EP1100517A1 - Compositions nutritives et therapeutiques pour le traitement du cancer - Google Patents

Compositions nutritives et therapeutiques pour le traitement du cancer

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Publication number
EP1100517A1
EP1100517A1 EP99938977A EP99938977A EP1100517A1 EP 1100517 A1 EP1100517 A1 EP 1100517A1 EP 99938977 A EP99938977 A EP 99938977A EP 99938977 A EP99938977 A EP 99938977A EP 1100517 A1 EP1100517 A1 EP 1100517A1
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Prior art keywords
composition
vitamin
components
amount effective
cancer
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EP99938977A
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German (de)
English (en)
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John V. Kosbab
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Individual
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Cancer-protective and cancer-therapeutic compositions of this invention include antioxidants, neovascular regulators, promoters or cofactors involved in collagen synthesis, as well as vitamins and minerals to supplement nutrient deficiencies.
  • Cancerous cells exhibit certain characteristics that distinguish them from normal cells. These cells exhibit aberrant metabolism and growth, often the result of genetic damage; they exhibit proliferation due to inappropriate vascularization leading to tumor development; and they can undergo metastasis leading to the spread and recurrence of cancer.
  • the present invention is, in contrast, designed to utilize multi-component formulations the combined ingredients of which simultaneously interfere with a variety of factors or mechanisms that promote the generation, growth and spread of cancerous cells and tissue. More specifically the formulas of the present invention contain components which inhibit the development of cancer cells, inhibit proliferation of cancer cells and inhibit metathesis. Formulas of this invention contain additional components that promote cellular repair and the restoration of collagen matrices in tissues. Further formula ingredients are provided to restore and maintain pH balance and to stimulate the immune system. Vitamins and minerals are also included to supplement deficiencies including those that can result from cachexia induced by tumor development and growth and help restore normal biochemical function to cells and tissue.
  • Additional formula components are included to control the level and type of blood-born lipids which may be related to increased cancer risk.
  • the control of lipoprotein (a) is of particular importance.
  • optional formula ingredients can be included to control blood glucose levels, control insulin levels and reduce homocysteine levels.
  • compositions of this invention and treatment methods using them are based, at least in part, on a recognition that cancer is the result of a multi-factor etiology requiring utilization of multiple biochemical factors to successfully ameliorate or reverse conditions or symptoms of cancer.
  • protective and therapeutic formulas of this invention include components that are directed to simultaneously inhibit cancer at various stages, i.e., to inhibit development of cancer cells, to inhibit growth and proliferation of cancer cells and tissue and to inhibit metathesis.
  • Formulas provided in the present invention are useful as cancer-protective nutrient compositions that may be employed as dietary supplements and as cancer therapeutic compositions that may be combined with traditional forms of cancer treatment. Additional formulas include those directed to female cancers, including hormone-dependent cancers.
  • compositions of this invention can employ a mixture of different components having the same or similar biochemical or therapeutic functionality. These functionally similar components may differ in source (e.g., extracts of different plants), differ in chemical structure, differ in specific site of action and/or differ in effective half-life on administration. Such combinations of different components with similar activities provide synergistic nonadditive benefits and improvements.
  • Components of the compositions of this invention may themselves be multi-component mixtures with each subcomponent having one or more differing functionalities. Different composition components may have more than one biological function in the mixture and different components may have distinct, yet overlapping, biological functions.
  • the cancer protective and therapeutic compositions of this invention combine components which control oxidative stress, provide for appropriate neovascular regulation, provide factors necessary for stimulation or promotion of collagen maintenance and synthesis and tissue restoration.
  • Preferred combinations of antioxidants and neovascular regulators include combinations of a plant extract providing antioxidant effect comprising bioflavanoids, e.g., proanthocyanidins, with a neovascular regulator selected from the group genistein, daidzein, soy isolate (a specific source of plant isoflavones, e.g., genistein, and daidzein), cartilage or preferably chondroitin sulphate.
  • a preferred neovascular regulator is genistein from soy isolate.
  • Preferred compositions can further comprise components which regulate blood lipids, glucose or insulin, decrease homocysteine levels and stimulate or promote immune response or cell differentiation.
  • Preferred compositions can further comprise components which provide cell protection from mutation and toxins.
  • the antioxidant components of the present formulas are believed to protect cells from damage which may lead to mutation and the generation of cancerous cells.
  • Antioxidant components are also believed to promote restoration of healthy cells and tissue.
  • Neovascular regulators i.e., angiogenesis inhibitors, are believed to prevent inappropriate vascularization, help regulate growth factors to deprive cancerous cells of a blood supply and to inhibit cancer cell proliferation.
  • Components that promote collagen synthesis are believed to also inhibit inappropriate vascularization help restore growth factors, and to generally restore or promote healthy tissue thereby inhibiting metastasis and recurrence of cancers.
  • Components that regulate blood lipid levels are believed to generally inhibit cancer development, growth and recurrence.
  • Components that control blood glucose levels are also believed to generally inhibit (directly or indirectly) cancer development, growth and recurrence.
  • Components that stimulate the immune response are believed generally to inhibit metastasis and cancer recurrence.
  • Components that promote pH balance are believed to provide additional protection from cell damage due to oxidative stress.
  • Components that inhibit aberrant methylation protect cells from genetic damage and inhibit carcinogenesis.
  • Vitamins, minerals and cofactors are generally believed to improve cell and tissue health and to help maintain and/or restore normal biochemical function to cells and tissue and thereby prevent development, growth and recurrence of cancer.
  • Nutrient components provided in the formulas herein are also believed to protect against and/or ameliorate cachexia which may result from tumor growth.
  • compositions of this invention combine two or more antioxidant components, two or more neovascular regulators, a component that stimulates or enhances collagen synthesis, a component that regulates blood lipid levels, a component that stimulates the body's immune response, a component that regulates blood glucose levels and mineral, vitamin and cofactor components to supplement deficiencies and help to maintain and restore normal cell biochemistry.
  • this invention provides preferred protective and therapeutic formulas for female cancers including hormone-dependent cancers and cancers that have a higher occurrence rates in women (e.g., breast cancer, ovarian cancer, colon cancer, etc.).
