WO2009123821A2 - Dietary supplement and related method - Google Patents
Dietary supplement and related method Download PDFInfo
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- WO2009123821A2 WO2009123821A2 PCT/US2009/036147 US2009036147W WO2009123821A2 WO 2009123821 A2 WO2009123821 A2 WO 2009123821A2 US 2009036147 W US2009036147 W US 2009036147W WO 2009123821 A2 WO2009123821 A2 WO 2009123821A2
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Definitions
- the present invention relates to a composition and method for correcting a dietary deficiency, including an inadequacy of phytochemicals, vitamins and minerals.
- the benefits of consuming a sufficient amount and variety of fruits and vegetables are many. For example, consuming fruits and vegetables has been shown to reduce the risk of a variety of degenerative diseases.
- consuming fruits and vegetables has been shown to reduce the risk of a variety of degenerative diseases.
- the association of fruit and vegetable consumption with lung cancer risk was investigated. The researchers found that the risk of lung cancer was approximately halved when the consumption of fruits and vegetables increased from 24 or less servings to an excess of 48 servings per week. Similarly, the risk of lung cancer was approximately halved when the consumption of green leafy vegetables, including spinach and parsley sources, increased from one or fewer servings to six or more servings per week. Steinmetz, K.
- herbs In addition to fruits and vegetables, herbs also provide health benefits.
- the herb, rosemary contains antioxidants such as carnosol, which may play a preventive role in cholesterol oxidation.
- the herb, basil is known for its antioxidant activity.
- the dietary intake of beneficial herbs is unsatisfactory.
- Phytochemicals generally refer to plant-derived compounds which, when taken daily in combination with vitamins and minerals, provide improved cardiovascular and bone health, an improved antioxidant profile, decreased free radical damage, and overall enhancement of the body's natural defense system.
- the typical diet especially the U.S. diet, includes an inadequate amount and variety of fruits, vegetables and herbs, as well as the phytochemicals and associated antioxidants present in these materials.
- a typical diet is similarly deficient in necessary vitamins and minerals associated with fruits and vegetables.
- conventional multivitamins can supplement western diets with needed vitamins and minerals, many of these multivitamins fail to provide phytochemicals that target free radicals in the body and thereby improve the antioxidant profile of the supplement.
- the present invention provides a composition including a unique combination of fruit, vegetable, and herb dehydrates, concentrates, or extracts; and optionally vitamins, minerals and specialty ingredients to correct a dietary deficiency of those materials.
- the composition of the present invention provides substantial health benefits. For example, in one embodiment, it can support the health of people who consume a nutritionally deficient diet; improve antioxidant and nutrient status; replenish serum nutrient and phytochemical levels as a result of inadequate diets to levels associated with decreased risk of certain degenerative disease states; minimize free radical damage that occurs as a result of normal aging processes and exposure to environmental stresses; and/or improve the status of specific biomarkers indicative of optimal health, namely homocysteine, lipid byproducts, mineral status and glutathione peroxidase.
- the composition of the present invention can provide ⁇ -carotene, ⁇ -lipoic acid, selenium, and vitamins C and E, which improve the antioxidant profile of a person.
- Increased levels of folic acid and vitamins E target and improve cardiovascular health.
- Calcium, magnesium, and vitamin D targets and improves bone health.
- B vitamins improve energy metabolism.
- the compositions according to the invention can provide 100% of the U.S. Recommended Daily Intake of all vitamins and most minerals.
- the composition also can provide a variety of phytochemicals to produce a diverse antioxidant profile.
- the composition can include a combination of fruit, vegetable and herbal ingredients, wherein the fruit ingredients are selected from acerola, apple, blueberry, citrus bioflavonoids, cranberry, grape skin, plum, and pomegranate; wherein the vegetable ingredients are selected from asparagus, alfalfa, brassica, kale, lutein, lycopene, and watercress; and wherein the herbal ingredients are selected from basil, oregano, parsley, sage and rosemary. These ingredients can be concentrated, for example they may be extracted from raw ingredients.
- the fruit ingredients, vegetable ingredients and herbal ingredients can be present in the composition in a ratio of about 3.5:1:1 by weight.
- Specialty ingredients such as alpha lipoic acid and inositol can be added to the composition.
- the composition can include at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, plum and raspberry; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.
- a method for enhancing the immune system, as well as treating and/or reducing the risk of DNA damage of the human body comprising administering an effective amount of a composition including at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, and plum; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.
- a composition including at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, and plum; at least one vegetable ingredient selected from the group consisting of asparagus,
- Figure 1 is a graph depicting the effect the composition has on Vitamin C levels.
- Figure 2 is a graph depicting the effect the composition has on beta carotene levels.
- Figure 3 is a graph depicting the effect the composition has on Vitamin B 6 levels.
- Figure 4 is a graph depicting the effect the composition has on Vitamin B 12 levels.
- Figure 5 is a graph depicting the effect the composition has on Folate levels.
- Figure 6 is a graph depicting the effect the composition has on homocysteine levels.
- Figure 7 is a graph depicting the numbers of genes related to DNA or chromatin maintenance or repair that were modulated by consumption of the composition.
- Figures 8A and 8B which are a diagram ( Figure 8A) and a graph ( Figure 8B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 2-hydroxybutarate.
- Figures 9A and 9B are a diagram ( Figure 9A) and a graph ( Figure 9B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 5-oxoproline.
- Figure 10 is a graph depicting the change in plasma beta-carotene concentration after treatment.
- Figure 11 is a graph depicting the change in plasma folate concentration after treatment.
- Figure 12 is a graph depicting the change in plasma vitamin B6 concentration after treatment.
- Figure 13 is a graph depicting the change in plasma vitamin B 12 concentration after treatment.
- Figure 14 is a graph depicting the change in plasma homocysteine concentration after treatment.
- Figure 15 is a graph depicting the change in DNA damage after treatment.
- Figure 16 is a graph depicting the change in baseline expression activity of genes associated with DNA maintenance genes after treatment.
- the invention relates to a composition comprising fruits, vegetables and herbs.
- the composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary.
- the composition can also be combined with a known therapy that can impact chromatin stability thereby limiting the detrimental effects of such therapy.
- the following fruit ingredients also can be present in the composition: acerola, apple, blueberry, cranberry, grape skin, and plum.
- the following vegetable ingredients also can be present in the composition: alfalfa, brassica, and kale.
- the following herbal ingredients also can be present in the composition: sage and parsley.
- composition has a synergistic effect in the treatments discussed herein.
- the components of the composition together are more effective that individually.
- the composition modulates, and more specifically as discussed herein up-regulates, genes associated with chromatin stability, examples of which are discussed in the figures and examples.
