commonly caused by atherosclerotic or thrombotic blockages which lead to the reduction or loss of oxygen delivery to the cardiac tissues by the cardiac arterial and capillary blood supply.
  • Such cardiac ischemia or hypoxia may cause pain and necrosis of the affected cardiac muscle, and ultimately may lead to cardiac failure.
  • Ischemia or hypoxia in skeletal muscle or smooth muscle may arise from similar causes.
  • ischemia or hypoxia in intestinal smooth muscle or skeletal muscle of the limbs may also be caused by atherosclerotic or thrombotic blockages.
  • Reperfusion is the restoration of blood flow to any organ or tissue in which the flow of blood is decreased or blocked.
  • blood flow can be restored to any organ or tissue affected by ischemia or hypoxia.
  • the restoration of blood flow can occur by any method known to those in the art. For instance, reperfusion of ischemic cardiac tissues may arise from angioplasty, coronary artery bypass graft, or the use of thrombolytic drugs.
  • tocopherols are useful in reducing oxLDL-induced CD36 mRNA and protein levels, and foam cell formation in mouse peritoneal macrophages.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe
  • tocopherols are useful in reducing infarct volume and hemispheric swelling in a subject suffering from acute cerebral ischemia.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing infarct volume and hemispheric swelling in a subject suffering from acute cerebral ischemia.
  • tocopherols are useful in reducing the decrease in reduced glutathione (GSH) in post-ischemic brain in a subject in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing the decrease in reduced glutathione (GSH) in post-ischemic brain in a subject in need thereof.
  • tocopherols are useful in reducing CD36 expression in post-ischemic brain in a subject in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing CD36 expression in post-ischemic brain in a subject in need thereof.
  • tocopherols are useful in reducing CD36 expression in renal tubular cells after unilateral ureteral obstruction (UUO) in a subject in need thereof.
  • UUO unilateral ureteral obstruction
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • the peptide conjugates of the present technology are useful in reducing CD36 expression in renal tubular cells after unilateral ureteral obstruction (UUO) in a subject in need thereof.
  • UUO unilateral ureteral obstruction
  • tocopherols are useful in reducing lipid peroxidation in a kidney after UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing lipid peroxidation in a kidney after UUO.
  • tocopherols are useful in reducing tubular cell apoptosis in an obstructed kidney after UUO.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing tubular cell apoptosis in an obstructed kidney after UUO.
  • tocopherols are useful in reducing macrophage infiltration in an obstructed kidney induced by UUO.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing macrophage infiltration in an obstructed kidney induced by UUO.
  • tocopherols are useful in reducing interstitial fibrosis in an obstructed kidney after UUO.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing interstitial fibrosis in an obstructed kidney after UUO.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing up-regulation of CD36 expression in cold storage of isolated hearts.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing up-regulation of CD36 expression in cold storage of isolated hearts.
  • tocopherols are useful in reducing lipid peroxidation in cardiac tissue (e.g. , heart) subjected to warm reperfusion after prolonged cold ischemia.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • the peptide conjugates of the present technology are useful in reducing lipid peroxidation in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • tocopherols are useful in abolishing endothelial apoptosis in cardiac tissue (e.g. , heart) subjected to warm reperfusion after prolonged cold ischemia.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • the peptide conjugates of the present technology are useful in abolishing endothelial apoptosis in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • cardiac tissue e.g., heart
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • cardiac tissue e.g., heart
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • the peptide conjugates of the present technology are useful in preserving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • tocopherols are useful in preventing damage to renal proximal tubules in diabetic subjects.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in preventing damage to renal proximal tubules in diabetic subjects.
  • tocopherols are useful in preventing renal tubular epithelial cell apoptosis in diabetic subjects.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in preventing renal tubular epithelial cell apoptosis in diabetic subjects.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in methods for reducing elevated CD36 expression associated with various diseases and conditions.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys
  • diseases and conditions characterized by increased CD36 expression include, but are not limited to atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy and obesity.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in methods for reducing CD36 expression in subjects suffering from complications of diabetes.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-L
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in methods for reducing CD36 expression in removed organs and tissues.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • the method comprises contacting the removed organ or tissue with an effective amount of a composition described herein.
  • An organ or tissue may, for example, be removed from a donor for autologous or heterologous transplantation. Examples of organs and tissues amenable to methods of the present technology include, but are not limited to, heart, lungs, pancreas, kidney, liver, skin, etc.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) will translocate to and accumulate within mitochondria.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology will translocate to and accumulate within mitochondria.
  • tocopherols are useful in protecting against mitochondrial permeability transition (MPT) induced by Ca 2+ overload and 3-nitropropionic acid (3NP).
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • MTT mitochondrial permeability transition
  • 3NP 3-nitropropionic acid
  • tocopherols are useful in inhibiting mitochondrial swelling and cytochrome c release.
  • tocopherols in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in inhibiting mitochondrial swelling and cytochrome c release.
  • tocopherols are useful in protecting myocardial contractile force during ischemia-reperfusion in cardiac tissue.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic
  • the peptide conjugates of the present technology are useful in protecting myocardial contractile force during ischemia-reperfusion in cardiac tissue.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • a cardioplegic solution are useful in enhancing contractile function after prolonged ischemia in isolated perfused cardiac tissue (e.g., heart).
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology e.g., those including 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH2, Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2
  • a cardioplegic solution e.g., those including 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH2, Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2
  • a cardioplegic solution e.g., those including 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH2, Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof or peptide conjugates of the present technology (e.g. , those including 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2 ) are useful in treating any disease or condition that is associated with, for example, MPT.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology e.g. , those including 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2
  • tocopherols or derivatives, an
  • Such diseases and conditions include, but are not limited to, e.g., ischemia and/or reperfusion of a tissue or organ, hypoxia, diseases and conditions of the eye, myocardial infarction and any of a number of neurodegenerative diseases. Mammals in need of treatment or prevention of MPT are those mammals suffering from these diseases or conditions.