  • the formulas of this invention can also be combined with components that ameliorate the symptoms and conditions associated with osteoporosis.
  • this invention provides protective and therapeutic formulas for the treatment of osteoporosis.
  • These formulas combine antioxidants, components that promote collagen synthesis, contribute bone matrix and structure and inhibit bone resorption with selected minerals vitamins and cofactors that provide particular benefit to ameliorate other symptoms and conditions associated with osteoporosis which are more likely to occur in post-menopausal women.
  • formulas of this invention for both cancer therapy and for treatment of osteoporosis, can be combined wherein indicated in a given individual with drugs and compositions for hormone replacement therapy.
  • Formulas of this invention can be combined with male hormone supplements where appropriate in a given individual.
  • This invention also encompasses methods of treatment to prevent or ameliorate the symptoms and disease conditions associated with various forms of cancer. These methods comprise administration of the compositions of this invention to an individual suffering from symptoms or conditions resulting from cancer. Cancer protection methods comprise administration of the nutrient compositions of this invention to an individual desirous of obtaining such benefit. Methods of this invention can be combined with other compatible known methods for cancer treatment, known methods for hormone replacement therapy and known methods for treatment of osteoporosis.
  • Antioxidants and antioxidant precursors are included in the compositions of this invention to generally combat oxidative stress and resultant genetic damage and slow the deterioration of collagen tissues.
  • antioxidants are believed to protect cells from cell damage leading to generation of cancerous cells.
  • antioxidants generally protect tissue, particularly vascular and capillary tissue, from deterioration, which is believed to inhibit metastasis and cancer recurrence.
  • a complementary antioxidant strategy is employed. Different chemical types of antioxidants are combined to provide enhanced antioxidant effect.
  • Preferred antioxidant combinations include both hydrophilic (having affinity for water or polar groups) and hydrophobic (having an affinity for lipids) antioxidants and combinations of antioxidants from different natural plant sources.
  • antioxidant vitamins (vitamins C or E) the mineral zinc and potassium and different plant bioflavonoid sources are combined to achieve complementary and synergistic antioxidant effects related to cell and tissue protection and healing.
  • Bioflavonoids containing proanthocyanidins scavenge free radicals and chelate some minerals to prevent them from causing oxidation. These bioflavonoids are found in most plants from which they can be extracted.
  • Commercially available proanthocyanidin- containing plant extracts include: grape seed extract (also called leucoanthocyanidin), pine bark extract (including "Pycnogenol” (Trademark, Horphag)), and bilberry extract. Ginkgo biloba and other plants which can also provide bioflavonoids, but of generally lower proanthocyanidin content, can also supplement antioxidant effect.
  • These materials and extracts contain rather complex mixtures of catechins, tannins, oligomers and proanthocyanidins, at least some of which protect membranes from lipid peroxidation, and inhibit superoxides. They are hydrophilic antioxidants, which are many times more effective than most antioxidant nutrients at controlling free radicals, superoxides and lipid peroxides. Individual plant materials which can provide proanthocyanidins may also provide other therapeutic benefits, for example, garlic and willow bark (a source of salicylic acid) may provide additional benefit.
  • Oligomeric proanthocyanidins are polymer chains of 10 or less catechins which yield red anthocyanidin when boiled in an aqueous solution of 10% hydrochloric acid.
  • Proanthocyanidins do not contain condensed tannins but are composed of nearly 60% catechin forms which have an extremely high affinity for collagen.
  • Catechin binds tightly to collagen, modifies its structure by crosslinking and causes it to be resistant to enzyme degradation, such as by collagenase, or by lipid peroxidation and superoxide radicals.
  • Proanthocyanidins inhibit capillary resistance and capillary permeability and, thus, improve vascular damage and deterioration.
  • Collagen accumulates in vessel walls in endothelia, the connective matrix, elastin and phospholipids which helps to maintain structural integrity and protect these structures from peroxide anion damage.
  • Plant extracts employed in this invention as sources for proanthocyanidins contain varying levels of OPCs. Antioxidant effectiveness of an extract generally increases with increasing levels of OPCs in the extract.
  • Red wine extract is a source of proanthocyanidins, bioflavanoids (e.g., malvidin) and tannins. Such extracts have antioxidant effect and may function to prevent platelet aggregation.
  • Catechins normally protect cell membranes from lipid peroxidation.
  • Proanthocyanidins also help to deliver and bind vitamin C to cell sites and can function to replace vitamin C at times of ascorbic acid deprivation.
  • compositions of this invention can contain one or more sources of proanthocyanidins which are included as antioxidants in the formula.
  • Proanthocyanidins also promote vascular healing and integrity by restoring the collagen matrix.
  • Different sources of proanthocyanidins i.e., plant extracts, can also display other therapeutically beneficial functions in compositions of this invention.
  • Bilberry extract may contain 5 types of anthocyanocides which account for most of its activity and 25% of its volume. While bilberry extract inhibits superoxides and lipid peroxide to some degree, it is low in oligomeric proanthocyanidins (OPCs) and therefore is less effective at controlling these free radical forms than leucoanthocyanidin (grape seed extract, for example) described below. Bilberry has an unusual anti-inflammatory effect, possibly because it can suppress leukotriene production. Proanthocyanidins can achieve concentrations in tissue (kidney and skin) up to 5 times the level contained in the bloodstream. High tissue concentrations can remain up to 24 hours after serum concentrations have been depleted. These factors contribute to the protective effect of proanthocyanidins.
  • OPCs oligomeric proanthocyanidins
  • the proanthocyanidin-containing extract of grape seeds includes the material called leucoanthocyanidin.
  • leucoanthocyanidin This commercially available material is obtained from white grape pips and is the most effective form of proanthocyanidin, yet discovered, for inhibiting superoxides and lipid peroxidation. This is believed to be due to the high level of oligomeric proanthocyanidins (OPCs) in the grape seed extract which strongly relates to vascular stabilization as described above. Red grape extract which is a good source of resveratrol can also be employed in this invention for antioxidant effect and other benefits. Pine bark extract, some preparations of which are known by the trade name "Pycnogenol,” is similar to leucoanthocyanidin, having relatively high OPC levels, but may possess better ability to suppress phagocytes.
