Compositions and Methods for Treatment of Prediabetes

Abstract

The invention provides compositions and methods to treat prediabetes. In particular, the inventor has discovered that particular combinations of diverse types of antioxidants have synergistic and surprising effects for use against prediabetes. The composition includes: a plurality of heteroatom-based antioxidants having the formula X—CH.sub.2—CH(R)—(CH.sub.2).sub.m—Z; a plurality of antioxidants with a conjugated segment; an antioxidant that is a flavan-3-ol; and an antioxidant that contains a disulfide bond. The antioxidants are chosen such that at least one has a pro-oxidative effect.

Claims

1) An improved composition for treatment of prediabetes comprising therapeutically effective amounts of at least four types of antioxidant compounds, characterized in that: a) a plurality of heteroatom-containing natural antioxidant compounds have the formula X—CH(R.sup.1)—CH(R.sup.2)—(CH.sub.2).sub.m—Z, wherein: i) X is one of the following moieties or a pharmaceutically acceptable salt thereof: —NH.sub.2 or —N(CH.sub.3).sub.3; ii) le is —H, —CO.sub.2H, or a pharmaceutically acceptable salt of —CO.sub.2H; iii) R.sup.2 is —H, —OH, or —O—acetyl; iv) m is 0, 1, 2, or 3; and v) Z is one of the following moieties or a pharmaceutically acceptable salt thereof: —SH, —SO.sub.2H, —SO.sub.3H, —CO.sub.2H, —N═C(—NH.sub.2)—NH.sub.2, —CH(—NH.sub.2)—CO.sub.2H; —imidazolyl; or —C(═O)—NH—CH(—CO.sub.2H)—CH.sub.2—Y where Y is 4-imidazolyl or 1-methyl-4-imidazolyl; b) a plurality of antioxidant compounds have a conjugated segment, comprising at least one vitamin D compound and at least one cobalamin compound; c) at least one of the antioxidant compounds comprises a disulfide bond; and d) at least one of the antioxidant compounds is a flavan-3-ol compound; wherein at least one antioxidant compound in the composition is also a pro-oxidant.

2) The composition of claim 1 wherein the compounds having the formula X—CH.sub.2—CH(R)—(CH.sub.2).sub.m—Z comprise a plurality selected from the group consisting of the following compounds and their pharmaceutically acceptable salts: taurine, beta-alanine, acetyl-L-carnitine, agmatine, carnosine, cysteine, sulfinoalanine, hypotaurine, carnitine, lysine, anserine, histidine, arginine, and ornithine.

3) The composition of claim 1 wherein the compounds having the formula X—CH.sub.2—CH(R)—(CH.sub.2).sub.m—Z comprise at least each of taurine, beta-alanine, acetyl-L-carnitine, agmatine, and L-carnosine.

4) The composition of claim 1 wherein the plurality of antioxidant compounds having a conjugated segment comprises at least one of vitamin D.sub.3 and methylcobalamin.

5) The composition of claim 1 wherein the plurality of antioxidant compounds having a conjugated segment further comprise a carotenoid selected from the group consisting of lettered carotenes, lycopene, neurosporene, phytofluene, phytoene, canthaxanthin, cryptoxanthin, zeaxanthin, astaxanthin, lutein, and rubixanthin.

6) The composition of claim 1 wherein the at least one antioxidant compound comprising a disulfide bond is selected from the group consisting of alpha-lipoic acid, lipoamide, glutathione disulfide, L-cystine, asparagusic acid, lenthionine, ajoene, allithiamine, allyl propyl disulfide, diallyl disulfide, fursultiamine, pantethine and its salts prosultiamine, pyritinol, and sulbutiamine.

7) The composition of claim 1 wherein the at least one antioxidant compound comprising a disulfide bond comprises alpha-lipoic acid.

8) The composition of claim 1 wherein the at least one flavan-3-ol compound is selected from the group consisting of monomers, oligomers, polymers, glycosides and pharmaceutically acceptable salts of the following: (+)-catechin, (−)-epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, epiafzelechin, and fisetinidol.

9) The composition of claim 1 wherein the at least one flavan-3-ol compound is provided in the form of grape seed extract.

10) The composition of claim 1 wherein at least one of a disulfide compound or a flavan-3-ol is both an antioxidant and a pro-oxidant.

11) The composition of claim 1 wherein: a) compounds having the formula X—CH.sub.2—CH(R)—(CH.sub.2).sub.m—Z comprise at least: i) taurine in an amount selected from the range of 40 to 360 mg; ii) beta-alanine in an amount selected from the range of 10 to 90 mg; iii) acetyl-L-carnosine in an amount selected from the range of 20 to 180 mg; iv) agmatine in an amount selected from the range of 25 to 225 mg; and v) L-carnosine in an amount selected from the range of 5 to 45 mg; b) compounds having a conjugated segment comprise at least: i) vitamin D.sub.3 in an amount selected from the range of 500 to 4,500 I.U.; and ii) methylcobalamin in an amount selected from the range of 20 to 220 μg; and c) a plurality of flavan-3-ols is provided in the form of grape seed extract in an amount selected from the range of 10 to 90 mg.

12) The composition of claim 11 wherein the composition further comprises: a) a carotenoid, lutein, in an amount selected from the range of 1 to 9 mg; and b) a disulfide compound, alpha-lipoic acid, in an amount selected from the range of 100 to 900 μg.

13) The composition of claim 1 wherein the composition comprises: a) taurine in an amount of 200 mg; b) beta-alanine in an amount of 50 mg; c) acetyl-L-carnosine in an amount of 100 mg; d) agmatine in an amount selected of 125 mg; e) L-carnosine in an amount of 25 mg; f) vitamin D.sub.3 in an amount of 2,500 I.U.; g) methylcobalamin in an amount of 120 μg; h) lutein in an amount of 5 mg; i) grape seed extract in an amount of 50 mg; and j) alpha-lipoic acid in an amount of 500 μg.