  • compositions of the present disclosure can also be used in the treatment or prophylaxis of neurodegenerative diseases associated with MPT.
  • Neurodegenerative diseases associated with MPT include, for instance, Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig's disease).
  • ALS Amyotrophic Lateral Sclerosis
  • the methods and compositions disclosed herein can be used to delay the onset or slow the progression of these and other neurodegenerative diseases associated with MPT.
  • the methods and compositions of the present technology are useful in the treatment of humans suffering from the early stages of neurodegenerative diseases associated with MPT and in humans predisposed to these diseases.
  • tocopherols are useful in preserving an organ of a mammal prior to
  • tocopherols or derivatives, analogues, or
  • an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in preserving an organ of a mammal prior to
  • compositions of the present disclosure can be administered to a subject prior to organ removal, for example, and used to prevent MPT in the removed organ.
  • the removed organ may be placed in a standard buffered solution, such as those commonly used in the art.
  • a removed heart may be placed in a cardioplegic solution containing the compositions described herein.
  • concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.1 nM to about 10 ⁇ .
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology may also be administered to a mammal taking a drug to treat a condition or disease.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology may also be administered to a mammal taking a drug to treat a condition or disease.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • a side effect of the drug includes MPT
  • mammals taking such drugs would greatly benefit from administration of the compositions disclosed herein.
  • An example of a drug which induces cell toxicity by effecting MPT is the chemotherapy drug Adriamycin.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in ameliorating, diminishing or preventing the side effects of drugs such as adriamycin.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe
  • tocopherols are useful in dose-dependently scavenging H 2 0 2 .
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6
  • tocopherols are useful in dose-dependently inhibiting linoleic acid peroxidation induced by ABAP and reducing the rate of linoleic acid peroxidation induced by ABAP.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2
  • tocopherols are useful in inhibiting mitochondrial production of hydrogen peroxide, e.g., as measured by luminol chemiluminescence under basal conditions and/or upon stimulation by antimycin.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • peptide conjugates of the present technology are useful in inhibiting mitochondrial production of hydrogen peroxide, e.g., as measured by luminol chemiluminescence under basal conditions and/or upon stimulation by antimycin.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing spontaneous generation of hydrogen peroxide by mitochondria in certain stress or disease states.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing spontaneous generation of hydrogen peroxide by mitochondria in certain stress or disease states.
  • tocopherols are useful in inhibiting spontaneous production of hydrogen peroxide in mitochondria and hydrogen peroxide production, e.g., as stimulated by antimycin.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in inhibiting spontaneous production of hydrogen peroxide in mitochondria and hydrogen peroxide production, e.g., as stimulated by antimycin.
  • tocopherols are useful in decreasing intracellular ROS (reactive oxygen species) and increasing survival in cells of a subject in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic
  • tocopherols are useful in preventing loss of cell viability in subjects suffering from a disease or condition characterized by mitochondrial permeability transition.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an
  • tocopherols are useful in decreasing the percent of cells showing increased caspase activity in a subject in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide
  • tocopherols are useful in decreasing the rate of ROS accumulation in a subject in need thereof.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in decreasing the rate of ROS accumulation in a subject in need thereof.
  • tocopherols are useful in inhibiting lipid peroxidation in a subject in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • peptide conjugates of the present technology are useful in inhibiting lipid peroxidation in a subject in need thereof.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing mitochondrial depolarization and ROS accumulation in a subject in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2
  • tocopherols are useful in preventing apoptosis in a subject in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2'
  • tocopherols are useful in improving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in improving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • tocopherols are useful in preventing apoptosis in endothelial cells and myocytes in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • cardiac tissue e.g., heart
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof.
  • an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NI3 ⁇ 4, or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NI3 ⁇ 4, or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in preventing apoptosis in endothelial cells and myocytes in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • tocopherols are useful in improving survival of pancreatic cells in a subject in need thereof.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in improving survival of pancreatic cells in a subject in need thereof.
  • tocopherols are useful in reducing apoptosis and increasing viability in islet cells of pancreas in subjects in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing apoptosis and increasing viability in islet cells of pancreas in subjects in need thereof.
  • tocopherols are useful in reducing oxidative damage in pancreatic islet cells in subjects in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing oxidative damage in pancreatic islet cells in subjects in need thereof.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in protecting dopaminergic cells against MPP+ toxicity in subjects in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in protecting dopaminergic cells against MPP+ toxicity in subjects in need thereof.
  • tocopherols are useful in preventing loss of dopaminergic neurons in subject in need thereof.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
  • tocopherols are useful in increasing striatal dopamine, DOPAC (3,4- dihydroxyphenylacetic acid) and HVA (homo vanillic acid) levels in subjects in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in increasing striatal dopamine, DOPAC and HVA levels in subjects in need thereof.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology e.g. , those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
  • D-Arg-2'6'-Dmt-Lys-Phe-NH 2 are useful to reduce oxidative damage in a mammal in need thereof.
  • tocopherols in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • mammals in need of reducing oxidative damage are those mammals suffering from a disease, condition or treatment associated with oxidative damage.
  • the oxidative damage is caused by free radicals, such as reactive oxygen species (ROS) and/or reactive nitrogen species (RNS).
  • ROS and RNS include hydroxyl radical ( ⁇ ' ), superoxide anion radical (0 2 ⁇ ), nitric oxide (NO ' ), hydrogen peroxide (H 2 0 2 ), hypochlorous acid (HOC1), and peroxynitrite anion (ONOO ).
  • a mammal in need thereof may be a mammal undergoing a treatment associated with oxidative damage.
  • the mammal may be undergoing reperfusion.