  • Ginkgo biloba is a "middle range" proanthocyanidin possessing many of the functional characteristics of both bilberry extract and grape seed extract, but these active components are apparently present in lower concentrations. Ginkgo biloba can cause dilation of arteries, capillaries and veins and inhibit platelet aggregation. Ginkgo biloba also functions to inhibit high blood pressure and would be a preferred ingredient in formulations adapted for use by those with hypertension and related disorders. Green tea extract, tea polyphenols, contains a small amount of 2-3% of proanthocyanidin. It nevertheless is a potent antioxidant for lipid peroxides, superoxides and hydroxyl radicals.
  • tea polyphenols also have anti-platelet, anti-cholesterolemia, anti-hypertension, anti-hyperglycemic and anti- mutagenic activities. Tea polyphenols also assist theoflavin digallate in acting as an angiotensin converting enzyme inhibitor, but do not have the undesired pro-oxidant properties of captopril.
  • Silymarin is an antioxidant bioflavonoid isolated from milk thistle (Silybum marianum). Silymarin is contains the flavonoid silybin as a major component and related compounds silydianin and silychrysin (among others) as minor components. Silymarin is typically obtained as a concentrate (80% silymarin) from milk thistle seed extract. Silymarin can also be obtained from milk thistle berries. Silymarin is reported to provide a protective effect to the liver and is believed to protect liver cells from damage due to toxins (Ferenci, P. et al. (1989) J. Hepatol. 9(1):105-113).
  • Antioxidant bioflavanoids also include, among others, the flavanone glycosides quercitin, naringin, rutin and their aglucons, which are superoxide scavengers and inhibit oxidation of LDL.
  • Additional antioxidant bioflavanoids include: curcumin, kaempferol, fisetin, ipriflavone, apigenein, coumadin, zingiber, malviden, galangin, robinetin, myricitin, hesperiden, taxifolin, morin, deonidin, chrysin, perlargonidin, caffeic acid any of which can be included or admixed for additional antioxidant and/or collagen-binding effect.
  • Bioflavanoids may also be contained in plant preparations and extracts, e.g., nutgall (containing tannins and gallic acid), ginger and cinnamon extract. In preferred antioxidant combinations, two or more antioxidant bioflavanoids are combined.
  • bioflavonoids e.g., bilberry, grape seed extract (leucoanthocyanidin), Ginkgo biloba, pine bark extract (“Pycnogenol”), green tea extract (tea polyphenols) and individual bioflavanoids described above have significant complementary and synergistic chemical function that in combination with other ingredients and antioxidants in the formulas of this invention promote cell protection and repair.
  • Bioflavanoids can also exhibit other beneficial activities. For example, quercitin and ipriflavone may also have benefit in treatment and prevention of osteoporosis. Supplementation with these bioflavanoids decreases bone resorption and/or effects bone development.
  • Vitamin C or ascorbic acid can be provided in compositions of this invention in a variety of forms.
  • Vitamin C is available from a variety of natural sources, which may also be employed in the compositions of this invention.
  • Vitamin C is a hydrophilic antioxidant generally found in hydrophilic environments in the body, i.e., the bloodstream, the eye, interstitial spaces between cells and within cell membranes. It not only functions as a scavenger for singlet oxygen and hydroxy radicals, but it also replenishes spent vitamin E by replacing electrons. In the bloodstream, vitamin C reduces platelet aggregation, an anti- sclerotic effect. Vitamin C, however, has a short half-life and may interfere with diabetic glucose testing.
  • vitamin C suitable for use in the formulas of this invention include ascorbic acid, isoascorbic acid, ascorbigen, calcium, zinc, magnesium, and/or sodium ascorbate, ascorbyl palmitate, and nicotinamide ascorbate.
  • Mixtures of ascorbate complexes are also useful in the formulas of this invention to provide a variety of half-lives, differences in collagen matrix affinity and in matrix building.
  • combinations of vitamin C and cupric sulfate may have direct cell killing action to inhibit tumor growth. Vitamin C supplementation can increase bone mass and may have an additional benefit in osteoporosis.
  • Indole-3-carbinol is an antioxidant that provides functions similar to that provided by vitamin C, however, it is considered to provide protection against a broader range of biological oxidation agents.
  • Vitamin A or retinol or its derivatives and esters thereof are lipid-based antioxidants that can be provided in compositions of this invention in a variety of forms. Vitamin A is available from various natural sources. Vitamin A can be provided, for example, as retinol palmitate. Vitamin A and derivatives thereof are included in the formulas of this invention for their antioxidant function. Vitamin A function can be provided for example by retinol, retinal, retinoic acid (particularly 13-cis-retinoic acid and beta-trans-retinoic acid), and aromatic retinoids.
  • Tocopherols (Vitamin E, d-alpha-tocopheryl salts) are hydrophobic, lipid-based compounds with antioxidant function. They are believed to have a primary role in protecting cell membranes from lipid peroxidation. Tocopherols also scavenge free radicals in the blood and help to protect Vitamin A and selenium. D-alpha tocopherol forms, the natural forms of Vitamin E, are preferred over the less bioactive d,l-tocopherol forms. Tocopherols can be provided in a variety of forms with different counterions. D-alpha-tocopheryl acetate and gamma-tocopherol are preferred for use in the compositions of this invention.
  • Vitamin E succinate has been reported to exhibit inhibition of proliferation of tumor cells (Kline et al. (1990) Nutrition and Cancer 14:27-41).
  • Lutien also called xanthophyll, a carotinoid related to beta-carotene, but not a pro- Vitamin A carotinoid, is itself a lipid peroxide scavenger and appears to promote the production of zeaxanthin, another abundant and powerful lipid-based antioxidant. Lutien is an important blood-borne carotenoid strongly related to cardiovascular health. It is found in the human retina and is believed to act, possibly in a complementary manner with zinc, to protect retinal and macular tissue from oxidative damage. Zeaxanthin, an isomer of lutein, isolated from yellow corn grits, can be employed in compositions of this invention in place of or in addition to lutien.