14) A method for treatment of prediabetes comprising administration of a composition that comprises therapeutically effective amounts of at least four types of antioxidant compounds, characterized in that: a) a plurality of heteroatom-containing natural antioxidant compounds have the formula X—CH(R.sup.1)—CH(R.sup.2)—(CH.sub.2).sub.m—Z, wherein: i) X is one of the following moieties or a pharmaceutically acceptable salt thereof: —NH.sub.2 or —N(CH.sub.3).sub.3; ii) R.sup.1 is —H, —CO.sub.2H, or a pharmaceutically acceptable salt of —CO.sub.2H; iii) R.sup.2 is —H, —OH, or —O—acetyl; iv) m is 0, 1, 2, or 3; and v) Z is one of the following moieties or a pharmaceutically acceptable salt thereof: —SH, —SO.sub.2H, —SO.sub.3H, —CO.sub.2H, —N═C(—NH.sub.2)—NH.sub.2, —CH(—NH.sub.2)—CO.sub.2H; —imidazolyl; or —C(═O)—NH—CH(—CO.sub.2H)—CH.sub.2—Y where Y is 4-imidazolyl or 1-methyl-4-imidazolyl; b) a plurality of antioxidant compounds have a conjugated segment, comprising at least one vitamin D compound and at least one cobalamin compound; c) at least one of the antioxidant compounds comprises a disulfide bond; and d) at least one of the antioxidant compounds is a flavan-3-ol compound; wherein at least one antioxidant compound in the composition is also a pro-oxidant.

15) The method of claim 14 wherein the compounds having the formula X—CH.sub.2—CH(R)—(CH.sub.2).sub.m—Z comprise a plurality selected from the group consisting of the following compounds and their pharmaceutically acceptable salts: taurine, beta-alanine, acetyl-L-carnitine, agmatine, L-carnosine, cysteine, sulfinoalanine, hypotaurine, L-carnitine, L-lysine, anserine, histidine, arginine, and ornithine.

16) The method of claim 14 wherein the compounds having the formula X—CH.sub.2—CH(R) —(CH.sub.2).sub.m—Z comprise at least each of taurine, beta-alanine, acetyl-L-carnitine, agmatine, and L-carnosine.

17) The method of claim 14 wherein the plurality of antioxidant compounds having a conjugated segment comprises at least one of vitamin D.sub.3 and methylcobalamin.

18) The method of claim 14 wherein the plurality of antioxidant compounds having a conjugated segment further comprise a carotenoid selected from the group consisting of carotenes, lycopene, neurosporene, phytofluene, phytoene, canthaxanthin, cryptoxanthin, zeaxanthin, astaxanthin, lutein, and rubixanthin.

19) The method of claim 14 wherein the at least one antioxidant compound comprising a disulfide bond is selected from the group consisting of alpha-lipoic acid, lipoamide, glutathione disulfide, L-cystine, asparagusic acid, lenthionine, ajoene, allithiamine, allyl propyl disulfide, diallyl disulfide, fursultiamine, pantethine and its salts prosultiamine, pyritinol, and sulbutiamine.

20) The method of claim 14 wherein the at least one antioxidant compound comprising a disulfide bond comprises alpha-lipoic acid.

21) The method of claim 14 wherein the at least one flavan-3-ol compound is selected from the group consisting of monomers, oligomers, polymers, glycosides and pharmaceutically acceptable salts of the following: (+)-catechin, (−)-epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, epiafzelechin, and fisetinidol.

22) The method of claim 14 wherein the at least one flavan-3-ol compound is provided in the form of grape seed extract.

23) The method of claim 14 wherein at least one of a disulfide compound or a flavan-3-ol is both an antioxidant and a pro-oxidant.

24) The method of claim 14 wherein: a) compounds having the formula X—CH.sub.2—CH(R)—(CH.sub.2).sub.m—Z comprise at least: i) taurine in an amount selected from the range of 40 to 360 mg; ii) beta-alanine in an amount selected from the range of 10 to 90 mg; iii) acetyl-L-carnosine in an amount selected from the range of 20 to 180 mg; iv) agmatine in an amount selected from the range of 25 to 225 mg; and v) L-carnosine in an amount selected from the range of 5 to 45 mg; b) compounds having a conjugated segment comprise at least: i) vitamin D.sub.3 in an amount selected from the range of 500 to 4,500 I.U.; and ii) methylcobalamin in an amount selected from the range of 20 to 220 μg; and c) a plurality of flavan-3-ols is provided in the form of grape seed extract in an amount selected from the range of 10 to 90 mg.

25) The method of claim 24 wherein the composition further comprises: a) a carotenoid, lutein, in an amount selected from the range of 1 to 9 mg; and b) a disulfide compound, alpha-lipoic acid, in an amount selected from the range of 100 to 900 μg.

26) The method of claim 14 wherein the composition comprises: a) taurine in an amount of 200 mg; b) beta-alanine in an amount of 50 mg; c) acetyl-L-carnosine in an amount of 100 mg; d) agmatine in an amount selected of 125 mg; e) L-carnosine in an amount of 25 mg; f) vitamin D.sub.3 in an amount of 2,500 I.U.; g) methylcobalamin in an amount of 120 μg; h) lutein in an amount of 5 mg; i) grape seed extract in an amount of 50 mg; and j) alpha-lipoic acid in an amount of 500 μg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0036] The invention may be better understood by consideration of the following definitions of the terms as used herein.

[0037] The term “composition” as used with reference to compositions of the invention means a food supplement composition or pharmaceutical composition.