  • “Reperfusion” refers to the restoration of blood flow to any organ or tissue in which the flow of blood is decreased or blocked. The restoration of blood flow during reperfusion leads to respiratory burst and formation of free radicals.
  • a mammal in need thereof is a mammal suffering from a disease or condition associated with oxidative damage.
  • the oxidative damage can occur in any cell, tissue or organ of the mammal.
  • cells, tissues or organs affected by oxidative damage include, but are not limited to, endothelial cells, epithelial cells, nervous system cells, skin, heart, lung, kidney, eye and liver.
  • lipid peroxidation and an inflammatory process are associated with oxidative damage for a disease or condition.
  • Lipid peroxidation refers to oxidative modification of lipids.
  • the lipids can be present in the membrane of a cell. This modification of membrane lipids typically results in change and/or damage to the membrane function of a cell.
  • lipid peroxidation can also occur in lipids or lipoproteins exogenous to a cell. For example, low-density
  • lipoproteins are susceptible to lipid peroxidation.
  • An example of a condition associated with lipid peroxidation is atherosclerosis. Reducing oxidative damage associated with
  • Atherosclerosis is important because atherosclerosis is implicated in, for example, heart attacks and coronary artery disease.
  • Intravirus process refers to the activation of the immune system.
  • the immune system is activated by an antigenic substance.
  • the antigenic substance can be any substance recognized by the immune system, and include self-derived and foreign- derived substances.
  • diseases or conditions resulting from an inflammatory response to self-derived substances include arthritis and multiple sclerosis.
  • foreign substances include viruses and bacteria.
  • the virus can be any virus which activates an inflammatory process, and associated with oxidative damage.
  • viruses include, hepatitis A, B or C virus, human immunodeficiency virus, influenza virus, and bovine diarrhea virus.
  • hepatitis virus can elicit an inflammatory process and formation of free radicals, thereby damaging the liver.
  • the bacteria can be any bacteria, and include gram-negative and gram-positive bacteria.
  • Gram-negative bacteria contain lipopolysaccharide in the bacteria wall. Examples of gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Proteus species, Pseudomonas aeruginosa, Serratia, and Bacteroides. Examples of gram-positive bacteria include pneumococci and streptococci.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • the peptide conjugates of the present technology ⁇ e.g. , those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
  • D-Arg-2'6'-Dmt-Lys-Phe-NH 2 are useful in reducing oxidative damage associated with a neurodegenerative disease or condition.
  • tocopherols in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • the neurodegenerative disease can affect any cell, tissue or organ of the central and peripheral nervous system. Non-limiting examples of such cells, tissues and organs include, the brain, spinal cord, neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia.
  • the neurodegenerative condition can be an acute condition, such as a stroke or a traumatic brain or spinal cord injury.
  • the neurodegenerative disease or condition is a chronic neurodegenerative condition.
  • the free radicals can, for example, cause damage to a protein.
  • An example of such a protein is amyloid precursor protein.
  • Non-limiting examples of chronic neurodegenerative diseases associated with damage by free radicals include Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS).
  • tocopherols are useful in treating preeclampsia, diabetes, and symptoms of and conditions associated with aging, such as macular degeneration, and wrinkles.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in reducing oxidative damage in an organ of a mammal prior to transplantation.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • the organ can be any organ suitable for transplantation.
  • the organ is a removed organ.
  • examples of such organs include, the heart, liver, kidney, lung, and pancreatic islets.
  • the removed organ is placed in a suitable medium, such as in a standard buffered solution commonly used in the art.
  • the concentration of disclosed compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.01 nM to about 10 ⁇ , about 0.1 nM to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , or about 1 nM to about 100 nM.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in reducing oxidative damage in a cell in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-
  • Cells in need of reducing oxidative damage are generally those cells in which the cell membrane or DNA has been damaged by free radicals, for example, ROS and/or RNS.
  • free radicals for example, ROS and/or RNS.
  • Examples of cells capable of sustaining oxidative damage include, but are not limited to, pancreatic islet cells, myocytes, endothelial cells, neuronal cells, stem cells, and other cell types discussed herein.
  • the cells can be tissue culture cells. Alternatively, the cells may be obtained from a mammal. In one instance, the cells can be damaged by oxidative damage as a result of a cellular insult.
  • Cellular insults include, for example, a disease or condition (e.g., diabetes, etc.) or ultraviolet radiation (e.g., sun, etc.).
  • pancreatic islet cells damaged by oxidative damage as a result of diabetes can be obtained from a mammal.
  • the treated cells may be capable of regenerating.
  • Such regenerated cells may be re-introduced into the mammal from which they were derived as a therapeutic treatment for a disease or condition.
  • a disease or condition is diabetes.
  • Oxidative damage is considered to be "reduced” if the amount of oxidative damage in a mammal, a removed organ, or a cell is decreased after administration of an effective amount of the compositions described herein. Typically, oxidative damage is considered to be reduced if the oxidative damage is decreased by at least about 1%, 5%, 10%, at least about 25%, at least about 50%>, at least about 75%, or at least about 90%.
  • tocopherols are useful in regulating oxidation state of muscle tissue.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe- NH 2
  • tocopherols are useful in regulating oxidation state of muscle tissue in lean and obese human subjects.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in regulating oxidation state of muscle tissue in lean and obese human subjects.
  • tocopherols are useful in regulating insulin resistance in muscle tissue.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe- NH 2
  • insulin resistance induced by obesity or a high-fat diet affects mitochondrial bioenergetics.
  • mitochondrial bioenergetics it is thought that the oversupply of metabolic substrates causes a reduction on the function of the mitochondrial respiratory system, and an increase in ROS production and shift in the overall redox environment to a more oxidized state. If persistent, this leads to development of insulin resistance.
  • Linking mitochondrial bioenergetics to the etiology of insulin resistance has a number of clinical implications.