- Example of genes involved in telomere maintenance include, but are not limited to, Ku, Cdc 13 protein, the catalytic subunit EST2, and three other genes, ESTl, EST3, EST4/CDC13, MREIl, RAD50, XRS2 (yeast)/NBSl, p53, hTERT, ATM, TRF2, the TERF family of genes.
- the composition of the present invention can either treat or reduce the occurrences/risks of chromatin damage, and thus support genome stability, by increasing the expression of genes involved in identifying and correcting damage to DNA as well as associated protein structures (i.e., chromatin).
- the reduction in the occurrence/risk of chromatin damage includes any statistically significant reduction that correlates to a biological response or outcome.
- mismatch repair mainly removes bulky DNA adducts.
- BER base-excision repair
- DSB double- strand-break
- genes include, but are not limited to ERCC, RAD2, RAD6, RAD7, RAD18, RAD23, RAD51, RAD54, CDC7, CDC8, CDC9, MAGl, PHRl, DINl, DDR48, RNRl, RNR2, RNR3, UB14, repB, repD and APE. These genes are impacted by the composition of the present invention can modulate any of the types of damage disclosed above.
- composition can thus be used to treat diseases associated with DNA repair problems including, but not limited to, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Werner's syndrome, Bloom's syndrome and ataxia telangiectasia. All of which are associated with improper repair of DNA.
- the composition can also be used to affect/modulate the fuction of mitochondria function-specific genes, examples of such genes are provided in Table 8 below. These genes generally fall into four categories. First, genes for mitochondrial transcription/translation, examples of which include, but are not limited to, MTRFlL, which is involved in mitochondrial translational machinery, GFM2, which is a protein involved in protein elongation, MRPL3, which is a mitochondrial ribosomal protein, TOMM20, which is a central component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins and together with TOM22 functions as the transit peptide receptor at the surface of the mitochondrion outer membrane and facilitates the movement of preproteins into the TOM40 translocation pore, COXl 5, which is predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos) involved in heme biosynthesis, POLG2, mtDNA that is replicated accurately by DNA polymerase gamma, and MRPSl
- genes for mitochondrial structure examples of such genes include, but are not limited to, DNMIL, which is critical for maintenance of mitochondrial morphology, OPAl, which is a major organizer of the mitochondrial inner membrane and is required for the maintenance of cristae integrity, MFNl, which is an essential transmembrane GTPase, which mediates mitochondrial fusion (MFNl acts independently of the cytoskeleton.), BNIP3, which provides regulation of mitochondrial permeability, COXl 8, which is required for the insertion of integral membrane proteins into the mitochondrial inner membrane and is essential for the activity and assembly of cytochrome c oxidase and plays a central role in the translocation and export of the C-terminal part of the COX2 protein into the mitochondrial intermembrane space, and DNMlL, which functions in mitochondrial and peroxisomal division probably by regulating membrane fission and enzyme hydrolyzing GTP that oligomerizes to form ring-like structures and is able to remodel membranes.
- DNMlL
- miscellaneous mitochondrial proteins examples of such genes include, but are not limited to, WWOX, a tumor suppressor gene, PPIF, for protein folding, CoQ9, 1OB, which is involved in the final steps in the synthesis of CoQ, SLC25A37, which is a mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis, ABCB7, which is involved in the transport of heme from the mitochondria to the cytosol, and SLC25A36, which is a transporter for mitochondria.
- WWOX a tumor suppressor gene
- PPIF for protein folding
- CoQ9, 1OB which is involved in the final steps in the synthesis of CoQ
- SLC25A37 which is a mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis
- ABCB7 which is involved in the transport of heme from the mitochondria to the cytosol
- genes for mitochondrial enzymes examples include, but are not limited to, SDHD, which is part of the respiratory chain, ATPAFl enzymes which are critical for generation of ATP, NARS2, IARS2, EARS2, LARS2, HARS2, which are enzymes involved in the production of amino acid, ASN, ILE and GLN, LEU and HIS respectively, HIBADH, which is an enzyme providing succinyl coA for TCA cycle, ACADSB, which is an enzyme catalyzing one of the steps in fatty acid beta oxidation, MIBl, which is a E3 ligase necessary for protein ubiquitnation (deletion lethal), BCKDHB and ACAD8, for the generation of succiny Co A for TCA, AFG3L2, which is a AAA protease protecting against oxiative stress, PEOl, which is a DNA helicase, critical for lifetime maintenance of mtDNA integrity and to maintain mtDNA copy number, HK2 (Hexokinase 2), and
- composition can also be combined with a known therapy to create a combinatorial therapy.
- a known therapy has known detrimental side effects that impact DNA stability, such as chemotherapeutics and radiotherapeutics.
- Other compounds can also be used that negatively impact DNA repair and stability.
- the composition can include a combination of fruit, vegetable, herbal and other ingredients that provide significant health benefits.
- the following tables illustrate representative daily amounts of suitable fruits, vegetables, herbs, vitamins, and minerals which can be included in the composition.
- the dosages and methods of administration can be varied as desired from application to application.
- Dosage A represents a range of dosages of the respective ingredients that is suitable for purposes of the present invention.
- Dosage B represents a dosage of a particular embodiment.
- the unit "mg" in Tables 1-5 means that that the amount recited is given in the number of, e.g., milligrams, provided in a two-tablets per day dosage, unless otherwise noted, e.g., "JU" is recited.
- Table 1 To determine the amount of a specific ingredient per single tablet, the amount recited in the respective tables must be halved.
- the citrus bioflavonoids are commercially available from Access Business Group International LLC of Ada, Michigan.
- This ingredient can be in a concentrate form, and can include, but are not limited to, naringen, hesperidin, narirutin, diosmin, rutin, tangeretin, diosmetin, neohesperidin, nobiletin, and quercetin.
- NUTRILITE watercress is available from Access Business Group International LLC.
- the Brassica and/or kale can be in dehydrated, powdered form.
- the Brassica ingredient may include any material derived from plants in the Brassicae family, for example, broccoli.
- the lutein esters used in the composition can be of the type sold under the name Xangold 10% beadlets, which is available from Cognis Nutrition & Health of Cincinnati, Ohio.
- the lycopene used in the composition can be of the type sold under the name Lycobeads 5%, which is available from H. Reisman Corp. of Orange, New Jersey.
- compositions and methods of the present invention can include, vitamin A, vitamin Bl, vitamin B2, vitamin B6, vitamin B 12, niacin/niacinamide, pantothenic acid, folic acid, biotin, choline, vitamin C, vitamin D, and vitamin E.