  • Beta-carotene is a lipid-based, pro-vitamin A antioxidant which quenches singlet oxygen and scavenges free radicals. It plays a role in protecting against lipid peroxidation. Beta-carotene may also have a synergistic effect with other carotenoids, including lutein or zeaxanthin, for enhanced antioxidant function. Lycopene, canthaxanthin, and apo-carotenal are other antioxidant carotenoids that are useful in the formulas herein. In preferred antioxidant combinations, two or more carotinoid antioxidants are combined.
  • Alpha-lipoic acid which can be provided in the acid form or as an appropriate lipoate salt, e.g., sodium lipoate, is an antioxidant and free radical scavenger that reacts with reactive oxygen species including superoxide, hydroxyl radical, hypochlorous acid, peroxyl radical, and singlet oxygen. Its reduced form, dihydrolipoate, is also an effective antioxidant.
  • the d-form is the naturally-occurring optical isomer and preferred.
  • the dl-form is available and can be employed in place of the d-form.
  • Alpha-lipoic acid and its reduced dihydrolipoate form can bind to proteins including albumin which can prevent glycation reaction.
  • the mineral zinc which is discussed in more detail below, is associated with protection against lipid peroxidation in retinal and epithelial vascular tissue, possibly due to its enhancement of superoxide dismutase function.
  • the mineral potassium also discussed below, inhibits superoxide anion.
  • N-Acetyl-1-cysteine and glutathione are free radical scavengers. N-Acetyl-1-cysteine is also very effective for lowering lipoprotein (a) [LP(a)] concentrations in vivo.
  • compositions of this invention comprise more than one chemical type of angiogenesis regulator or more than one source of an angiogenesis regulator. Different regulators are believed to function in a complimentary manner to achieve a biochemical balance.
  • components of the compositions, other than specifically listed neovascular agents, may also affect angiogenesis.
  • antioxidants and free-radical scavengers can control free radicals which, by various mechanisms, may destroy angiogenesis regulation.
  • the control of oxidative stress due to antioxidants may have a significant effect on beneficial neovascular control.
  • conservative doses of several angiogenic regulators are believed to be more beneficial, i.e., enhanced effectiveness with minimal potential for toxic effect, than larger doses of a single chemical.
  • Cartilage an avascular tissue, is a source of angiogenesis inhibitor(s). Shark and bovine cartilage, among others, are sources of angiogenesis inhibitor and may provide collagenase inhibition as well.
  • Chondroitin sulphate a mucoploysaccharide found in most mammalian cartilaginous tissues and shark cartilage, is believed by many to be the most active angiogenesis regulating component of shark cartilage.
  • the restoration of depleted chondroitin sulphates may also affect collagen stabilization which would help to normalize the collagen matrix of vascular tissue and therefore create a more stable vascular structure.
  • Chondroitin sulphate can be provided in a number of forms with different counterions, e.g., sodium, potassium, etc.
  • Sodium chondroitin sulphate is the form preferred for use in compositions of this invention.
  • Protamine sulphate is a mixture of the sulphates of basic peptides that can be prepared from the sperm or the mature testes of certain species of fish. It is an arginine rich basic protein which has been shown to be a specific inhibitor of angiogenesis, possibly due to its ability to bind to heparin. Protamine has been used in some insulin preparations to prolong the effects of insulin. Protamine is usually given as the sulphate, but the hydrochloride form may also be used.
  • Genistein as well as daidzein are plant-derived isoflavonoids found, for example, in soybeans, that exhibit an ability to inhibit neovascularization by controlling endothelial cell proliferation in vitro.
  • Soy isolate is a natural source of genistein, daidzein or the glycoside derivatives (e.g., genistein, daidzem and sophoricoside) of these isoflavones. Soy isolate also provides nutritional benefit and may supplement depleted amino acids.
  • Additional plant- derived isoflavonoids include kievitone. Genistein and possibly kievitone may also function as a tyrosine kinase inhibitor causing apoptosis in certain cancer cells.
  • Certain plant derived isoflavonoids such as genistein, exhibit estrogenic function. Such isoflavonoids can function, like estrogen, to inhibit bone loss. Phytosestrogen, particularly those isolatable from soy, can have inhibitory effects upon cancer.
  • Gymnema sylvestre which normalizes heparin levels is provided in the compositions of this invention, at least in part, to affect heparin levels which in turn may affect angiogenic regulation due to shark cartilage and protamine sulfate which both bind to heparin.
  • the Gymnema sylvestre also provides for insulin/glucose stabilization which can further reduce the oxidative stress that contributes to the neovascularization factors described above.
  • Garlic extract (allicin), licorice extract (glyzzeryn), ginger, red wine extract, citrus pectin and/or marine tunicates can function for neovascular regulation and may provide additional therapeutic or nutritive benefit.
  • building blocks for collagen synthesis, growth regulators related to collagen synthesis and repair, cofactors for synthesis of collagen, calcium binding and/or regulatory agents and nutrients including various minerals associated with promotion of collagen synthesis are provided in formulas of this invention.
  • Glucosamines stimulate and provide building blocks for collagen synthesis.
  • Chondroitin sulphate is a flucosamine that functions for growth regulation and stimulates collagen synthesis.
  • Glucosamine sulphate is a preferred glucosamine for promoting collagen synthesis and repair.
  • Manganese is a cofactor which promotes collagen synthesis.
  • Amino acids, particularly branched chain amino acids (L-leucine, L-isoleucine and L-valine), provide protein for synthesis of collagen.
  • compositions of the present invention include various minerals including zinc, chromium, calcium, magnesium, potassium, manganese, and selenium.
  • Other minerals which may have beneficial or nutritional value for a given individual, particularly those minerals that are depleted can be provided individually or as a mineral complex.
  • Certain minerals can have additional therapeutic value in the compositions of this invention. For example as discussed above, zinc is believed to play a significant role as an antioxidant.
  • minerals can be provided in a variety of forms with various counterions.
  • the choice of a given form of mineral will depend generally on the type of dosage form that is employed, whether, for example, an oral or intravenous dosage form is employed.
  • Preferred forms of minerals are generally those that are more absorbable and those that have lower toxicity.
  • preferred forms will be generally compatible with the other components of a given mixture, will result in minimal irritation or other undesired side effects.