  • insulin resistance (NIDDM) in humans often results in weight gain and, in selected individuals, increased variability of blood sugar with resulting metabolic and clinical consequences.
  • NIDDM insulin resistance
  • the examples shown herein demonstrate that treatment of mitochondrial defects with the compositions disclosed herein provides a new and surprising approach to treating or preventing insulin resistance without the metabolic side-effects of increased insulin.
  • tocopherols are useful in reducing insulin resistance.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful for prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder, or a subject having a disorder associated with insulin resistance.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • nonalcoholic steatohepatitis fibrosis
  • cirrhosis fibrosis
  • cirrhosis cirrhosis
  • tocopherols are useful in methods for the prevention and/or treatment of insulin resistance and associated syndromes in a subject in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cati
  • tocopherols are useful in improving the sensitivity of mammalian skeletal muscle tissues to insulin.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2'
  • tocopherols are useful in preventing drug-induced obesity, insulin resistance, and/or diabetes, wherein the compound is administered with a drug that shows the side-effect of causing one or more of these conditions (e.g., olanzapine, ZYPREXA®).
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • peptide conjugates of the present technology are useful in preventing drug-induced obesity, insulin resistance, and/or diabetes, wherein the compound is administered with a drug that shows the side-effect of causing one or more of these conditions (e.g., olanzapine,
  • Increased or decreased insulin resistance or sensitivity can be readily detected by quantifying body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
  • OGTT oral glucose tolerance
  • markers of insulin signaling e.g., Akt-P, IRS-P
  • mitochondrial function e.g., respiration or H 2 0 2 production
  • markers of intracellular oxidative stress e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity
  • mitochondrial enzyme activity e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity
  • tocopherols are useful in methods for preventing, in a subject, a disease or condition associated with insulin resistance in skeletal muscle tissues via modulating one or more signs or markers of insulin resistance, e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
  • signs or markers of insulin resistance e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • peptide conjugates of the present technology are useful in methods for preventing, in a subject, a disease or condition associated with insulin resistance in skeletal muscle tissues via modulating one or more signs or markers of insulin resistance, e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • a disease or condition associated with insulin resistance e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OG
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • compositions of the present technology are administered to a subject susceptible to, or otherwise at risk of a disease or condition in an amount sufficient to eliminate or reduce the risk, or delay the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • a prophylactic tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the compositions of the present technology will act to enhance or improve mitochondrial function, and can be used for treating the subject.
  • tocopherols are useful in methods of modulating insulin resistance or sensitivity in a subject for therapeutic purposes.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • peptide conjugates of the present technology are useful in methods of modulating insulin resistance or sensitivity in a subject for therapeutic purposes.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • curing or partially arresting the symptoms of the disease biochemical, histological and/or behavioral, including its complications and intermediate pathological phenotypes in development of the disease.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2
  • the present technology provides methods of treating an individual afflicted with an insulin resistance-associated disease or disorder.
  • tocopherols are useful in improving the histopathological score resulting from ischemia and reperfusion.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptid
  • tocopherols are useful in increasing the rate of ATP production after reperfusion in renal tissue following ischemia.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic
  • tocopherols are useful in improving renal mitochondrial respiration following ischemia.
  • tocopherols in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-
  • tocopherols are useful in decreasing medullary fibrosis in UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-
  • tocopherols are useful in decreasing interstitial fibrosis in UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-d
  • tocopherols are useful in decreasing tubular apoptosis in UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-
  • tocopherols are useful in decreasing macrophage infiltration in UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl
  • tocopherols are useful in increasing tubular proliferation in UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-T
  • tocopherols are useful in decreasing oxidative damage in UUO.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-
  • tocopherols are useful in reducing renal dysfunction caused by a radiocontrast dye.
  • tocopherols in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic- cationic peptide such as 2',
  • tocopherols are useful in protecting renal tubules from radiocontrast dye injury.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6
  • tocopherols are useful in preventing renal tubular apoptosis induced by radiocontrast dye injury.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cati
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in protecting a subject's kidney from renal injury.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • Acute renal injury (ARI) refers to a reduction of renal function and filtration of waste products from a patient's blood. ARI is typically
  • GFR glomerular filtration rate
  • ARI causes of ARI may be caused by various factors, falling into three categories: (1) pre -renal ARI, in which the kidneys fail to receive adequate blood supply, e.g., due to reduced systemic blood pressure as in shock/cardiac arrest, or subsequent to hemorrhage; (2) intrinsic ARI, in which the failure occurs within the kidney, e.g., due to drug-induced toxicity; and (3) post-renal ARI, caused by impairment of urine flow out of the kidney, as in ureteral obstruction due to kidney stones or bladder/prostate cancer. ARI may be associated with any one or a combination of these categories. [0319] An example of a condition in which kidneys fail to receive adequate blood supply to the kidney is ischemia.
  • Ischemia is a major cause of ARI. Ischemia of one or both kidneys is a common problem experienced during aortic surgery, renal transplantation, or during cardiovascular anesthesia. Surgical procedures involving clamping of the aorta and/or renal arteries, e.g., surgery for supra- and juxta-renal abdominal aortic aneurysms and renal transplantation, are also particularly liable to produce renal ischemia, leading to significant postoperative complications and early allograft rejection. In high-risk patients undergoing these surgeries, the incidence of renal dysfunction has been reported to be as high as 50%. The skilled artisan will understand that the above described causes of ischemia are not limited to the kidney, but may occur in other organs during surgical procedures.
  • Renal ischemia may be caused by loss of blood, loss of fluid from the body as a result of severe diarrhea or burns, shock, and ischemia associated with storage of the donor kidney prior to transplantation.
  • the blood flow to the kidney may be reduced to a dangerously low level for a time period great enough to cause ischemic injury to the tubular epithelial cells, sloughing off of the epithelial cells into the tubular lumen, obstruction of tubular flow that leads to loss of glomerular filtration and ARI.