- suitable vitamins for use in the compositions and methods of the present invention can include, vitamin A, vitamin Bl, vitamin B2, vitamin B6, vitamin B 12, niacin/niacinamide, pantothenic acid, folic acid, biotin, choline, vitamin C, vitamin D, and vitamin E.
- Table 4 below includes a suitable vitamin profile. Table 4
- minerals for use in the compositions and methods of the present invention include, for example, boron, calcium, chromium, copper, iodine, magnesium, manganese, molybdenum, potassium, selenium, vanadium, and zinc. Other vitamins and minerals may also be used. Table 5 below includes a mineral profile suitable for the composition of the present invention.
- the composition of the present invention can provide a significant portion of, and in many cases exceed, the recommended daily requirement for a variety of vitamins and minerals.
- Tables 6 and 7 below illustrate the potency of the composition, when taken in the above daily amounts, in terms of percentages of the daily requirements for the listed vitamins and minerals.
- Additional specialty ingredients which can be used in the composition include, for example, methyl sulfonyl methane (MSM), ⁇ -lipoic acid (10 mg/day), catechins, polyphenols, flavanoids, lycopene, lutein, yeast, inositol, and para-aminobenzoic acid (PABA).
- MSM methyl sulfonyl methane
- ⁇ -lipoic acid 10 mg/day
- catechins polyphenols
- flavanoids flavanoids
- lycopene lycopene
- lutein lutein
- yeast inositol
- PABA para-aminobenzoic acid
- composition of the present invention can be formulated using any pharmaceutically acceptable form of respective fruit concentrates, vegetable concentrates, herb concentrates, phytochemicals, vitamins, minerals, and other nutrients, including their salts.
- the compositions can be formulated into tablets, powders, gels, or liquids (a tablet, for the purposes of the present invention and as used throughout the application disclosure, refers to any form of a solid oral dosage, including but not limited to tablets, caplets, capsules, powders, etc.).
- the compositions can be formulated as powders, for example, for mixing with consumable liquids such as milk, juice, water, or consumable gels or syrups for mixing into other liquids or foods.
- compositions can also be formulated with other foods or liquids to provide pre-measured compositional foods, for example, single-serving bars. Flavorings, binders, protein, complex carbohydrates, and the like can be added as needed. According to one aspect of the invention, the composition is administered as three separate tablets, all three of which are administered twice a day; however, the composition may be administered in other forms and unit dosages as desired.
- the first tablet includes the fruit, vegetable and herbal ingredients of Tables 1-3.
- the amount of each ingredient in this first tablet is half of the amount listed in the Dosage B of the Tables, as the table-listed amount is the amount present in two such tablets.
- the first tablet may also include carriers and other tableting aids such as silicon dioxide, magnesium oxide, calcium carbonate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate in amounts that may be varied for purposes well known to those of skill in the art.
- the second tablet includes vitamins of Table 4. The amount of each ingredient in this second tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets.
- the second tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.
- the third tablet includes minerals of Table 5. The amount of each ingredient in this third tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets.
- the third tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide. The three tablets, when administered twice a day, complete the gap in phytochemicals that is present in the typical diet. EXAMPLE 2
- Tables 1-5 tablets including the fruit, vegetable and herbal ingredients from Tables 1-3 are referred to as "Tablet 1"; tablets including the vitamin ingredients from Table 4 are referred to as “Tablet 2"; and tablets including the mineral ingredients from Table 5 are referred to as "Tablet 3.” It is noted that other methods for preparing the tablets and other suitable delivery vehicles can be used as desired.
- Tablet 1 Mixed tocopherols, D-alpha-tocopherol (succinate), and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.
- Magnesium oxide (D.C. heavy) Acerola concentrate, citrus bioflavonoids complex, plum extract, apple extract, rosemary extract, basil extract, grape skin extract, cranberry extract, kale powder, asparagus extract, blueberry extract, parsley dehydrate, oregano extract, sage extract, pomegranate extract, and inositol are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.
- Lycopene (5%), lutein ester (beadlets), mixed tocopherols, calcium carbonate
- magnesium stearate (Kosher) is passed through a
- SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.
- Acerola concentrate, microcrystalline cellulose (silicified) and alpha lipoic acid are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot P.K. blender. The ingredients are blended for ten minutes. Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: thiamine mononitrate (97%), riboflavin, niacinamide, biotin trituration
- magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets. Tablet 3
- Zinc amino acid chelate, mixed tocopherols and silicon dioxide are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.
- Co-processed alfalfa concentrate/microcrystalline cellulose/calcium carbonate, selenium yeast, microcrystalline cellulose, copper amino acid chelate, manganese amino acid chelate, potassium iodide trituration, chromium amino acid chelate, molybdenum amino acid chelate, brassica dehydrate, watercress dehyrdate and croscarmellose sodium are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.
- magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.
- Kosher magnesium stearate
- the clinical study was an Independent Review Board-approved, double-blind, placebo-controlled, parallel-groups study. Subjects Subjects were 120 healthy adult Japanese-Americans in California and Hawaii.
- Subjects were ethnically Japanese (both parents and four grandparents ethnically Japanese) and ate a mostly Japanese diet.
- composition was the same formula as is currently marketed in Japan under the Alticor name of Triple XTM. All products were coated and provided in coded foil packs to preserve double-blindedness.
- Placebo at baseline, Week 4, and Week 8.
- Nutrigenomic analyses were based on blood samples obtained from 14 subjects (7 treated with Triple X, and 7 treated with Placebo) at baseline and Week 2.
- Plasma nutrient and homocysteine change score results were assessed with independent- groups t-test for between-groups comparisons. A P value smaller than 0.05 was considered significant.
- Placebo subjects taking composition showed increased levels of folate, vitamin B6, vitamin B 12, and vitamin C, as well as decreased levels of homocysteine, all within 4 weeks of treatment, with results maintained at 8 weeks.
- Metabolomic analyses indicatedecreased oxidative stress.
- Nutrigenomic analyses indicate increased genomic integrity and tumor suppressor mechanisms, homocysteine metabolism, resistance to oxidative stress and lipid peroxidation.
- Clinical testing was conducted to confirm the efficacy of the composition of the present invention. It was expected that consumption of the composition would: correct dietary deficiencies of phytochemicals; improve the amount of antioxidants in the body; decrease free radical damage; increase plasma vitamin, mineral and phytochemical concentrations; and improve plasma and systemic antioxidant capacity, among other things.
- Inclusion criteria for this study were healthy men and women, from 18 to 80 years of age, who consume fewer than 12 items found on the Recommended Foods Checklist per week. These subjects are selected after administration of a food frequency questionnaire and application of the Recommended Foods Score (RFS).