[0038] The term “prediabetes” means a metabolic condition identified by at least one of the following: fasting plasma glucose level in the range of 100-125 mg/dL; blood sugar in an oral glucose tolerance test in the range of 140-199 mg/dL; or hemoglobin A1C in the range of 5.7% to 6.4% in a hemoglobin A1C test.

[0039] The terms “diabetes” means a metabolic condition identified by at least one of the following: fasting plasma glucose level ≧126 mg/dL; blood sugar in an oral glucose tolerance test ≧200 mg/dL; or hemoglobin A1C≧6.5% in a hemoglobin A1C test.

[0040] The term “symptom of prediabetes” means a symptom that is commonly used by the allopathic medical community to monitor or diagnose prediabetes. Examples of symptoms of prediabetes include: IFG; IGT; persistent hunger; obesity; abdominal obesity; visceral obesity; a body mass index over 25; weight gain; unexplained weight loss; flu-like weakness; fatigue; blurry vision; slowness of healing for cuts; slowness of healing for bruises; a tingling extremity; an insensate extremity; frequent need to urinate; a recurring infection of the skin; a recurring infection of the gums; a recurring infection of the bladder; a recurring infection of the vagina; blood sugar in the range of 100-125 mg/dL or 5.6 mM/L to 6.9 mM/L for the fasting plasma glucose test; blood sugar in the range of 140-199 mg/dL for the oral glucose tolerance test; or average hemoglobin A1C of 5.7% to 6.4% in the hemoglobin A1C test.

[0041] The term “reduce or mitigate” as used with respect to a symptom of prediabetes means to decrease the manifestation of the symptom by an amount that is customarily considered medically significant, measurable and relevant. In a particular embodiment the reduction or mitigation decreases the deviation from a healthy normal range by at least 10%.

[0042] The terms “method” as used with respect to treatment of prediabetes or its symptoms according to the invention means a protocol to reduce or mitigate the symptoms thereof by providing a composition of the invention. The term “treatment” as used with respect to prediabetes means use of such a method.

[0043] The term “administration of a composition” means to provide a dose of the composition for ingestion by someone in need thereof.

[0044] The term “antioxidant” as used with respect to a compound means that the molecule can inhibit oxidation or reactions promoted by oxygen, peroxides, or free radicals. Important examples of antioxidant compounds include vitamin C, vitamin E, phenols, and zinc. Various types of antioxidant activity exist. Some antioxidants such as zinc donate an electron to reduce a free radical or oxidizing species. Some antioxidants bond to a free radical species to terminate a radical chain reaction. Some antioxidants such as phenols donate a hydrogen atom to a free radical species to terminate a radical chain reaction and form a stabilized radical that then reacts by another type of reaction to eliminate the radical.

[0045] The term “pro-oxidant” as used with respect to a compound means that the molecule can promote oxidation or other reactions that are commonly mediated by oxygen, peroxides, or free radicals. This property is counterintuitive for antioxidants but several examples are known, particularly for vitamins C and E. Thus for instance ascorbate (vitamin C) reduces Fe(III) to produce Fe(II), which can then react with hydrogen peroxide (an oxidizing substance) by the Fenton reaction to generate hydroxyl free radicals by the following redox cycling reactions: 2 Fe.sup.2++2H.sub.2O.sub.2.fwdarw.2Fe.sup.3++2OH.+2OH.sup.−; 2Fe.sup.3++Ascorbate.fwdarw.2Fe.sup.2++Dehydroascorbate. Thus antioxidants that can serve as reduction agents may have a pro-oxidant effect at suitable concentrations and if O.sub.2 or peroxide and a transition metal are present.

[0046] The terms “pro-oxidative effect” and “pro-oxidant activity” as used with respect to a compound's effect are used synonymously and mean that the molecule acts as a pro-oxidant in that environment. Pro-oxidative effects may be associated with the generation of oxidative stress in tissues, however in some cases that stress may mimic a normal physiological signal, for instance for the conversion of fibroblasts to myofibroblasts in fibrosis or scar formation. Where an antioxidant has a pro-oxidative effect, the pro-oxidative effect may be different in mechanism and strength from that of the antioxidant activity of the molecule.

[0047] The term “pro-oxidative effect in the liver” as used with respect to a compound means that the molecule has pro-oxidant activity that is known to occur at least in the liver. In particularly useful embodiments of the invention one or more of the antioxidants that comprise stabilizing heteroatoms have pro-oxidant activity in the liver.

[0048] The term “type” as used with respect to an antioxidant compound means its structural category. As defined herein, types of antioxidant compound include at least: heteroatom-containing natural antioxidant compounds have the formula X—CH(R.sup.1)—CH(R.sup.2)—(CH.sub.2).sub.m—Z; those comprising a conjugated segment; those comprising a disulfide bond; and those having a flavan-3-ol skeleton. Typically there is no overlap between these categories, however the invention is not so limited.

[0049] The term “heteroatom-containing natural antioxidant compound” means a natural compound that is an antioxidant and that contains a heteroatom. As used herein this description is coupled with a generic chemical formula X—CH(R.sup.1)—CH(R.sup.2)—(CH.sub.2).sub.m—Z, wherein: [0050] i) X is one of the following moieties or a pharmaceutically acceptable salt thereof: —NH.sub.2 or —N(CH.sub.3).sub.3; [0051] ii) R.sup.1 is —H, —CO.sub.2H, or a pharmaceutically acceptable salt of —CO.sub.2H; [0052] iii) R.sup.2 is —H, —OH, or —O—acetyl; [0053] iv) m is 0, 1, 2, or 3; and [0054] v) Z is one of the following moieties or a pharmaceutically acceptable salt thereof: —SH, —SO.sub.2H, —SO.sub.3H, —CO.sub.2H, —N═C(—NH.sub.2)—NH.sub.2, —CH(—NH.sub.2)—CO.sub.2H; —imidazolyl; or —C(═O)—NH—CH(—CO.sub.2H)—CH.sub.2—Y where Y is 4-imidazolyl or 1-methyl-4-imidazolyl.
The chemical notations, terminology, and structural designations there follow the conventions of the art of chemistry, except that the identities X, Y, and Z are understood to correspond to moieties that are specific to the individual compound but vary across the category.