  • Choices of form of a given mineral provided in a given composition of this invention will also depend on the other ingredients in the composition, particularly to avoid excessive levels of a given counter ion.
  • Zinc can be provided in a variety of forms and with various counter ions, including among others zinc citrate, zinc fumarate, zinc gluconate, zinc alpha-ketoglutarate, zinc lactate, zinc malate, zinc succinate, zinc picolinate or mixtures thereof.
  • the preferred form of zinc in the compositions of this invention is zinc (Krebs) in which the counter ions are a mixture of the anions of the five primary organic acids of the tricarboxylic acid cycle (Krebs)
  • Zinc may have an indirect effect on bone resorption by inhibiting cadmium accumulation.
  • Chromium can be provided by a variety of dietary sources including, among others, brewer's yeast, liver, potatoes with skin, beef, fresh vegetables and cheese. Chromium exists in a dinicotino-glutathionine complex in natural foods. Such dietary and natural materials can provide sources of chromium for use in compositions of this invention. As with other minerals, there are generally a variety of forms of chromium that are useful in the compositions of this invention including, for example, chromium sulphate. Chromium nicotinate (Chromium-nicotinic acid complex) is a preferred form of chromium for use in the formulas of this invention. Chromium picolinate can be employed in the formulas of this invention, but is not generally preferred.
  • Chromium enhances insulin activity and as a result can affect blood lipids. For example, chromium nicotinate acid complexes can lower blood triglyceride levels. Chromium also decreases calcium excretion. Magnesium can be provided in a variety of forms and with various counter ions, including among others magnesium citrate, magnesium fumarate, magnesium gluconate, magnesium alpha-ketoglutarate, magnesium lactate, magnesium malate, magnesium succinate, magnesium picolinate, magnesium sulphate or mixtures thereof.
  • magnesium in the compositions of this invention are magnesium citrate, magnesium malate, magnesium malate-citrate, and magnesium (Krebs) in which the counter ions are a mixture of the anions of the five primary organic acids of the tricarboxylic acid cycle (Krebs Cycle) i.e., a mixture of the magnesium salts of citric, fumaric, malic, alpha-ketoglutaric and succinic acids.
  • Krebs Cycle a mixture of the magnesium salts of citric, fumaric, malic, alpha-ketoglutaric and succinic acids.
  • Magnesium deficiency may be a risk factor in osteoporosis.
  • Calcium can be provided in a variety of forms and with various counter ions, including among others calcium ascorbate, calcium carbonate, calcium citrate, calcium fumarate, calcium gluconate, calcium alpha-ketoglutarate, calcium levulinate, calcium lactate, calcium malate, calcium succinate, calcium picolinate or mixtures thereof. Calcium can also be provided in a variety of natural sources including dolomite, oyster shells, and bone meal.
  • the more preferred form of calcium in the compositions of this invention is calcium (Krebs) in which the counter ions are a mixture of the anions of the five primary organic acids of the tricarboxylic acid cycle (Krebs Cycle) i.e., a mixture of the calcium salts of citric, fumaric, malic, alpha-ketoglutaric and succinic acids.
  • the counter ions are a mixture of the anions of the five primary organic acids of the tricarboxylic acid cycle (Krebs Cycle) i.e., a mixture of the calcium salts of citric, fumaric, malic, alpha-ketoglutaric and succinic acids.
  • calcium carbonate, calcium citrate, and calcium malate-citrate which are noted for being highly absorbable.
  • Calcium is an important component of osteoporosis formulas increasing bone mass and decreasing bone fragility. Strontium, in low doses, reduces bone resorption and maintains high bone formation. Boron is included in osteoporosis formulas herein to balance in vivo potassium and calcium levels.
  • Potassium can be provided in a variety of forms and with various counter ions, including among others potassium citrate, potassium carbonate, potassium fumarate, potassium gluconate, potassium alpha-ketoglutarate, potassium lactate, potassium malate, potassium succinate, potassium picolinate or mixtures thereof.
  • the preferred form of potassium in the compositions of this invention is potassium citrate which has one of the highest levels of elemental potassium.
  • Manganese, selenium, and strontium can be provided in a variety of forms with various counterions.
  • Selenium is preferably supplied as an organoselenium compound, e.g., selenomethionine.
  • Manganese aspartate is a preferred form of manganese for use in the formulas of this invention.
  • Ranges of zinc (Krebs), calcium (Krebs), magnesium (Krebs), chromium nicotinate, potassium citrate and other minerals in an average daily dose of a composition of this invention are provided in Table 2.
  • the ranges given are maximum ranges which may need to be adjusted dependent upon the amount and form of other ingredients included in the composition. These ranges can be readily adjusted by those of ordinary skill in the art of nutrient and therapeutic formulation to other forms of the minerals noted above.
  • a mineral complex can optionally be combined with the compositions of this invention in addition to or substituted for specific minerals in the various formulas.
  • the mineral complex is used to supplement nutritional minerals not already included in specific formulation.
  • a preferred mineral complex includes absorbable salt or chelated forms of: major mineral components: calcium, magnesium, and potassium also chloride (e.g., as potassium chloride) and sulphate (e.g., as manganese sulphate); intermediate level components: zinc, manganese, boron and copper; minor components: chromium, selenium, iodine, molybdenum, vanadium, lithium, rubidium, silicon (as silica), nickel, phosphorus, strontium and cadmium; trace minerals: preferably from natural sources e.g., marine organic minerals or sea water concentrate.
  • the minerals may be provided in a variety of salt and complex forms, i.e., as the salts of Krebs cycle acid anions: aspartate, citrate, fumarate, malate and/or succinate salts; as salts of amino acids (e.g., arginates); as picolinate salts; as ascorbate salts, as nicotinate salts.
  • Silicon is preferably provided as the trisillicate anion, e.g., magnesium trisillicate.
  • Selenium is preferably provided as organoselenium compound, e.g., selenomethionine.
  • a variety of natural sources of minerals are known to the art including plant extracts, and can be used to provide minerals in the formula of this invention.
  • a preferred mineral complex provided in Table 1.
  • Minerals specifically included in a given formulation of this invention are preferably provided at the level indicated in that formulation.