- the RFS consists of 23 foods, 14 of which are fruits and vegetables, that when consumed on a weekly basis have been associated with reduced mortality. This was demonstrated in a cohort study of 42,254 women. Those with a mean RFS of 16.0 (highest quartile) had an all-cause mortality relative risk of 0.69 compared to those with a mean RFS of 6.4 (lowest quartile) who have an all-cause mortality relative risk. It was noted that those in the highest quartile consumed significantly more calories (131%), fiber (200%), Vitamin C (230%), folate (181%), and pro- Vitamin A carotenoids (253%) compared to those in the lowest quartile.
- the clinical study encompassed a double-blind (i.e. to subjects and investigators) study of 120 subjects over a six-week period. During the six-week trial, subjects were told to consume three tablets, either the composition, or a placebo, twice a day, such as morning and evening.
- the subjects were tested by taking blood and urine samples and performing the following assays: total polyphenols, plasma ORAC (Oxygen Radical Absorption Capacity), CP450 enzyme induction, cytokinesis block micronucleus assay, comet assay, bioenergetics assay, urinary bile acids, B6, B 12, folate, Vitamin C, homocysteine, alpha and gama tocopherols, beta-carotene, C-reactive protein and urinary 8-epi prostaglandins F2 ⁇ , which were tested at baseline, two weeks, four weeks and six weeks into the study.
- Improvement, and thus, efficacy of the composition was measured based on: plasma concentrations of vitamins, minerals and phytochemicals; plasma and systemic antioxidant capacity; detoxification capacity; cellular energy dynamics; genomic stability; other risk factors and subjective effects. It was expected that the results of the study would show that following six weeks of composition consumption, subjects would have significantly increased plasma levels of alpha tocopherols, B 12, B6, folate, Vitamin C, and other antioxidants, which indicates an improvement in the amount of antioxidants in the body and which is associated with a correction of dietary deficiencies in vitamins, nutrients and phytochemicals, and/or a decrease in free radical damage, as well as increased genomic stability (i.e., decreased DNA damage) among other things.
- results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking the composition showed increased plasma concentrations of Beta Carotene, Alpha-Tocopherol, Folate, and Vitamins B6 and B 12. Subjects taking composition also showed significantly reduced homocysteine, as well as decreased DNA damage as indicated by the cytokinesis micronucleus block assay. This shows that the consumption of the composition can increase plasma concentrations of antioxidant nutrients, decrease homocysteine, and decrease DNA damage.
- the above descriptions are those of the preferred embodiments of the invention.
Abstract
A composition including a unique combination of fruits, vegetables, herbs, and optionally vitamins, minerals and specialty ingredients. The composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can be administered to subjects to correct a dietary deficiency of phytochemicals and other nutrients, improve plasma concentrations of antioxidant nutrients,, and increase the activity of genetic mechanisms for DNA repair and stability.
Description
DIETARY SUPPLEMENT AND RELATED METHOD
This is a continuation-in-part application of U.S. Application 10/915,784, filed August 11, 2004, which is a continuation-in-part application of U.S. Application 10/360,789, filed May 7, 2002 (now U.S. Patent 6,989,161), which is a continuation-in-part application of U.S. Application 09/878,377, filed June 12, 2001 (now U.S. Patent 6,511,675), which claims benefit of U.S. Provisional Application No. 60/210,746, filed June 12, 2000, all of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION The present invention relates to a composition and method for correcting a dietary deficiency, including an inadequacy of phytochemicals, vitamins and minerals.
Many people fail to practice healthy eating habits, such as consuming an adequate quantity and variety of food to meet U.S. Recommended Dietary Allowances. Only 22% of the subjects of a National Cancer Institute Study consumed the recommended daily number of dietary servings of fruits and vegetables — despite the fact that the recommended dietary intake of fruits and vegetables is well-known. For example, The California Daily Food Guide: Dietary Guidelines for Calif ornians , California Department of Health Services (1990) recommends that each person consume at least five to nine servings of fruit and vegetables per day, including one serving of a vitamin A-rich deep green or dark orange fruit or vegetable, and at least one serving of a vitamin C-rich fruit or vegetable. Additionally, it is well reported that each person should consume at least 3 servings per week of vegetable protein in the form of legumes, nuts, or seeds. Some researchers suggest that a target of 400 grams (13 ounces) of fruits and vegetables is a
sensible goal for the optimal quantity to be consumed daily. In terms of variety, it is recommended that persons should eat at least three different colors of fruits and vegetables daily.
The benefits of consuming a sufficient amount and variety of fruits and vegetables are many. For example, consuming fruits and vegetables has been shown to reduce the risk of a variety of degenerative diseases. In a prospective cohort study of 41,837 postmenopausal women, the association of fruit and vegetable consumption with lung cancer risk was investigated. The researchers found that the risk of lung cancer was approximately halved when the consumption of fruits and vegetables increased from 24 or less servings to an excess of 48 servings per week. Similarly, the risk of lung cancer was approximately halved when the consumption of green leafy vegetables, including spinach and parsley sources, increased from one or fewer servings to six or more servings per week. Steinmetz, K. et al., "Vegetables, Fruit, and Lung Cancer in the Iowa Women's Health Study," Cancer Res. 53:536-43 (1993). Another study found that an increased intake of fresh tomatoes (a major source of lycopene) was associated with a pattern of protection for all sites of digestive tract cancer. Stahl, W. et al., "Lycopene: A Biologically Important Carotenoid for Humans?" Arc. Biochem. Biophys. 336:1-9
(1996).
In addition to fruits and vegetables, herbs also provide health benefits. For example, the herb, rosemary, contains antioxidants such as carnosol, which may play a preventive role in cholesterol oxidation. Likewise, the herb, basil is known for its antioxidant activity. Like fruits and vegetables, however, the dietary intake of beneficial herbs is unsatisfactory.
Further research has shown that the typical U.S. diet is lacking in phytochemicals. Phytochemicals generally refer to plant-derived compounds which, when taken daily in
combination with vitamins and minerals, provide improved cardiovascular and bone health, an improved antioxidant profile, decreased free radical damage, and overall enhancement of the body's natural defense system.
The typical diet, especially the U.S. diet, includes an inadequate amount and variety of fruits, vegetables and herbs, as well as the phytochemicals and associated antioxidants present in these materials. A typical diet is similarly deficient in necessary vitamins and minerals associated with fruits and vegetables. Although conventional multivitamins can supplement western diets with needed vitamins and minerals, many of these multivitamins fail to provide phytochemicals that target free radicals in the body and thereby improve the antioxidant profile of the supplement.