[0055] The term “heteroatom” means any atom in an organic molecule that is not carbon or hydrogen, where the term “organic” as used with respect to a molecule has its usual and ordinary meaning in organic chemistry. Illustrative examples of heteroatoms include but are not limited to nitrogen, oxygen, phosphorus, sulfur, selenium, boron, fluorine, chlorine, bromine, and iodine, as those atoms are named on the periodic table.

[0056] The term “stabilizing heteroatom” as used with respect to an antioxidant compound means a heteroatom that is capable of donating electron density toward a radical on a neighboring carbon atom in a molecule, and or that possesses an empty orbital to accept electron density from such a radical. Examples of stabilizing heteroatoms include boron, nitrogen, oxygen, phosphorus and sulfur but the invention is not so limited. Preferred stabilizing heteroatoms are nitrogen, oxygen and sulfur, and a particularly preferred stabilizing heteroatom is sulfur but the invention is not so limited.

[0057] The term “saturated carbon” as used with respect to an atom in a compound means that it is a carbon atom for which bonds to its neighboring atoms are all and only single bonds, wherein the recited carbon atom is bonded to at least one other carbon atom and to at least one hydrogen atom. As used herein, the term “saturated carbon” contemplates that the carbon atom may be covalently bonded to one or more heteroatoms, but does not necessarily have such a bond.

[0058] The term “adjacent to” as used with respect to one atom and another in a compound means that the two are covalently bonded to one another.

[0059] The terms “taurine”, “beta-alanine”, “acetyl-carnitine”, “agmatine”, “carnosine” “cysteine”, “sulfinoalanine”, “hypotaurine”, “carnitine”, “lysine”, “anserine”, “histidine”, “arginine”, and “ornithine” have their usual and ordinary meanings in the fields of chemistry and biochemistry.

[0060] The term “conjugated segment” as used with respect to a molecule means a portion of the molecular skeleton that has single bonds alternating with multiple bonds such as double or triple bonds. In particular embodiments the skeleton of the conjugated segment is composed entirely of carbon atoms. In further embodiments the skeleton of the conjugated segment is composed of carbon atoms and one or more heteroatoms. In preferred embodiments the conjugated segment is covalently bonded to at least one saturated carbon atom such as a methyl group (i.e. —CH.sub.3), a substituted methyl group (i.e., —CH.sub.2X or —CHXY where X and Y are, e.g., halogen atoms that may be the same or different), a methylene group (i.e., —CH.sub.2—), a singly substituted methylene group (i.e., —CHX—, where X is, e.g., a halogen atom), or a tertiary carbon that is bonded to hydrogen. Non-limiting illustrative examples of conjugated segments in compounds that are suitable for use with the invention include: the porphyrins rings of cobalamin compounds; the conjugated portions of rings, branches and linear backbone in vitamin D compounds such as ergocalciferol (vitamin D.sub.2) and cholecalciferol (vitamin D.sub.3); and the linear chains of the carotenoids, as well as cyclic end groups of the carotenoids to the extent that they possess a C═C double bond conjugated with the linear chain.

[0061] The term “vitamin D compound” means a molecule that is within the group known as vitamin D. These are secosteroids and in particular include the following: 7-dehydrocholesterol, also known as previtamin-D.sub.3; vitamin D.sub.2, also known as ergocholecalciferol; vitamin D.sub.3, also known as cholecalciferol and activated 7-dehydrocholesterol; 25-D, also known as 25-hydroxyvitamin D, calcidiol, and calcifediol; and 1,25-D, also known as 1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D.sub.3, and calcitriol.

[0062] The term “cobalamin compound” means a compounds having a skeleton of cobalamin (i.e., vitamin B.sub.12, i.e., α-(5,6-dimethylbenzimidazolyl)cobalamide) with an axial ligand on the cobalt atom, where the ligand is not bridged to the rest of the molecule. In nonlimiting illustrative examples that axial ligand is: —CH.sub.3 for methylcobalamin; —OH for hydroxocobalamin; —CN for cyanocobalamin; and -Ado for adenosylcobalamin, where -Ado is an adenosyl moiety. In a particular embodiment of the invention methylcobalamin is the form of cobalamin used, but the invention is not so limited. As used herein, the term “vitamin B.sub.12” is used synonymously with cobalamin, and includes all active forms of cobalamin. When a weight quantity of cobalamin or vitamin B.sub.12 is given herein, it will be understood to refer to the weight quantity of the particular cobalamin species under consideration, including the R-group, regardless of which R-group is appended.

[0063] The terms “vitamin D.sub.3” and “methylcobalamin” have their usual and ordinary meanings in the fields of chemistry and biochemistry.

[0064] The term “carotenoid” has its usual and ordinary meaning in natural products chemistry.

[0065] The terms “carotene”, “lycopene”, “neurosporene”, “phytofluene”, “phytoene”, “xanthophyll”, “canthaxanthin”, “cryptoxanthin”, “zeaxanthin”, “astaxanthin”, “lutein”, and “rubixanthin” have their usual and ordinary meaning in the fields of chemistry and natural products.