  • dosages of a given mineral may be increased as needed and additional minerals, e.g., iron, may be added to the mineral complex.
  • Vitamins are included in compositions of this invention to provide supplementation for depletion and dietary deficiencies and in some cases for specific therapeutic benefits. Vitamins may also complement the activity of other components of the composition. Vitamin C, i.e., ascorbic acid, vitamin E, i.e., alpha-tocopherol, and vitamin A provide general nutritional supplementation as well as antioxidant function, as discussed above. Vitamin B6, i.e., pyridoxine, vitamin B 12, i.e., cobalamine, and folic acid (folate) provide general nutritional supplementation, and more specific benefits. Folate and vitamins B6 and B12 have antianemia properties. Folic acid decreases homocysteine levels. Vitamin B2, i.e., riboflavin, provides general nutritional supplementation. Vitamin B6 deficiency may detrimentally effect bone formation. Vitamin D can provide positive beneficial effect in protection and/or inhibition of cancer. A preferred form of vitamin D is vitamin D3.
  • a vitamin B complex can be employed in addition to or substituted for Vitamin B components of the formulas of this invention.
  • a preferred Vitamin B complex includes:
  • Vitamin B2 riboflavin 10 ⁇ g - 50 mg (5%)
  • Vitamin B3 nicotinamide or niacinamide, preferably as niacinamide ascorbate
  • Vitamin B5 pantothenic acid 1 mg -200 mg (26%)
  • Vitamin B6 (pyridoxine HC1) 1 O ⁇ g - 3 mg (5%)
  • Vitamin B12 (cyanocobalamin) 1 ⁇ g - 200 ⁇ g (0.03%),
  • compositions of this invention include any of the following: alanine, arginine, aspartic acid, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, carnitive (all in the biologically active L-form) and gamma aminobutyric acid.
  • a specifically listed amino acid is preferably provided in the amount needed to provide the desired therapeutic effect.
  • Additional nutritional amino acids are preferably provided in an nutritionally effective amount.
  • amino acid deficiencies are generally important to maintain normal biochemical function.
  • Amino acid deficiencies particularly lysine deficiency, can reduce calcium utilization.
  • Lysine is provided in formulas herein to avoid such deficiency and enhance calcium utilization, particularly in osteoporosis formulas.
  • Aberrant methylation can result in DNA damage, mutation and result in cancerous cells.
  • Maintenance of normal methionine metabolism for example by supplementation with methionine or cysteine, may avoid DNA damage and insure DNA repair.
  • Normal methionine metabolism may also be promoted by supplementation with folic acid, choline and betaine.
  • Arginine may function as a non-specific immune modulator stimulating immune response.
  • Glutamine deficiency may occur in patients with cancerous tumors due to significant consumption of glutamine by the tumor.
  • Glutamine is provided in formulas herein to compensate for deficiency.
  • Branched amino acids are beneficial in collagen maintenance and synthesis providing protein components for collagen synthesis.
  • Other components are:
  • Sulforaphane is an isothiocyanate derived from Cruciferae. This material is reported to inhibit development of cancer by inducing detoxifying phase 2 enzymes (Raloff, J. (1997)
  • Broccoli sprout extracts are a good source of sulforaphane.
  • Fenugreek (Tigonella foenumgraecum L. Leguminous) is an annual herb, the seeds of which contain a number of alkaloids, including trigonelline and coumarin, and the steroidal sapogenin, diosgenin. Fenugreek provides phyto estrogens. Fenugreek seeds reduce serum cholesterol levels in animals. In particular, the defatted fraction of fenugreek seed which is rich in fiber (about 54%) and contains about 5% of steroidal sapogenin, including diosgenin significantly lowers plasma cholesterol, blood glucose and plasma glucagon levels. Fenugreek is included in certain preferred compositions of this invention for control of blood glucose levels. The preferred form of fenugreek for formulations of this invention is the defatted, fiber-rich fraction.
  • Terpenes/monoterpenes and metabolites thereof can exhibit inhibition of cancer cell growth. The effect may result from inhibition of enzymes needed for cell growth. Limonene (d-limonene), narigninen, tangeritin, nobelitin, iberene and d-carcone are exemplary monoterpenes. D-limonene is a preferred monoterpene for use in the formulas of this invention.
  • Omega-3 oils are a family of oils having relatively high concentrations of omega- 3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and alpha-linolenic acid. These oils exhibit a hypolipidaemic action, especially a reduction in plasma triglycerides linked to a reduction in very-low density lipoproteins (VLDL). They also exhibit anti- inflammatory effects. Fish oils and other marine oils typically contain high levels of omega- 3-fatty acids. In general, omega-3-fatty acids are believed to reduce blood pressure, and lower cholesterol and triglyceride levels. Omega-3 fatty acids are found in a variety of naturally-occurring sources and may be provided in their acid form or as fatty acid salts or fatty acid esters.
  • omega-3-fatty acid deficiency correlates with chronic nephropathic injury.
  • EPA and DHA docosahexanoic acid
  • HDL, triglycerides and fibrinogen have also been successfully reduced by omega-3-oils.
  • Omega-3-fatty acids are included in formulas herein, at least in part, for their function in the control of blood lipid levels.
  • Flaxseed also called Linseed
  • Linseed is a nutrient rich in omega-3-fatty acids. It is a major source of alpha-linolenic acid (an omega-3-fatty acid) and lignin.
  • Ground flaxseed is a preferred source of omega-3-fatty acids over fish oils for use in compositions of this invention.
  • the use of flaxseed oils particularly in cases where the formula is being used chronically for protective or prevention benefit, avoids the potential toxicity that has been associated with long term use of fish oils.
  • Fish and marine oils or individual omega-3-fatty acids, including EPA, and ALA (and their analogous fatty acid esters) can be used in these formulations in place of flaxseed. Omega-3 fatty acids may have a protective effect against tumorogenesis.
  • EFAs Essential fatty acids
  • Fresh, poly-unsaturated vegetable oils are a major source for EFAs (linoleic, linolenic and appropriate levels of arachidonic acids). EFAs have a variety of beneficial effects including reduction of blood pressure, lower cholesterol, and lower triglyceride levels.