SUMMARY OF THE INVENTION
The present invention provides a composition including a unique combination of fruit, vegetable, and herb dehydrates, concentrates, or extracts; and optionally vitamins, minerals and specialty ingredients to correct a dietary deficiency of those materials. The composition of the present invention provides substantial health benefits. For example, in one embodiment, it can support the health of people who consume a nutritionally deficient diet; improve antioxidant and nutrient status; replenish serum nutrient and phytochemical levels as a result of inadequate diets to levels associated with decreased risk of certain degenerative disease states; minimize free radical damage that occurs as a result of normal aging processes and exposure to environmental stresses; and/or improve the status of specific biomarkers indicative of optimal health, namely homocysteine, lipid byproducts, mineral status and glutathione peroxidase.
In a more specific embodiment, the composition of the present invention can provide β-carotene, α-lipoic acid, selenium, and vitamins C and E, which improve the antioxidant profile of a person. Increased levels of folic acid and vitamins E target and improve cardiovascular health. Calcium, magnesium, and vitamin D targets and improves bone health. B vitamins improve energy metabolism. The compositions according to the invention can provide 100% of the U.S. Recommended Daily Intake of all vitamins and most minerals. The composition also can provide a variety of phytochemicals to produce a diverse antioxidant profile.
In an even more specific embodiment, the composition can include a combination of fruit, vegetable and herbal ingredients, wherein the fruit ingredients are selected from acerola, apple, blueberry, citrus bioflavonoids, cranberry, grape skin, plum, and pomegranate; wherein the vegetable ingredients are selected from asparagus, alfalfa, brassica, kale, lutein, lycopene, and watercress; and wherein the herbal ingredients are selected from basil, oregano, parsley, sage and rosemary. These ingredients can be concentrated, for example they may be extracted from raw ingredients. Optionally, the fruit ingredients, vegetable ingredients and herbal ingredients can be present in the composition in a ratio of about 3.5:1:1 by weight. Specialty ingredients, such as alpha lipoic acid and inositol can be added to the composition.
In yet another embodiment, the composition can include at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, plum and raspberry; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal
ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.
In another embodiment, a method is provided for enhancing the immune system, as well as treating and/or reducing the risk of DNA damage of the human body comprising administering an effective amount of a composition including at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, and plum; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.
These and other objects, advantages and features of the invention will be more readily understood and appreciated by reference to the detailed description of the invention and the drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph depicting the effect the composition has on Vitamin C levels. Figure 2 is a graph depicting the effect the composition has on beta carotene levels.
Figure 3 is a graph depicting the effect the composition has on Vitamin B6 levels. Figure 4 is a graph depicting the effect the composition has on Vitamin B 12 levels. Figure 5 is a graph depicting the effect the composition has on Folate levels.
Figure 6 is a graph depicting the effect the composition has on homocysteine levels.
Figure 7 is a graph depicting the numbers of genes related to DNA or chromatin maintenance or repair that were modulated by consumption of the composition. Figures 8A and 8B which are a diagram (Figure 8A) and a graph (Figure 8B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 2-hydroxybutarate.
Figures 9A and 9B are a diagram (Figure 9A) and a graph (Figure 9B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 5-oxoproline.
Figure 10 is a graph depicting the change in plasma beta-carotene concentration after treatment.
Figure 11 is a graph depicting the change in plasma folate concentration after treatment. Figure 12 is a graph depicting the change in plasma vitamin B6 concentration after treatment.
Figure 13 is a graph depicting the change in plasma vitamin B 12 concentration after treatment.
Figure 14 is a graph depicting the change in plasma homocysteine concentration after treatment.
Figure 15 is a graph depicting the change in DNA damage after treatment. Figure 16 is a graph depicting the change in baseline expression activity of genes associated with DNA maintenance genes after treatment.
DETAILED DESCRIPTION OF THE INVENTION I. Overview
In general, the invention relates to a composition comprising fruits, vegetables and herbs. In one embodiment, the composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can also be combined with a known therapy that can impact chromatin stability thereby limiting the detrimental effects of such therapy. The following fruit ingredients also can be present in the composition: acerola, apple, blueberry, cranberry, grape skin, and plum. Further, the following vegetable ingredients also can be present in the composition: alfalfa, brassica, and kale. Finally, the following herbal ingredients also can be present in the composition: sage and parsley.
The composition has a synergistic effect in the treatments discussed herein. Thus, the components of the composition together are more effective that individually. Additionally, the composition modulates, and more specifically as discussed herein up-regulates, genes associated with chromatin stability, examples of which are discussed in the figures and examples.
Example of genes involved in telomere maintenance include, but are not limited to, Ku, Cdc 13 protein, the catalytic subunit EST2, and three other genes, ESTl, EST3, EST4/CDC13, MREIl, RAD50, XRS2 (yeast)/NBSl, p53, hTERT, ATM, TRF2, the TERF family of genes.
The composition of the present invention can either treat or reduce the occurrences/risks of chromatin damage, and thus support genome stability, by increasing the expression of genes involved in identifying and correcting damage to DNA as well as associated protein structures (i.e., chromatin). The reduction in the occurrence/risk of chromatin damage includes any statistically significant reduction that correlates to a biological response or outcome. These genes control activities including, but not limited to, repair of base pair mismatches, repair of double strand breaks, or other maintenance, repair or supervisory roles. Most damage is caused by oxidation, nutrient deficiency, radiation or toxins. There are four main types of damage to DNA due to endogenous cellular processes or exogenous insult such as ultraviolet radiation: oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species, alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1 -methyladenine, O6 methylguanine hydrolysis of bases, such as deamination, depurination and depyrimidination. mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted. There are four major DNA-repair pathways in human cells: mismatch repair, nucleotide-excision repair (NER), base-excision repair (BER), and double- strand-break (DSB) repair. The NER pathway mainly removes bulky DNA adducts. The BER pathway is responsible for removal of oxidized DNA bases that may arise endogenously or from exogenous agents. The DSB pathway is responsible for repairing double-strand breaks caused by a variety of exposures, including ionizing radiation, free radicals, and telomere dysfunction. Examples of such genes include, but are not limited to ERCC, RAD2, RAD6, RAD7, RAD18, RAD23, RAD51, RAD54, CDC7, CDC8, CDC9, MAGl, PHRl, DINl,
DDR48, RNRl, RNR2, RNR3, UB14, repB, repD and APE. These genes are impacted by the composition of the present invention can modulate any of the types of damage disclosed above.
The composition can thus be used to treat diseases associated with DNA repair problems including, but not limited to, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Werner's syndrome, Bloom's syndrome and ataxia telangiectasia. All of which are associated with improper repair of DNA.