[0066] The term “lettered carotenes” means carotene compounds designated by Greek letters and for example includes alpha-carotene, beta-carotene, gamma-carotene, delta-carotene, epsilon-carotene and zeta-carotene.

[0067] The term “disulfide bond” as used with respect to a molecule means a single covalent bond that links two neighboring divalent sulfur atoms, forming an —S—S— moiety in a molecule. As used herein with respect to a sulfur atom, the phrase “is not part of a disulfide bond” means that the atom is not part of an —S—S— moiety, whereas a sulfur atom that is part of a disulfide bond is part of an —S—S— moiety.

[0068] The terms “alpha-lipoic acid”, “lipoamide”, “glutathione disulfide”, “cystine”, “asparagusic acid”, “lenthionine”, “ajoene”, “allithiamine”, “allyl propyl disulfide”, “diallyl disulfide”, “fursultiamine”, “pantethine”, “prosultiamine”, “pyritinol”, and “sulbutiamine” have their usual and ordinary meanings in the fields of chemistry and biochemistry.

[0069] The term “phenolic group” as used with respect to a molecule means a benzene ring that bears at least one hydroxy (—OH) substituent. In certain embodiments the benzene ring may be a fused ring, for instance such as is found in flavan-3-ols. In certain embodiment the phenolic group may be part of a condensed phenolic system such as tannic acid or ellagic acid. Non-limiting illustrative examples of phenolic substituents that may be found in ingredients according to the invention include those bonded to the ring or by an ether or ester of phenol (hydroxybenzene), pyrocatechol (o-dihydroxybenzene), resorcinol (m-dihydroxybenzene), pyrogallol (1,2,3 -trihydroxybenzene), or phloroglucinol (1,3,5 -trihydroxybenzene). In some embodiments the phenol has a C—C or C—O bond to a sugar moiety.

[0070] The term “flavan-3-ol compound” means a natural derivative of flavan-3-ol, i.e., it has moieties bonded to the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton shown below.

##STR00001##

[0071] The moieties are typically hydroxyl groups on the aromatic rings, but may include covalent bonds that form an oligomer or polymer, and in some cases may include sugar groups as in a glycoside. The term flavan-3-ol compound as used herein includes but is not limited to catechin (C), epicatechin (EC), gallate (G), epigallocatechin (EGC), epigallocatechin gallate (EGCG), theaflavins, theaflavin-3-gallate, thearubigins, and stereoisomers and glycosides of those compounds. The term flavan-3-ol compound as used herein further includes oligomers and polymers of those compounds, in particular the proanthocyanidins and procyanidins. The terms “tannin”, “condensed tannin”, “hydrolysable tannin”, “proanthocyanidin”, “procyanidin”, “prodelphinidin”, “proguibourtinidin”, and “prorobinetinidin” as used herein have their usual and ordinary meanings in natural products and plant biochemistry, and are for instance consistent with the respective usage of such terms in CHEMISTRY AND SIGNIFICANCE OF CONDENSED TANNINS, Richard W. Hemingway and Joseph J. Karchesy, eds. (1989).

[0072] The term “glycoside” as used with respect to a compound or moiety means that it has a sugar residue covalently bonded thereto; the sugar may be a monosaccharide, disaccharide, trisaccharide, or higher order saccharide.

[0073] The terms “catechin”, “epicatechin”, “epigallocatechin”, “epicatechin gallate”, “epigallocatechin gallate”, “epiafzelechin”, “fisetinidol”, “guibourtinidol”, “mesquitol”, and robinetinidol” refer to flavan-3-ol compounds and have their usual and ordinary meaning in the fields of organic chemistry and natural products, and include the various stereoisomers thereof. The generic chemical structure for catechins and epicatechins is shown below. Where the C-2 and C-3 carbons define a trans configuration the molecule is a catechin. Where they define a cis configuration the molecule is an epicatechin.

##STR00002##

[0074] The term “derivative” as used with respect to a molecule means a variant in which the molecule is bonded to another chemical moiety.

[0075] The terms “monomer”, “oligomer”, and “polymer” as used herein with respect to a structural unit have their usual and ordinary meaning in the arts of chemistry, biochemistry and polymer science, where a monomer has one unit, an oligomer has at least two such units covalently bonded to one another, and a polymer has many such units. As an example, typically procyanidins are concatenated oligomers of catechins and or epicatechins, having from 2 to 50 or more structural units in a linear molecular chain. As a further example, proanthocyanidins, of which procyanidins are one subset, may further include gallate units, and their oligomers and polymers may be either linear or branched or in some cases cross-linked.

[0076] The term “extract” as used with respect to a botanical substance means a product that has been obtained by removal from a plant material but remains in a mixed form. Illustrative methods to obtain extracts include expression of oil; absorption by steeping the plant material in a solvent such as, e.g., water or ethanol; maceration of the plant material; and distillation. In some cases two or more of these methods are combined, e.g., maceration and distillation. Other methods include, for instance, spagyric extraction, often involving fermentation, distillation and extraction of mineral components from the ash of a plant. In particularly useful embodiments according to the invention the extract is a composite that includes flavan-3-ols extracted from plant tissue by means of a solvent such as water or ethanol. The plant tissue that has been extracted may be from the roots, leaves, stems, flowers, fruits, seeds, components of any of those, or another part of a plant.

[0077] The term “grape seed extract” means an extract of grape seed(s). In particularly useful embodiments of the invention the grape seed extract is a commercially available product, such as is sold by, e.g., the company Naturex, SA.