  • Linolenic acid is one essential fatty acid for formulations of this invention.
  • a natural source of linolenic acid is Evening Primrose Oil which also provides high levels of GLA (gamma-linoleic acid, about 9%) with minimal toxic properties.
  • Conjugated dienoic linoleic acid is a particularly preferred derivative of linoleic acid which may provide protection from oxidation that can lead to cell damage, mutation and carcinogenesis.
  • Taurine may have a protective effect on tissue and/or act as an antioxidant. Taurine has also been linked to inhibition of platelet aggregation and atherosclerotic lesions and has been found to help control blood pressure. Taurine can be provided from a variety of sources in different forms. Homotaurine, a taurine precursor, is a good bioavailable oral form to provide taurine. Compositions herein can contain taurine or homotaurine. Taurine appears to affect calcium levels and is included in osteoporosis formulas.
  • L-Carnitive is an essential co-factor of fatty acid metabolism. Faulty transport of fatty acids across mitochondrial membranes may lead to oxidative stress due to reduced lipid metabolism. Carnitive supplementation supports increases in fat utilization and oxygen uptake while decreasing plasma lactate levels and respiratory quotients. Carnitive has been shown to reduce ketones, LDL and triglycerides and increase HDL while acting as a vasodilator. L-Carnitive can be provided as N-acetyl-1-carnitive hydrochloride, the preferred form for this invention. Carnitive can be also be provided as the 1- or d,l-form as hydrochloride or other salts.
  • Sesamin/Sesamolin are constituents of sesame oil and/or sesame seeds. These components are believed to affect blood lipid levels.
  • Phytosterols including plant sterols, which comprise beta-sitosterol, campesterol, and/or stigmasterol have been shown to reduce the absorption of the LDL cholesterol component of foods in the gut on a dose dependent basis of approximately one-to-one sterols to cholesterol, while enhancing beneficial HDL to positively effect the LDL-HDL Ratio.
  • Plant sterols have been shown to primarily block harmful LDL cholesterol and admit beneficial HDL cholesterol, the levels of which can actually be elevated.
  • Plant sterols can be provided in the formulas of this invention in soy oil or by addition of individual sterol components.
  • Cholestatin III (about 62% beta-sitosterol, about 24% campesterol and about 14% stigmasterol), produced in bacterial fermentation, is preferred for use in the formulas of this invention.
  • Saw palmetto is another useful source of phytosterols.
  • Gymnemic acid the active ingredient in gymnema sylvestre, suppresses sensitivity to sugar and its absorption, thereby reducing blood glucose levels. It also restores the levels of three chondroitin sulfates which may assist in collagen repair and/or aid in angiogenesis regulation. Heparin sulphate levels are increased in diabetics while three chondroitin sulfates are decreased. Gymnema sylvestre which normalizes heparin levels could play a supporting role in the angiogenic regulation of other ingredients in this formulation, namely shark cartilage and protamine sulfate. Both are angiogenic regulators which bind to heparin.
  • Garlic/Garlic Extract Alicin and garlicin are active ingredients of garlic and garlic preparations that have been associated with control of blood glucose levels, cholesterol reduction and triglyceride reduction. These materials are included in the formulas herein for their general inhibitory activity against cancer. Dried powder and extract of Allium species (particularly garlic) can be employed to provide these functions.
  • Chlorophyll is the green pigment of plants found in both higher plants and algae. Dependent upon plant/algal source chlorophyll can contain mixtures of chlorophyll a, b, c or d. A variety of commercial chlorophyll preparations are available for use in the formulas herein. Chlorophyll is employed in the formulas herein to reduce the effect of carcinogens and inhibit carcinogenesis.
  • Calcitonin (Merck Index, Ninth Edition (1976) 1633 P.208) is a calcium regulating hormone secreted by mammalian thyroid gland that is employed in the treatment of bone disorders including osteoporosis.
  • Amylin (see U.S. patent 5,405,831) is a peptide found in amyloid deposits of diabetics (Type 2), which may be a peptide hormone having a role in storage and disposal of food as carbohydrate and fat. Amylin increases liver output of glucose, increases lactate production in muscle and decreased insulin action.
  • Calcium provided in combination with slow release sodium fluoride can inhibit development of fractures.
  • Sodium fluoride is provided in osteoporosis formulas herein. Other forms of fluoride may provide similar benefit.
  • Vitamin D3 is associated with calcium transport and bone calcium resorption. 1,25- dihydroxy vitamin D3 is reported to increase calcium absorption, lower blood pressure and increase sensitivity to insulin. Certain analogs and derivatives of 1,25-dihydroxy vitamin D3 are reported to induce minimal or no hypercalcemia. (Hypercalcemia is a significant contributing factor to the toxicity of vitamin D's.) A vitamin D derivative, 22-oxa- vitamin D3, is thus indicated to have reduced toxicity compared to vitamin D3. See: Abe, J. et al. ( ⁇ 99 ⁇ )Endrocrinology 129:832-837 and Mark, R. (1992) Pediatric Nephrology 6:345-348.
  • Vitamin D3 is also reported to be important in cell differentiation.
  • the inventor includes vitamin D3, particularly lower toxicity Vitamin D3 analogs (22-oxa- Vitamin D3) in the formulas of this invention as a calcium regulator that is a factor for promotion of collagen synthesis and more importantly for its additional function in stimulating or enhancing immune response.
  • Vitamin D3, preferably 22-oxa-vitamin D3, is also provided in osteoporosis formulas herein.
  • Vitamin K is also reported to be important in cell differentiation.
  • the inventor includes vitamin D3, particularly lower toxicity Vitamin D3 analogs (22-oxa- Vitamin D3) in the formulas of this invention as a calcium regulator that is a factor for promotion of collagen synthesis and more importantly for its additional function in stimulating or enhancing immune response.
  • Vitamin D3, preferably 22-oxa-vitamin D3 is also provided in osteoporosis formulas herein.
  • Vitamin K is a cofactor involved in blood coagulation.
  • Vitamin Kl or phylloquinone, is a preferred form of Vitamin K for use in the formulas herein.
  • Vitamin K is also reported to increase calcium binding affinity of certain proteins in bone formation.