The composition can also be used to affect/modulate the fuction of mitochondria function-specific genes, examples of such genes are provided in Table 8 below. These genes generally fall into four categories. First, genes for mitochondrial transcription/translation, examples of which include, but are not limited to, MTRFlL, which is involved in mitochondrial translational machinery, GFM2, which is a protein involved in protein elongation, MRPL3, which is a mitochondrial ribosomal protein, TOMM20, which is a central component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins and together with TOM22 functions as the transit peptide receptor at the surface of the mitochondrion outer membrane and facilitates the movement of preproteins into the TOM40 translocation pore, COXl 5, which is predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos) involved in heme biosynthesis, POLG2, mtDNA that is replicated accurately by DNA polymerase gamma, and MRPSlO, which is part of mitochondrial 28S Ribosomal protein. Second, genes for mitochondrial structure examples of such genes include, but are not limited to, DNMIL, which is critical for maintenance of mitochondrial morphology, OPAl, which is a major organizer of the mitochondrial inner membrane and is required for the maintenance of cristae integrity, MFNl, which is an essential transmembrane GTPase, which mediates mitochondrial fusion (MFNl acts
independently of the cytoskeleton.), BNIP3, which provides regulation of mitochondrial permeability, COXl 8, which is required for the insertion of integral membrane proteins into the mitochondrial inner membrane and is essential for the activity and assembly of cytochrome c oxidase and plays a central role in the translocation and export of the C-terminal part of the COX2 protein into the mitochondrial intermembrane space, and DNMlL, which functions in mitochondrial and peroxisomal division probably by regulating membrane fission and enzyme hydrolyzing GTP that oligomerizes to form ring-like structures and is able to remodel membranes. Third, miscellaneous mitochondrial proteins examples of such genes include, but are not limited to, WWOX, a tumor suppressor gene, PPIF, for protein folding, CoQ9, 1OB, which is involved in the final steps in the synthesis of CoQ, SLC25A37, which is a mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis, ABCB7, which is involved in the transport of heme from the mitochondria to the cytosol, and SLC25A36, which is a transporter for mitochondria. Fourth, genes for mitochondrial enzymes examples of such genes include, but are not limited to, SDHD, which is part of the respiratory chain, ATPAFl enzymes which are critical for generation of ATP, NARS2, IARS2, EARS2, LARS2, HARS2, which are enzymes involved in the production of amino acid, ASN, ILE and GLN, LEU and HIS respectively, HIBADH, which is an enzyme providing succinyl coA for TCA cycle, ACADSB, which is an enzyme catalyzing one of the steps in fatty acid beta oxidation, MIBl, which is a E3 ligase necessary for protein ubiquitnation (deletion lethal), BCKDHB and ACAD8, for the generation of succiny Co A for TCA, AFG3L2, which is a AAA protease protecting against oxiative stress, PEOl, which is a DNA helicase, critical for lifetime maintenance of mtDNA integrity and to
maintain mtDNA copy number, HK2 (Hexokinase 2), and HADHB, which is involved in fatty acid beta-oxidation.
The composition can also be combined with a known therapy to create a combinatorial therapy. This can primarily be used in instances where the known therapy has known detrimental side effects that impact DNA stability, such as chemotherapeutics and radiotherapeutics. Other compounds can also be used that negatively impact DNA repair and stability.
The invention also relates to a method for correcting a diet-induced deficiency of fruits, vegetables and herbs, and the nutrients present in such materials. The composition of the present invention additionally can contain phytochemicals, vitamins, and minerals known to improve the body's natural defenses against oxidants, free radicals, and diseases. II. Composition and Method of Manufacture
The composition can include a combination of fruit, vegetable, herbal and other ingredients that provide significant health benefits. The following tables illustrate representative daily amounts of suitable fruits, vegetables, herbs, vitamins, and minerals which can be included in the composition. The dosages and methods of administration can be varied as desired from application to application. For example, Dosage A represents a range of dosages of the respective ingredients that is suitable for purposes of the present invention. Dosage B represents a dosage of a particular embodiment. The unit "mg" in Tables 1-5 means that that the amount recited is given in the number of, e.g., milligrams, provided in a two-tablets per day dosage, unless otherwise noted, e.g., "JU" is recited. Thus, to determine the amount of a specific ingredient per single tablet, the amount recited in the respective tables must be halved.
Table 1
The citrus bioflavonoids are commercially available from Access Business Group International LLC of Ada, Michigan. This ingredient can be in a concentrate form, and can include, but are not limited to, naringen, hesperidin, narirutin, diosmin, rutin, tangeretin, diosmetin, neohesperidin, nobiletin, and quercetin.
Table 2
NUTRILITE watercress is available from Access Business Group International LLC. The Brassica and/or kale can be in dehydrated, powdered form. As used herein the Brassica ingredient may include any material derived from plants in the Brassicae family, for example, broccoli. The lutein esters used in the composition can be of the type sold under the name Xangold 10% beadlets, which is available from Cognis Nutrition & Health of Cincinnati, Ohio. The lycopene used in the composition can be of the type sold under the name Lycobeads 5%, which is available from H. Reisman Corp. of Orange, New Jersey.
Table 3
NUTRILITE parsley is available from Access Business Group International LLC. The composition can also include ingredients in addition to the fruit, vegetable and herbal ingredients noted above. For example, suitable vitamins for use in the compositions and methods of the present invention can include, vitamin A, vitamin Bl, vitamin B2, vitamin B6, vitamin B 12, niacin/niacinamide, pantothenic acid, folic acid, biotin, choline, vitamin C, vitamin D, and vitamin E. Table 4 below includes a suitable vitamin profile.
Table 4
In addition to the vitamins listed above, minerals for use in the compositions and methods of the present invention include, for example, boron, calcium, chromium, copper, iodine, magnesium, manganese, molybdenum, potassium, selenium, vanadium, and zinc. Other vitamins and minerals may also be used. Table 5 below includes a mineral profile suitable for the composition of the present invention.
Table 5
With the ingredients of Tables 1-3, and optionally the ingredients of Tables 4-5, the composition of the present invention can provide a significant portion of, and in many cases exceed, the recommended daily requirement for a variety of vitamins and minerals. Tables 6 and 7 below illustrate the potency of the composition, when taken in the above daily amounts, in terms of percentages of the daily requirements for the listed vitamins and minerals.
Table 6
Additional specialty ingredients which can be used in the composition include, for example, methyl sulfonyl methane (MSM), α-lipoic acid (10 mg/day), catechins, polyphenols, flavanoids, lycopene, lutein, yeast, inositol, and para-aminobenzoic acid (PABA).