[0078] The term “therapeutically effective amount” as used with respect to an ingredient or composition means an amount sufficient to elicit a desired biological response. The therapeutically effective amount or dose will depend on the age, sex and weight of the patient, and the current medical condition of the patient. The skilled artisan will be able to determine appropriate dosages depending on these and other factors in addition to the present disclosure. By definition, an amount of a vitamin or mineral adequate to correct or maintain basal levels of the vitamin or mineral above a depressed or deficient state are therapeutically effective. Non-limiting examples of therapeutically effective amounts for the present invention include the 2013 dietary reference intakes based on dietary equivalents (“Des”) for vitamin D compounds, cobalamin compounds (2.4 μg/day), and carotenoids such as vitamin A. For purposes of the present invention therapeutically effective amounts may include any larger amount up to the maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. The dietary reference intakes (DRI) for those, also known as recommended dietary allowances (“RDA”), are published by Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences.

[0079] The term “pharmaceutically acceptable” as used with respect to salts and complexes of compounds herein, means those which are useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes both those which are acceptable for veterinary use as well as those which are acceptable for human pharmaceutical use. Pharmaceutically acceptable salts are for example acid addition salts and basic salts but also include inner salts such as zwitterions. Acid addition salts are, e.g., salts made by addition of an acid, such as by HCl, HBr, H.sub.2SO.sub.4, H.sub.3PO.sub.4 or another inorganic acid or by citric acid or another organic acid. Basic salts are, e.g., salts having a cation selected from alkali or alkaline metals, e.g., Na.sup.+, K.sup.+, or Ca.sup.2+, or an ammonium ion N.sup.30 (R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C6-C10 aryl group, or an optionally substituted C6-C10 heteroaryl group. Further examples of pharmaceutically acceptable salts are described in REMINGTON'S PHARMACEUTICAL SCIENCES, 18 ed. (1990) and in ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY.

[0080] The terms and abbreviations “milligram” and “mg” are equivalent. The terms and abbreviations “microgram” and “mcg” and “μg” are equivalent. And terms of measurement conform to their respective meanings in the International System of Units, also known as the Système international d'unités.

[0081] The abbreviation “I.U.” as used with respect to amounts of an ingredient means International Unit(s) as they are stated in the art of pharmacology for biologically active quantities of vitamins, hormones, some medications, vaccines, blood products, and similar biologically active substances.

[0082] The inventor has discovered that combining antioxidants from four particular classes provides surprisingly good benefits against prediabetes and its symptoms. Although vitamin C and vitamin E are commonly provided in prior art antioxidant supplements, the present invention does not require them nor does either of those vitamins fall into one of the four classes herein. The discovery further finds that providing at least one antioxidant that can also serve as a pro-oxidant is beneficial. Without being bound by the mechanism it is theorized that prediabetes is associated with increased damage to biochemical intermediates and tissues from specific types and ratios of free radicals, and that the present invention addresses their relative reactivity and prevalence. Moreover the varieties of compounds taught for use here will distribute to different tissues and cellular components, and thus without being bound by theory are believed to address the damage in each of those places that represent a signature pattern of prediabetes and diabetes.

CATEGORY I

Heteroatom-based Natural Antioxidant Compounds

[0083] These fall within a generic structural family having a short (2-5 carbons) alkyl chain with at one end a simple nitrogen group such as an unsubstituted amine or tri-methyl ammonium group, and at the neighboring carbon optionally an —O-acetyl or carboxyl group, and at the other end a group from an acid or acid derivative, such as a sulfonic, carboxylic or amide group, optionally augmented by an acid and or diimidazole group. The inventor theorizes without being so limited that radical oxidizing species in the body abstract a H• atom from the alpha-carbon for the terminal amine of the antioxidant, and that the nitrogen atom is able to donate electron density (or in the case of the ammonium species, the nitrogen atom is able to donate electron density after a demethylation) to stabilize the adjacent radical. The radical may be further stabilized by donation from an acetyl ester oxygen at the same site. Or a captodative (“push-pull”) effect may stabilize the radical where an amine donates electron density from one side of the unpaired electron and a carboxyl center draws electron density from the other. Some molecules may have additional sited for stabilized abstraction of a hydrogen atom. This hypothesis assumes that the stabilized radical is less aggressively reactive and thus can be rehydrogenated or metabolized without perpetuating the more destructive branches of a reactive radical manifold. Again, the invention is not limited by this hypothetical mechanism.

[0084] In general it appears that it is most helpful to include a plurality of antioxidant compounds from this category, and the invention finds that it is useful to include as many as five or more. Preferred compounds include taurine, beta-alanine, acetyl-carnitine, agmatine, carnosine, cysteine, sulfinoalanine, hypotaurine, carnitine, lysine, anserine, histidine, arginine and ornithine. Particularly preferred compounds are taurine, carnosine, carnitine, acetylcarnitine, and agmatine, depicted in Table I below. However the invention is not so limited. Natural compounds, and particularly compounds having the stereoisomer found in the body are preferred, because they are safer in some cases (e.g., L-carnitine is less toxic than D-carnitine) and have an inherent advantage for docking with and being transported by or through natural stereoisomers of lipids, proteins, carbohydrates and nucleic acids. However the invention is not so limited.