  • Subjects may also become vulnerable to ARI after receiving anesthesia, surgery, or a-adrenergic agonists because of related systemic or renal vasoconstriction. Additionally, systemic vasodilation caused by anaphylaxis, and anti-hypertensive drugs, sepsis or drug overdose may also cause ARI because the body's natural defense is to shut down, i.e., vasoconstriction of non-essential organs such as the kidneys.
  • a subject at risk for ARI may be a subject undergoing an interruption or reduction of blood supply or blood pressure to the kidney.
  • these subjects may be administered tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology prior to or simultaneously with such interruption or reduction of blood supply.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6
  • ARI a pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • Another cause of ARI includes drug-induced toxicity.
  • nephrotoxins can cause direct toxicity on tubular epithelial cells.
  • Nephrotoxins include, but are not limited to, therapeutic drugs, e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides ⁇ e.g., paraquat), and environmental contaminants ⁇ e.g., trichloroethylene and dichloroacetylene).
  • therapeutic drugs e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides ⁇ e.g., paraquat), and environmental contaminants ⁇ e.g., trichloroethylene and dichloroacetylene).
  • PAN puromycin aminonucleoside
  • aminoglycosides such as gentamicin
  • cephalosporins such as cephaloridine
  • calcineurin inhibitors such as tacrolimus or sirolimus.
  • Drug-induced nephrotoxicity may also be caused by non-steroidal anti-inflammatories, anti- retrovirals, anticytokines, immunosuppressants, oncological drugs, or angiotensin-converting- enzyme (ACE) inhibitors.
  • ACE angiotensin-converting- enzyme
  • the drug-induced nephrotoxicity may further be caused by analgesic abuse, ciprofloxacin, clopidogrel, cocaine, cox-2 inhibitors, diuretics, foscamet, gold, ifosfamide, immunoglobulin, Chinese herbs, interferon, lithium, mannitol, mesalamine, mitomycin, nitrosoureas, penicillamine, penicillins, pentamidine, quinine, rifampin, streptozocin, sulfonamides, ticlopidine, triamterene, valproic acid, doxorubicin, glycerol, cidofovir, tobramycin, neomycin sulfate, colistimethate, vancomycin, amikacin, cefotaxime, cisplatin, acyclovir, lithium, interleukin-2, cyclosporin, or indinavir.
  • analgesic abuse ciprofloxaci
  • nephrotoxins In addition to direct toxicity on tubular epithelial cells, some nephrotoxins also reduce renal perfusion, causing injury to zones known to have limited oxygen availability (inner medullary region). Such nephrotoxins include amphotericin and radiocontrast dyes. Renal failure can result even from clinically relevant doses of these drugs when combined with ischemia, volume depletion, obstruction, or infection. An example is the use of radiocontrast dye in patients with impaired renal function. The incidence of contrast dye- induced nephropathy (CIN) is 3-8% in the normal patient, but increases to 25% for patients with diabetes mellitus. Most cases of ARI occur in patients with predisposing co-morbidities (McCombs, P.R. & Roberts, B., Surg Gynecol. Obstet., 148: 175-178 (1979)).
  • CIN contrast dye- induced nephropathy
  • a subject at risk for ARI is receiving one or more therapeutic drugs that have a nephrotoxic effect.
  • the subject is administered tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr- D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology prior to or simultaneously with such therapeutic agents.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr- D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof alone or in combination with one or more active agents ⁇ e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology may be administered after the therapeutic agent to treat nephrotoxicity.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic- cationic
  • tocopherols alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject at risk for CIN, in order to prevent the condition.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • CIN is an important cause of acute renal failure.
  • CIN is defined as acute renal failure occurring within 48 hours of exposure to intravascular radiographic
  • CIN arises when a subject is exposed to radiocontrast dye, such as during coronary, cardiac, or neuro-angiography procedures. Contrast dye is essential for many diagnostic and interventional procedures because it enables doctors to visualize blocked body tissues.
  • a creatinine test can be used to monitor the onset of CIN, treatment of the condition, and efficacy of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology in treating or preventing CIN.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-di
  • tocopherols alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject prior to or simultaneously with the administration of a contrast agent in order to provide protection against CIN.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-
  • the subject may receive the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, or about 1 to 48 hours prior to receiving the contrast agent.
  • the subject may be administered the compositions at about the same time as the contrast agent.
  • administration of the compositions to the subject may continue following administration of the contrast agent.
  • the subject continues to receive the compositions at intervals of about 1 , 2, 3, 4, 5, 6, 7, 8, 12, 24, and 48 hours following administration of the contrast agent, in order to provide a protective or prophylactic effect against CIN.
  • tocopherols alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject after administration of a contrast agent in order to treat CIN.
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the subject receives the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, about 1 to 48 hours, or about 1 to 72 hours after receiving the contrast agent.
  • the subject may exhibit one or more signs or symptoms of CIN prior to receiving the compositions of the present technology, such as increased serum creatinine levels and/or decreased urine volume.
  • Administration of the compositions of the present technology improves one or more of these indicators of kidney function in the subject compared to a control subject not administered the compositions.
  • a subject in need thereof may be a subject having impairment of urine flow.
  • Obstruction of the flow of urine can occur anywhere in the urinary tract and has many possible causes, including but not limited to, kidney stones or
  • UUO is a common clinical disorder associated with obstructed urine flow. It is also associated with tubular cell apoptosis, macrophage infiltration, and interstitial fibrosis. Interstitial fibrosis leads to a hypoxic environment and contributes to progressive decline in renal function despite surgical correction.