The composition of the present invention can be formulated using any pharmaceutically acceptable form of respective fruit concentrates, vegetable concentrates, herb concentrates, phytochemicals, vitamins, minerals, and other nutrients, including their salts. The compositions can be formulated into tablets, powders, gels, or liquids (a tablet, for the purposes of the present invention and as used throughout the application disclosure, refers to any form of a solid oral dosage, including but not limited to tablets, caplets, capsules, powders, etc.). The compositions can be formulated as powders, for example, for mixing with consumable liquids such as milk, juice, water, or consumable gels or syrups for mixing into other liquids or foods. The compositions can also be formulated with other foods or liquids to provide pre-measured compositional foods, for example, single-serving bars. Flavorings, binders, protein, complex carbohydrates, and the like can be added as needed. According to one aspect of the invention, the composition is administered as three separate tablets, all three of which are administered twice a day; however, the composition may be administered in other forms and unit dosages as desired.
The composition of the present invention will be illustrated by, but is not intended to be limited to, the following examples.
EXAMPLE 1
Three tablets may be prepared to provide a) fruit, vegetable and herbal ingredients, b) vitamins and c) minerals. The first tablet includes the fruit, vegetable and herbal ingredients of Tables 1-3. The amount of each ingredient in this first tablet is half of the amount listed in the Dosage B of the Tables, as the table-listed amount is the amount present in two such tablets. The first tablet may also include carriers and other tableting aids such as silicon dioxide, magnesium oxide, calcium carbonate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate in amounts that may be varied for purposes well known to those of skill in the art. The second tablet includes vitamins of Table 4. The amount of each ingredient in this second tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The second tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide. The third tablet includes minerals of Table 5. The amount of each ingredient in this third tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The third tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide. The three tablets, when administered twice a day, complete the gap in phytochemicals that is present in the typical diet.
EXAMPLE 2
The following examples relate to methods of preparing the above three tablets. The ingredients are the same as those referred to above in Tables 1-5. For purposes of the following examples, however, tablets including the fruit, vegetable and herbal ingredients from Tables 1-3 are referred to as "Tablet 1"; tablets including the vitamin ingredients from Table 4 are referred to as "Tablet 2"; and tablets including the mineral ingredients from Table 5 are referred to as "Tablet 3." It is noted that other methods for preparing the tablets and other suitable delivery vehicles can be used as desired.
Tablet 1 Mixed tocopherols, D-alpha-tocopherol (succinate), and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Magnesium oxide (D.C. heavy), Acerola concentrate, citrus bioflavonoids complex, plum extract, apple extract, rosemary extract, basil extract, grape skin extract, cranberry extract, kale powder, asparagus extract, blueberry extract, parsley dehydrate, oregano extract, sage extract, pomegranate extract, and inositol are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.
Lycopene (5%), lutein ester (beadlets), mixed tocopherols, calcium carbonate
(granular), croscarmellose sodium and microcrystalline cellulose (silicified) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender.
The mixture is blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a
SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender.
The ingredients are blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.
Tablet 2
Acerola concentrate, microcrystalline cellulose (silicified) and alpha lipoic acid are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot P.K. blender. The ingredients are blended for ten minutes. Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: thiamine mononitrate (97%), riboflavin, niacinamide, biotin trituration
(1%), vitamin B12 (1.1%), calcium pantothenate granular, folic acid, pyridoxine HCl (95%), and choline bitartrate. The ingredients are blended for ten minutes. Next, the following items are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: beta carotene (beadlets), vitamin D3 (beadlets), yeast (standardized) and vitamin A (acetate). The mixture is blended for an additional ten minutes.
Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: ascorbic acid (97%), calcium carbonate (granular), croscarmellose sodium, d-alpha-tocopherol succinate, silicon dioxide (NF fine powder). The mixture is blended for an additional ten minutes.
Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.
Tablet 3
Zinc amino acid chelate, mixed tocopherols and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Co-processed alfalfa concentrate/microcrystalline cellulose/calcium carbonate, selenium yeast, microcrystalline cellulose, copper amino acid chelate, manganese amino acid chelate, potassium iodide trituration, chromium amino acid chelate, molybdenum amino acid chelate, brassica dehydrate, watercress dehyrdate and croscarmellose sodium are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.
Potassium chloride, magnesium oxide (D.C. heavy) and calcium carbonate
(granulation) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional ten minutes.
Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets. EXAMPLE 3
The clinical study was an Independent Review Board-approved, double-blind, placebo-controlled, parallel-groups study. Subjects
Subjects were 120 healthy adult Japanese-Americans in California and Hawaii.
Subjects were ethnically Japanese (both parents and four grandparents ethnically Japanese) and ate a mostly Japanese diet.
Treatment Subjects took either composition or placebo as directed (12 tablets a day) for 8 weeks. The composition is the same formula as is currently marketed in Japan under the Alticor name of Triple X™. All products were coated and provided in coded foil packs to preserve double-blindedness.
Outcome Measures There were four main categories of outcome measures: (1) plasma concentrations of a representative water-soluble antioxidant nutrient [vitamin c], and a representative fat-soluble antioxidant nutrient [beta carotene], (2) plasma concentrations of the "anti -homocysteine triad" vitamin B6, vitamin B 12, and folate, as well as plasma concentrations of homocysteine, (3) nutrigenomic mechanisms of genomic stability, and (4) plasma metabolomic profile changes. Analyses for plasma nutrient and homocysteine concentrations were based on blood samples obtained from 120 subjects (60 treated with Triple X, and 60 treated with
Placebo), at baseline, Week 4, and Week 8.
Nutrigenomic analyses were based on blood samples obtained from 14 subjects (7 treated with Triple X, and 7 treated with Placebo) at baseline and Week 2.
Statistics
Plasma nutrient and homocysteine change score results were assessed with independent- groups t-test for between-groups comparisons. A P value smaller than 0.05 was considered significant.
Nutrigenomic data were first analyzed with paired t-tests within the composition- treated group only to identify which from among 44,000 genes measured showed a significant change in expression level following treatment. A P value smaller than 0.05 was considered significant. A Q value (false discovery rate) of 0.4 was used to control for false positive findings. This analysis identified about 2,000 genes, which were then examined for biologically relevant patterns of change. Results from the clinical study were as follows. Compared to subjects taking
Placebo, subjects taking composition showed increased levels of folate, vitamin B6, vitamin B 12, and vitamin C, as well as decreased levels of homocysteine, all within 4 weeks of treatment, with results maintained at 8 weeks. Metabolomic analyses indicatedecreased oxidative stress. Nutrigenomic analyses indicate increased genomic integrity and tumor suppressor mechanisms, homocysteine metabolism, resistance to oxidative stress and lipid peroxidation.