[0085] In particular embodiments the composition is provided in a dose form. In certain embodiments the dose form includes taurine provided in a range selected from: 40 to 360 mg; 60 to 340 mg; 80 to 320 mg; 100 to 300 mg; 120 to 280 mg; 140 to 260 mg; 160 to 240 mg; 180 to 220 mg; or about 200 mg. In some embodiments the dose form includes beta-alanine provided in a range selected from: 10 to 90 mg; 15 to 85 mg; 20 to 80 mg; 25 to 75 mg; 30 to 70 mg; 35 to 65 mg; 40 to 60 mg; 45 to 55 mg; or about 50 mg. In various embodiments the dose form includes acetyl-L-carnitine provided in a range selected from: 20 to 180 mg; 30 to 170 mg; 40 to 160 mg; 50 to 150 mg; 60 to 140 mg; 70 to 130 mg; 80 to 120 mg; 90 to 110 mg; or about 100 mg. In particular embodiments the dose form includes agmatine provided in a range selected from: 25 to 225 mg; 40 to 210 mg; 55 to 195 mg; 70 to 180 mg; 85 to 165 mg; 100 to 150 mg; 115 to 135 mg; or about 125 mg. In further embodiments the dose form provides L-carnosine provided in a range selected from: 5 to 45 mg; 7.5 to 42.5 mg; 10 to 40 mg; 12.5 to 37.5 mg; 15 to 35 mg; 17.5 to 32.5 mg; 20 to 30 mg; 22.5 to 27.5 mg; or about 25 mg. In some embodiments the dose form provides an 8:2:4:5:1 respective ratio of taurine, beta-alanine, acetyl-L-carnitine, agmatine, and L-carnosine.

TABLE-US-00001 TABLE I ANTIOXIDANTS WITH A STABILIZING HETEROATOM Taurine [00003] Beta-alanine [00004] Agmatine [00005] Acetyl-L-carnitine [00006] L-carnosine [00007]

CATEGORY II

Natural Compounds Having a Conjugated Segment

[0086] Conjugation is the alternation of double and single bonds, and particularly where several double bonds are involved in the sequence, this provides a stabilized site for hydrogen abstraction at saturated carbon atoms that are adjacent to a double bond in the series, whether at the terminus of a conjugated segment, or at a branch along the chain. This is true even when the branch is as short as a methyl group.

[0087] The inventor has found that vitamin D compounds and cobalamin compounds are useful of this purpose, and that including a representative antioxidant compound from each of those categories is particularly useful. In certain embodiments at least one carotenoid is also included.

[0088] Useful vitamin D compounds for purposes of the invention include: 7-dehydrocholesterol, also known as previtamin-D.sub.3; vitamin D.sub.2, also known as ergocholecalciferol; vitamin D.sub.3, also known as cholecalciferol and activated 7-dehydrocholesterol; 25-D, also known as 25-hydroxyvitamin D, calcidiol and calcifediol; and 1,25-D, also known as 1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D.sub.3 and calcitriol. In particularly preferred embodiments the vitamin D compound is vitamin D.sub.3, depicted in Table II below, but the invention is not so limited. In particular embodiments the composition is provided in a dose form comprising vitamin D.sub.3 provided in a range selected from: 500 to 4,500 I.U.; 750 to 4,250 I.U.; 1,000 to 4,000 I.U.; 1,250 to 3,750 I.U.; 1,500 to 3,500 I.U.; 1,750 to 3,250 I.U.; 2,000 to 3,000 I.U.; 2,250 to 2,750 I.U.; or about 2,500 I.U.

[0089] Preferred cobalamin compounds for the invention include: methylcobalamin;

[0090] hydroxocobalamin; cyanocobalamin; and adenosylcobalamin. Among other properties cobalamin compounds can bind the radical NO•. Methylcobalamin is particularly preferred, and is depicted in Table II below, but the invention is not so limited. In some embodiments the composition is provided in a dose form comprising a cobalamin compound provided in a range selected from: 20 to 220 μg; 30 to 210 μg; 40 to 200 μg; 50 to 190 μg; 60 to 180 μg; 70 to 170 μg; 80 to 160 μg; 90 to 150 μg; 100 to 140 μg; 110 to 130 μg; or about 120 μg.

[0091] Preferred carotenoids for purposes of the invention include the lettered carotenes, lycopene, neurosporene, phytofluene, phytoene, xanthophyll, canthaxanthin, cryptoxanthin, zeaxanthin, astaxanthin, lutein, and rubixanthin. A particularly preferred carotenoid is lutein, depicted in Table II below, but the invention is not so limited. In certain embodiments the composition is provided in a dose form comprising lutein in a range selected from: 1 to 9 mg; 1.5 to 8.5 mg; 2 to 8 mg; 2.5 to 7.5 mg; 3 to 7 mg; 3.5 to 6.5 mg; 4 to 6 mg; 4.5 to 5.5 mg; or about 5 mg.

[0092] In certain embodiments the composition is provided in a dose form that comprises per each milligram of carotenoid compound: 500 I.U. vitamin D compound and 24 μg cobalamin compound.

TABLE-US-00002 TABLE II ANTIOXIDANTS WITH CONJUGATED SEGMENTS Vitamin D3 [00008] Methylcobalamin [00009] Lutein [00010] [00011]

CATEGORY III

Compounds That Have a Disulfide Bond

[0093] Aggressive radicals can attack disulfide bonds, such as by abstracting an electron from one of the sulfurs, or by forming a bond with one of the S atoms while breaking the S—S bond and leaving the other S atom as a radical —S• that is stabilized by the electron-rich environment of the sulfur atom itself.

[0094] Particularly useful disulfides include: natural products and especially botanical natural products; derivatives of B-vitamins; and lipoic acid and its derivatives. Certain preferred disulfide antioxidants are natural products, including: lipoic acid, glutathione disulfide, and L-cystine, each of which is common in mammalian metabolism; asparagusic acid, commonly found in asparagus plants; lenthionine, commonly found in Shiitake mushrooms; and disulfide compounds from the Allium (onion and garlic) family, including ajoene, allithiamine, allyl propyl disulfide, and diallyl disulfide. Certain other preferred disulfide antioxidants are derivatives of small-molecule B vitamins, including fursultiamine (for B.sub.1), pantethine and its salts (for B.sub.5). prosultiamine (for B.sub.1), pyritinol (for B.sub.6), and sulbutiamine (for B.sub.1), each of which is depicted in Table III below. Particularly preferred disulfide antioxidants for purposes of the invention are lipoic acid or its derivative lipoamide, but the invention is not so limited.