  • a subject having or at risk for UUO may be administered tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to prevent or treat ARI.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cati
  • a method for protecting a kidney from renal fibrosis in a mammal in need thereof comprises administering to the mammal an effective amount of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology as described herein.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Ly
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in methods for treating ARI in a mammal in need thereof.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-L
  • the method comprises administering to the mammal an effective amount of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology as described herein.
  • active agents e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic
  • the methods of the present technology may be particularly useful in patients with renal insufficiency, renal failure, or end-stage renal disease attributable at least in part to a nephrotoxicity of a drug or chemical.
  • Other indications may include creatinine clearance levels of lower than 97 (men) and 88 (women) mL/min, or a blood urea level of 20-25 mg/dl or higher.
  • the treatment may be useful in patients with microalbuminuria, macroalbuminuria, and/or proteinuria levels of over 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 g or more per a 24 hour period, and/or serum creatinine levels of about 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4.0, 4.5, 5, 5.5, 6, 7, 8, 9, 10 mg/dl or higher.
  • the methods of the present technology can be used to slow or reverse the progression of renal disease in patients whose renal function is below normal, relative to control subjects.
  • the methods of the present technology slow the loss of renal function.
  • loss of renal function is slowed by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90%), 100%) or more, relative to control subjects.
  • the methods of the present technology improve the patient's serum creatinine levels, proteinuria, and/or urinary albumin excretion.
  • the patient's serum creatinine levels, proteinuria, and/or urinary albumin excretion is improved by at least 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or more, relative to control subjects.
  • Non-limiting illustrative methods for assessing renal function are described herein and, for example, in WO 01/66140.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in protecting a subject's kidney from ARI prior to transplantation.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-
  • a removed kidney can be placed in a solution containing the compositions described herein.
  • concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.01 nM to about 10 ⁇ , about 0.1 nM to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , or about 1 nM to about 100 nM.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in preventing or treating ARI and are also applicable to tissue injury and organ failure in other systems besides the kidney.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in methods of treating a subject having a tissue injury, e.g., noninfectious pathological conditions such as pancreatitis, ischemia, multiple trauma, hemorrhagic shock, and immune- mediated organ injury.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the tissue injury can be associated with, for example, aortic aneurysm repair, multiple trauma, peripheral vascular disease, renal vascular disease, myocardial infarction, stroke, sepsis, and multi-organ failure.
  • the present technology relates to a method of treating a subject having a tissue such as from heart, brain, vasculature, gut, liver, kidney and eye that is subject to an injury and/or ischemic event.
  • the method includes administering to the subject a therapeutically effective amount of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to provide a therapeutic or prophylactic effect.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in improving a function of one or more organs selected from the group consisting of: renal, lung, heart, liver, brain, pancreas, and the like.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • the improvement in lung function is selected from the group consisting of lower levels of edema, improved
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in the prevention and/or treatment of acute hepatic injury caused by ischemia, drugs (e.g. , acetaminophen, alcohol), viruses, obesity (e.g., non-alcoholic steatohepatitis), and obstruction (e.g., bile duct obstruction, tumors).
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in preventing or treating acute liver failure (ALF) in a subject.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys
  • ALF is a clinical condition that results from severe and extensive damage of liver cells leading to failure of the liver to function normally. ALF results from massive necrosis of liver cells leading to hepatic encephalopathy and severe impairment of hepatic function. It has various causes, such as viral hepatitis (A, B, C), drug toxicity, frequent alcohol intoxication, and autoimmune hepatitis. ALF is a very severe clinical condition with high mortality rate. Drug-related hepatotoxicity is the leading cause of ALF in the United States.
  • tocopherols alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject prior to or simultaneously with the administration of a drug or agent known or suspected to induced hepatotoxicity, e.g.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptid
  • the subject may receive the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, or about 1 to 48 hours prior to receiving the drug or agent.
  • the subject may be administered the compositions at about the same time as the drug or agent to provide a prophylactic effect against ALF caused by the drug or agent.
  • administration of the compositions to the subject may continue following administration of the drug or agent.
  • the subject may continue to receive the compositions at intervals of about 1 , 2, 3, 4, 5, 6, 7, 8, 12, 24, and 48 hours following administration of the drug or agent, in order to provide a protective or prophylactic effect.
  • tocopherols alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject exhibiting one or more signs or symptoms of ALF, including, but not limited to, elevated levels of hepatic enzymes (transaminases, alkaline phosphatase), elevated serum bilirubin, ammonia, glucose, lactate, or creatinine.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg
  • compositions of the present technology improves one or more of these indicators of liver function in the subject compared to a control subject not administered the compositions.
  • the subject may receive tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, about 1 to 48 hours, or about 1 to 72 hours after the first signs or symptoms of ALF.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in treating or ameliorating the local and distant pathophysiological effects of burn injury, including, but not limited to, hypermetabolism and organ damage.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in treating or preventing burn injuries and systemic conditions associated with a burn injury.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-L
  • tocopherols alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject following a burn and after the onset of detectable symptoms of systemic injury.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2
  • treatment is used herein in its broadest sense and refers to use of a composition for a partial or complete cure of
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject following a burn, but before the onset of detectable symptoms of systemic injury in order to protect against or provide prophylaxis for the systemic injury, such as organ damage or hypermetabolism.
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-
  • prevention is used herein in its broadest sense and refers to a prophylactic use which completely or partially prevents local injury to the skin or systemic injury, such as organ dysfunction or hypermetabolism following burns. It is also contemplated that the compositions may be administered to a subject at risk of receiving burns.