Clinical interpretation of nutrigenomic data revealed the unexpected finding that about 150 genes [Do you have a listing of the genes?], each known to function to support genomic stability (via chromatin maintenance, damage detection, and repair), were significantly increased in the Triple X group compared to the placebo group. Subsequent analysis of these genes in the Placebo-treated group showed no change following Placebo treatment. Compared to baseline, consumption of the composition of the present invention led to statistically significant increases in the expression of genes related to DNA maintenance, replication, or repair (Figure
V).
Clinical interpretation of metabolomic data revealed the unexpected findings that consumption of Triple X led to significant decrease increases in 2-hydroxybutyrate, a metabolite related to oxidative stress (Figure 9), as well as a trend towards a decrease in 5-oxoproline, also a metabolite related to oxidative stress (Figure 10). This shows that the consumption of the composition can lead to increased plasma concentration of antioxidant nutrients, increased expression of chromatin maintenance and repair genes, decreased homocysteine, and decreased metabolomic indicators of oxidative stress.
EXAMPLE 4
Clinical testing was conducted to confirm the efficacy of the composition of the present invention. It was expected that consumption of the composition would: correct dietary deficiencies of phytochemicals; improve the amount of antioxidants in the body; decrease free radical damage; increase plasma vitamin, mineral and phytochemical concentrations; and improve plasma and systemic antioxidant capacity, among other things.
Inclusion criteria for this study were healthy men and women, from 18 to 80 years of age, who consume fewer than 12 items found on the Recommended Foods Checklist per week. These subjects are selected after administration of a food frequency questionnaire and application of the Recommended Foods Score (RFS). The RFS consists of 23 foods, 14 of which are fruits and vegetables, that when consumed on a weekly basis have been associated with reduced mortality. This was demonstrated in a cohort study of 42,254 women. Those with a mean RFS of 16.0 (highest quartile) had an all-cause mortality relative risk of 0.69 compared to those with a mean RFS of 6.4 (lowest quartile) who have an all-cause mortality relative risk. It was noted that those in the highest quartile consumed significantly more calories (131%), fiber
(200%), Vitamin C (230%), folate (181%), and pro- Vitamin A carotenoids (253%) compared to those in the lowest quartile.
The clinical study encompassed a double-blind (i.e. to subjects and investigators) study of 120 subjects over a six-week period. During the six-week trial, subjects were told to consume three tablets, either the composition, or a placebo, twice a day, such as morning and evening. The subjects were tested by taking blood and urine samples and performing the following assays: total polyphenols, plasma ORAC (Oxygen Radical Absorption Capacity), CP450 enzyme induction, cytokinesis block micronucleus assay, comet assay, bioenergetics assay, urinary bile acids, B6, B 12, folate, Vitamin C, homocysteine, alpha and gama tocopherols, beta-carotene, C-reactive protein and urinary 8-epi prostaglandins F2α, which were tested at baseline, two weeks, four weeks and six weeks into the study. Improvement, and thus, efficacy of the composition, was measured based on: plasma concentrations of vitamins, minerals and phytochemicals; plasma and systemic antioxidant capacity; detoxification capacity; cellular energy dynamics; genomic stability; other risk factors and subjective effects. It was expected that the results of the study would show that following six weeks of composition consumption, subjects would have significantly increased plasma levels of alpha tocopherols, B 12, B6, folate, Vitamin C, and other antioxidants, which indicates an improvement in the amount of antioxidants in the body and which is associated with a correction of dietary deficiencies in vitamins, nutrients and phytochemicals, and/or a decrease in free radical damage, as well as increased genomic stability (i.e., decreased DNA damage) among other things.
Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking the composition showed increased plasma concentrations of Beta Carotene, Alpha-Tocopherol, Folate, and Vitamins B6 and B 12. Subjects taking composition
also showed significantly reduced homocysteine, as well as decreased DNA damage as indicated by the cytokinesis micronucleus block assay. This shows that the consumption of the composition can increase plasma concentrations of antioxidant nutrients, decrease homocysteine, and decrease DNA damage. The above descriptions are those of the preferred embodiments of the invention.
Various alterations and changes can be made without departing from the spirit and broader aspects of the invention as defined in the appended claims, which are to be interpreted in accordance with the principles of patent law including the doctrine of equivalents. Any references to claim elements in the singular, for example, using the articles "a," "an," "the," or "said," is not to be construed as limiting the element to the singular.
Table 8
Claims
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: L A method for modulating the expression of genes related to chromatin stability by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes related to chromatin stability
2. The method of claim 1, wherein said administering step includes administering the composition to a subject in the form of three tablets, each tablet administered twice a day.
3. The method of claim 1, wherein said administering step includes administering a composition that up-regulates the expression of chromatin stability-related genes.
4. A method of modulating the expression of DNA repair-related genes by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes related to DNA repair.
5. The method of claim 4, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.
6. The method of claim 4, wherein said administering step includes administering the composition thereby up-regulating the expression of DNA repair-related genes.
7. A method for reducing the risk of chromatin damage by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes thereby reducing the risk of chromatin damage.
8. The method of claim 7, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.
9. The method of claim 7, wherein said administering step includes administering a composition that up-regulates the expression of chromatin stability-related genes.
10. A combinatorial therapy comprising: an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes thereby reducing a risk of chromatin damage; and a second composition for treating a disease, wherein said second composition alters chromatin stability.
11. The combinatorial therapy of claim 10 further comprising alfalfa, brassica, and kale.
12. The combinatorial therapy of claim 10 further comprising vitamins and minerals.
13. The combinatorial therapy of claim 12, wherein the vitamins are chosen from vitamin A, vitamin C, vitamin D, vitamin E, niacin, vitamin B6, vitamin B 12, folic acid, biotin, and pantothenic acid.
14. The combinatorial therapy of claim 12 wherein the minerals are chosen from calcium, magnesium, iodine, potassium, copper, zinc, phosphorus, manganese, chromium, selenium, and molybdenum.
15. The combinatorial therapy of claim 10 wherein the citrus bioflavonoids are in concentrate form and include naringen, hesperidin and narirutin.
16. The combinatorial therapy of claim 10 wherein the fruit ingredient, the vegetable ingredient and the herbal ingredient are present in a ratio of 3.5 : 1 : 1.
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AU2009322474A1 (en) * | 2008-12-01 | 2011-07-21 | Lifespan Extension Llc | Methods and compositions for altering health, wellbeing, and lifespan |
AU2011276549A1 (en) * | 2010-06-28 | 2012-12-20 | Nestec S.A. | Methods for administering tube feed formulations |
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US9289374B2 (en) | 2014-04-23 | 2016-03-22 | Lifevantage Corporation | Topical compositions and methods for reducing oxidative stress |
CN108025034B (en) * | 2015-07-15 | 2022-09-30 | 新加坡科技研究局 | Regulation of hepatitis b virus replication |
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US20080226744A1 (en) | 2008-09-18 |
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