[0095] In certain embodiments the composition is provided in a dose form comprising alpha-lipoic acid provided in a range selected from: 100 to 900 μg; 150 to 850 μg; 200 to 800 μg; 250 to 750 μg; 300 to 700 μg; 350 to 650 μg; 400 to 600 μg; 450 to 550 μg; or about 500 μg.

TABLE-US-00003 TABLE III DISULFIDES Lipoic Acid [00012] Lipoamide [00013] Asparagusic acid [00014] Diallyl disulfide [00015] Allyl propyl sulfide [00016] Ajoene [00017] Lenthionine [00018] Pyritinol [00019] Cystine [00020] Allithiamine [00021] Fursultiamine [00022] Prosultiamine [00023] Sulbutiamine [00024] Pantethine [00025] Glutathione disulfide [00026]

CATEGORY IV

Flavan-3-ol Compounds

[0096] Flavanol-3-ol compounds are flavonoids with numerous sites for abstraction of a phenolic hydrogen, to leave an aromatically delocalized and thus stabilized oxyradical —O•.

[0097] Preferred flavan-3-ols for purposes of the invention are depicted in Table IV below: catechin (C), epicatechin (E), gallate (G), epigallocatechin (EGC), epigallocatechin gallate (EGCG), theaflavins, theaflavin-3-gallate, and thearubigins. Molecular variants based on stereoisomers, glycosides, oligomers and polymers are also preferred, in particular proanthocyanidins and their subset the procyanidins. Particularly preferred flavan-3-ols are (+)-catechin, (+)-gallocatechin, (−)-epicatechin, (−)-epigallocatechin, (−)-epigallocatechin gallate (EGCG), (−)-epicatechin 3-gallate, and procyanidins and other proanthocyanidins.

[0098] In certain preferred embodiments the flavan-3-ols are provided in the form of a mixture found in nature, such as in grape seed extract. Grape seed extract comprises phenolic antioxidants, such as for instance, epicatechin and oligomers of epicatechin. However the invention is not so limited. Other desirable sources of mixed flavan-3ols include, for example, apples (especially Red Delicious and Granny Smith varieties), maritime pine bark, cinnamon, aronia fruit, cocoa beans, grape skins, red wine, bilberry, cranberry, black currant, green tea, black tea, oak heartwood (Quercus petraea and Q. robur), acai oil, field beans (Vicia faba), and Gallipoli rose. In various embodiments the composition is provided in a dose form that comprises grape seed extract in a range selected from: 10-90 mg; 15 to 85 mg; 20 to 80 mg; 25 to 75 mg; 30 to 70 mg; 35 to 65 mg; 40 to 60 mg; 45 to 55 mg; or about 50 mg.

TABLE-US-00004 TABLE IV ILLUSTRATIVE FLAVAN-3-OLS (+)-Catechin, C, [Oligomers = Procyanidins] [00027] (−)-Epicatechin (cis), EC [Oligomers = Procyanidins] [00028] (−)-Epigallocatechin, EGC [Oligomers = Prodelphinidins] [00029] (−)-Epicatechin gallate, ECG [00030] (−)-Epigallocatechin gallate, EGCG, [00031] Epiafzelechin [00032] Fisetinidol [00033] Mesquitol [00034] Guibourtinidol [Oligomers = Proguibourtinidins] [00035] Robinetinidol [Oligomers = Prorobinetinidins] [00036]

Antioxidants That are Also Pro-Oxidants

[0099] Without being bound by theory it is believed that the pro-oxidant properties of some antioxidants employed in the present invention contribute to establishing an oxidative balance in the tissues, and to maintaining an equilibrium in the oxidation states of the metals that are active there. It is also conceivable that this may help to expose and flush out latent populations of deleteriously oxidizing species found there. Among other observations, antioxidants that exert a pro-oxidant effect in the liver are particularly useful. This may possibly arise from a readier flushing of some metals from that tissue when they are in an alternative oxidation state. Comments follow on the pro-oxidant capabilities of the antioxidant classes for which use is taught here. Note that some members of an antioxidant class may be pro-oxidants while others may not be.

[0100] Most compounds with a stabilizing heteroatom do not appear to be pro-oxidants. Their role in up- and down-regulation of biochemical pathways in some cases can alter the oxidative stress. However for purposes of the invention that alone does not make them pro-oxidants.

[0101] The pro-oxidant properties of vitamin D in native tissues are not clear, though it has pro-oxidative effects in breast cancer cells. Cobalamin compounds do not appear to be pro-oxidants, nor do most carotenoids.

[0102] Antioxidants with disulfide bonds may be pro-oxidants, for instance alpha-lipoic acid is.

[0103] Flavan-3-ols behave somewhat analogously to ascorbate and commonly have prooxidant activity even at low concentrations (unlike the sterically protected phenolics such as the synthetic antioxidants BHA and BHT); this is evident for instance by their initiation of lipid peroxidation in the presence of O.sub.2 and a metal such as Cu, Al, Zn, Ca, Mg or Cd.

RELATIVE RATIOS IN THE COMPOSTIONS

[0104] In certain embodiments the composition is provided in a dose form in which the total weight of compounds from each of Categories, I, II, III and IV is provided in a respective ratio of 1,000:10:100:1, or wherein each number in the ratio may be varied by ±80% independently of the others.

[0105] The embodiments of the invention as described herein are merely illustrative and are not exclusive. Numerous additions, variations, derivations, permutations, equivalents, combinations and modifications of the above-described invention will be apparent to persons of ordinary skill in the relevant arts and are within the scope and spirit of the invention. The invention as described herein contemplates the use of those alternative embodiments without limitation.