  • Burns are generally classified according to their severity and extent. First degree burns are the mildest and typically affect only the epidermis. The burn site appears red, and is painful, dry, devoid of blisters, and may be slightly moist due to fluid leakage. Mild sunburn is typical of a first degree burn. In second degree burns, both the epidermis and dermis are affected. Blisters usually appear on the skin, with damage to nerves and sebaceous glands. Third degree burns are the most serious, with damage to all layers of the skin, including subcutaneous tissue. Typically there are no blisters, with the burned surface appearing white or black due to charring, or bright red due to blood in the bottom of the wound. In most cases, the burn penetrates the superficial fascia, extending into the muscle layers where arteries and veins are affected. Because of nerve damage, it is possible for the burn to be painless.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in the treatment of burns from any cause, including dry heat or cold burns, scalds, sunburn, electrical burns, chemical agents such as acids and alkalis, including hydrofluoric acid, formic acid, anhydrous ammonia, cement, and phenol, or radiation burns.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • Burns resulting from exposure to either high or low temperature are within the scope of the present technology. The severity and extent of the burn may vary, but secondary organ damage or
  • hypermetabolism will usually arise when the burns are very extensive or very severe (second or third degree burns).
  • secondary organ dysfunction or failure is dependent on the extent of the burn, the response of the patient's immune system and other factors, such as infection and sepsis.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in treating or preventing organ dysfunction secondary to a burn.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe
  • catecholamines, vasopressin, and angiotensin causes peripheral and splanchnic bed vasoconstriction that can compromise the perfusion of organs remote to the injury.
  • Myocardial contractility also may be reduced by the release of TNF-a.
  • Activated neutrophils are sequestered in dermal and distant organs, such as the lung, within hours following a burn injury, resulting in the release of toxic reactive oxygen species and proteases and producing vascular endothelial cell damage.
  • plasma and blood leak into the interstitial and intra-alveolar spaces, resulting in pulmonary edema.
  • a decrease in pulmonary function can occur in severely burned patients, as a result of bronchoconstriction caused by humoral factors, such as histamine, serotonin, and thromboxane A2.
  • Burn-induced mitochondrial skeletal muscle dysfunction is thought to result from defects in oxidative phosphorylation (OXPHOS) via stimulation of mitochondrial production of reactive oxygen species (ROS) and the resulting damage to the mitochondrial DNA (mtDNA).
  • OXPHOS oxidative phosphorylation
  • ROS reactive oxygen species
  • mtDNA mitochondrial DNA
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in inducing ATP synthesis via a recovery of the
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in treating a wound resulting from a burn injury.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-
  • Tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology may be administered systemically or topically to the wound. Burn wounds are typically uneven in depth and severity.
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2
  • peptide conjugates of the present technology slows or ameliorates the effects of wound contraction.
  • Wound contraction is the process which diminishes the size of a full-thickness open wound, especially a full-thickness burn.
  • the tensions developed during contracture and the formation of subcutaneous fibrous tissue can result in deformity, and in particular to fixed flexure or fixed extension of a joint where the wound involves an area over the joint.
  • Such complications are especially relevant in burn healing. No wound contraction will occur when there is no injury to the tissue, and maximum contraction will occur when the burn is full thickness and no viable tissue remains in the wound.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in preventing progression of a burn injury from a second degree burn to a third degree burn.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in decreasing scarring or the formation of scar tissue attendant the healing process at a burn site.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • Scarring is the formation of fibrous tissue at sites where normal tissue has been destroyed.
  • the present disclosure thus also includes a method for decreasing scarring following a second or third degree burn.
  • This method comprises treating an animal with a second or third degree burn with an effective amount of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology are useful in treating or preventing damage to distant organs or tissues in a subject suffering from a burn.
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • systemic inflammatory responses arise in subjects following burn injury, and that it is this generalized inflammation which leads to remote tissue injury which is expressed as the dysfunction and failure of organs remote from the injury site.
  • Systemic injury including organ dysfunction and hypermetabolism, is typically associated with second and third degree burns.
  • a characteristic of the systemic injury, i.e., organ dysfunction or hypermetabolism, is that the burn which provokes the subsequent injury or condition does not directly affect the organ in question, i.e., the injury is secondary to the burn.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in treating or protecting damage to liver tissues secondary to a burn.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • liver function methods for assessing liver function are well known in the art and include, but are not limited to, using blood tests for serum alanine aminotransferase (ALT) levels, alkaline phosphatase (AP), or bilirubin levels. Methods for assessing deterioration of liver structure are also well known. Such methods include liver imaging ⁇ e.g., MRT, ultrasound), or histological evaluation of liver biopsy.
  • ALT serum alanine aminotransferase
  • AP alkaline phosphatase
  • bilirubin levels methods for assessing deterioration of liver structure are also well known. Such methods include liver imaging ⁇ e.g., MRT, ultrasound), or histological evaluation of liver biopsy.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in treating or protecting damage to kidney tissues secondary to a burn.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • kidney imaging ⁇ e.g. , MRI, ultrasound
  • histological evaluation of kidney biopsy
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in preventing or treating hypermetabolism associated with a burn injury.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • a hypermetabolic state may be associated with hyperglycemia, protein loss, and a significant reduction of lean body mass. Reversal of the hypermetabolic response may be accomplished by administering tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr- D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology and by manipulating the subject's physiologic and biochemical environment through the administration of specific nutrients, growth factors, or other agents.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr- D-Arg-Phe-Lys-NH 2 , P
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology may be administered to a subject suffering from a burn in order to treat or prevent hypermetabolism.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic
  • the disclosure provides method for preventing in a subject, a burn injury or a condition associated with a burn injury, by administering tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr- D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to the subject.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr- D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH
  • Tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology may be administered to a subject at risk of receiving burns.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2
  • compositions or medicaments are administered to a subject already suffering from a burn injury in an amount sufficient to cure, or partially arrest, the symptoms of the injury, including its complications and intermediate pathological phenotypes in development of the disease.
  • Tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology may be administered to a subject following a burn, but before the development of detectable symptoms of a systemic injury, such as organ dysfunction or failure, and thus the term "prevention" as used herein in its broadest sense and refers to a prophylactic use which completely or partially prevents systemic injury, such as organ dysfunction or failure or hypermetabolism following burns.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology can prevent or treat Metabolic Syndrome in mammalian subjects.
  • tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe
  • the Metabolic Syndrome may be due to a high-fat diet or, more generally, over-nutrition and lack of exercise, tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology may reduce one or more signs or symptoms of Metabolic Syndrome, including, but not limited to, dyslipidemia, central obesity, blood fat disorders, and insulin resistance.
  • tocopherols or derivatives, analogues, or
  • an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • Metabolic Syndrome is generally associated with type II diabetes, coronary artery disease, renal dysfunction, atherosclerosis, obesity, dyslipidemia, and essential hypertension.
  • the present methods provide for the prevention and/or treatment of Metabolic Syndrome or associated conditions in a subject by administering an effective amount of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to a subject in need thereof.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe
  • a subject may be administered tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to improve one or more of the factors contributing to Metabolic Syndrome.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g.,
  • tocopherols in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the technology may provide a method of treating or preventing the specific disorders associated with Metabolic Syndrome, such as obesity, diabetes, hypertension, and hyperlipidemia, in a mammal by administering tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
  • the specific disorder may be obesity.
  • the specific disorder may be dyslipidemia (i.e., hyperlipidemia).
  • tocopherols or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • peptide conjugates of the present technology to a subject exhibiting one or more conditions associated with Metabolic Syndrome will cause an improvement in one or more of those conditions (e.g., an aromatic-cationic
  • a subject may exhibit at least about 5%, at least about 10%, at least about 20%), or at least about 50%> reduction in body weight compared to the subject prior to receiving the tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt
  • a subject may exhibit at least about 5%, at least about 10%, at least about 20%, or at least about 50% reduction in LDL cholesterol and/or at least about 5%, at least about 10%, at least about 20%, or at least about 50% increase in HDL cholesterol compared to the subject prior to receiving the tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ), or peptide conjugates of the present technology.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-
  • a subject may exhibit at least about 5%, at least about 10%), at least about 20%>, or at least about 50%> reduction in some triglycerides compared to the subject prior to receiving the tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-D
  • a subject may exhibit at least about 5%, at least about 10%, at least about 20%, or at least about 50% improvement in oral glucose tolerance (OGTT) compared to the subject prior to receiving the tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D- Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
  • the subject may show observable improvement in more than one condition associated with Metabolic Syndrome.
  • the present technology provides a method for preventing, in a subject, a disease or condition associated with Metabolic Syndrome in skeletal muscle tissues, by administering to the subject tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology that modulate one or more signs or markers of metabolic syndrome, e.g., body weight, serum triglycerides or cholesterol, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt- P, IRS-P
  • active agents e.
  • Subjects at risk for Metabolic Syndrome can be identified by, e.g., any or a combination of diagnostic or prognostic assays as described herein.
  • pharmaceutical compositions or medicaments of tocopherols (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-

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Abstract

L'invention concerne des procédés et des compositions de traitement et/ou de prévention de maladies ou d'états pathologiques consistant à administrer du tocophérol, et/ou des dérivés ou des analogues de celui-ci d'origine naturelle ou artificielle, ou des sels de celui-ci pharmaceutiquement acceptables, seuls ou en combinaison avec un ou plusieurs agents actifs (p. ex. un peptide aromatique-cationique).<i /> La présente technologie concerne des compositions à base de peptides aromatiques-cationiques liés à un tocophérol, ainsi que des utilisations de ces compositions. Dans certains modes de réalisation, le peptide aromatique-cationique comprend un composé 2',6'-diméthyl-Tyr-D-Arg-Phe-Lys-NH2, Phe-D-Arg-Phe-Lys-NH2 ou D-Arg-2',6'-Dmt-Lys-Phe-NH2.
PCT/US2015/032715 2014-05-28 2015-05-27 Compositions thérapeutiques contenant un tocophérol et leurs utilisations Ceased WO2015183984A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
WO2020236802A1 (fr) * 2019-05-20 2020-11-26 Poviva Corp. Compositions comprenant des agents biologiquement actifs et des sels biliaires
US11325943B2 (en) * 2017-06-02 2022-05-10 Stealth Biotherapeutics Inc. Crystalline salt forms of SBT-20
US12252554B2 (en) 2018-12-18 2025-03-18 Stealth Biotherapeutics Inc. Analogs that target mitochondrial diseases

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AR036711A1 (es) * 2001-10-05 2004-09-29 Bayer Corp Peptidos que actuan como agonistas del receptor del glp-1 y como antagonistas del receptor del glucagon y sus metodos de uso farmacologico
WO2009100216A1 (fr) * 2008-02-08 2009-08-13 Qps Llc Composition pour une administration à libération prolongée de protéines ou de peptides
EP3375449A1 (fr) * 2010-03-15 2018-09-19 Stealth Peptides International, Inc. Thérapies combinées à l'aide de cyclosporine et de peptides cationiques aromatiques
JP2015529655A (ja) * 2012-08-02 2015-10-08 ステルス ペプチドズ インターナショナル インコーポレイテッド アテローム性硬化症の処置方法
JP2016506391A (ja) * 2012-12-06 2016-03-03 ステルス ペプチドズ インターナショナル インコーポレイテッド ペプチド治療薬およびその使用方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US10981855B2 (en) 2015-12-17 2021-04-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US11680034B2 (en) 2015-12-17 2023-06-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US11325943B2 (en) * 2017-06-02 2022-05-10 Stealth Biotherapeutics Inc. Crystalline salt forms of SBT-20
US12252554B2 (en) 2018-12-18 2025-03-18 Stealth Biotherapeutics Inc. Analogs that target mitochondrial diseases
WO2020236802A1 (fr) * 2019-05-20 2020-11-26 Poviva Corp. Compositions comprenant des agents biologiquement actifs et des sels biliaires

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