  • Vitamin K is included in formulas of this invention to supplement any vitamin or cofactor deficiency and for its calcium-binding function which indicates usefulness in tissue regeneration and benefit for osteoporosis.
  • Melatonin a hormone, provides for inhibition of prolactin which is a stimulator of growth of breast cancer cells. Melatonin thus provides indirect inhibition of cancer cells. Betaine HC1, Pepsin and Sodium Bicarbonate Inappropriate acidity is believed to be a factor in the pathogenesis of chronic disease.
  • Mitochondrial antagonism resulting in oxidative stress is a probable mechanism.
  • Betaine HC1, pepsin and sodium bicarbonate have all demonstrated the ability to help regulate hyperacidity.
  • betaine HC1 and pepsin are among digestive enzymes often deficient in the elderly as well as chronic disease sufferers. Betaine may also effect methionine metabolism to provide protection from DNA damage due to aberrant methylation.
  • composition I which comprises: (i) antioxidants selected from:
  • a plant extract having antioxidant effect comprising bioflavanoids, particularly an extract providing a major source of proanthocyanidins, such as bilberry extract, grape seed extract, or pine bark extract.
  • Bioflavanoids of lower proanthocyanidin content for example, ginkgo biloba, can also be used to supplement major sources; combinations of plant materials and extracts can also be employed;
  • antioxidant vitamins e.g., vitamin C and/or vitamin E
  • tea polyphenols providing for additional antioxidant benefit
  • absorbable zinc preferably zinc(Krebs) to supplement dietary deficiency; which may be provided in a mineral complex
  • a neovascular regulator selected from genistein, kievitone, daidzein or a related isoflavonoid, and chondroitin sulphate or cartilage;
  • Isoflavonid may be provided as soy isolate comprising genistein and/or daidzein; Genistein is the preferred isoflavonoid; and
  • Formula II which comprises: (i) antioxidants including the bioflavanoids: pine bark extract (preferably high OPCs, e.g., 85% or greater oligomeric proanthocyanidins (OPCs)); and bilberry extract (preferably low OPCs, e.g., 25% oligomers OPCs); and the antioxidants: vitamin A and vitamin E; (ii) tea polyphenols; (iii) absorbable zinc;
  • arginine which may be provided in an amino acid complex.
  • Formula III which comprises: (i) pine bark extract, bilberry extract, grape seed extract
  • antioxidant carotenoids e.g., beta-carotene, lutein, lycopene, luteolin, zeaxanthin or apo-carotenal (beta-carotene being preferred);
  • L-arginine or amino acid complex (viii) L-arginine or amino acid complex; and (ix) a source of omega-3 fatty acids, particularly conjugated dienoic fatty acids, e.g., linoleic acid (ALA) and/or enosapentaenoic acid (EPA), a preferred source is ground flax seed;.
  • omega-3 fatty acids particularly conjugated dienoic fatty acids, e.g., linoleic acid (ALA) and/or enosapentaenoic acid (EPA)
  • ALA linoleic acid
  • EPA enosapentaenoic acid
  • Formula IV which comprises: The components of Formula III; and protamine sulphate and/or glucosamine sulphate (a preferred glycosaminoglycan and source of glycosamine, a building block for collagen synthesis); vitamin D3, preferably derivatives thereof which induce little or substantially no hypercalcification (e.g., 22-oxa-vitamin D3); and branched amino acids.
  • protamine sulphate and/or glucosamine sulphate a preferred glycosaminoglycan and source of glycosamine, a building block for collagen synthesis
  • vitamin D3 preferably derivatives thereof which induce little or substantially no hypercalcification (e.g., 22-oxa-vitamin D3)
  • branched amino acids branched amino acids
  • Formula IV The components of Formula IV and quercitin; Saw palmetto; vitamin B12 and folic acid (or optionally vitamin B-complex); absorbable potassium and selenium; alpha-lipoic acid (also called thiotic acid); and allicin (or garlic extract);.
  • Formula 5 A which comprises the components of Formula 5 where the antioxidant carotenoids are a mixture of beta-carotene and lutein.
  • Formula 5B which comprises the components of Formula 5 which contains a mixture of chondroitin sulphate, protamine sulphate and shark cartilage and where the antioxidant carotenoids are a mixture of beta-carotene and lutein.
  • Formula VI which comprises:
  • Formula 6A comprises the components of Formula 6 and contains a mixture of chondroitin sulphate, protamine sulphate, glucosamine sulphate and optionally shark or animal (e.g., bovine) cartilage.
  • Formula 6B comprises the components of Formula 6 and contains a mixture of the monoterpenes limonene and naringinen and a mixture of the carotenoids beta-carotene, lutein and lycopene.
  • Formula VII which comprises the components of Formulas VI, A or B and absorbable chromium; resveratol; kaempferol; sesamin; melatonin; and coenzyme Q, particularly coenzyme Q 10 (CoQ10).
  • Formula 7 A comprises the components of Formula 7 and contains a mixture of chondroitin sulphate, protamine sulphate, glucosamine sulphate and a cartilage preparation (shark and/or bovine cartilage).
  • Formula 7B comprises the components of Formula 7 and contains a mixture of genistein and kievitone.
  • Formula VIII which comprises: The components of Formulas VII, 7 A or 7B and
  • Gymnema sylvestre biotin; garlicin; chlorophyll; glutathione; and a source of taurine.
  • Formula 8 A comprises the components of Formula VIII and contains a mixture of carotenoids including beta-carotene, lutein, lycopene, and luteolin.
  • Formula 8B comprises the components of Formula VIII and contains a mixture of monterpenes including limonene, naringinen, and tangeritin.
  • Formula IX which comprises The components of Formulas VIII, 8 A or 8B and cinnamon extract; absorbable copper; indole-3-carbinol; fenugreek seed (preferably defatted powder);
  • N-acetylcysteine N-acetylcysteine
  • pectin e.g., citrus or apple pectin
  • betaine HC1 betaine HC1 and pepsin.
  • Formula 9A comprises the components of Formula IX containing a mixture of monoterpenes: limonene, naringenin, tangeritin and nobelitin.
  • Formula 10A comprises the components of Formula X and contains a mixture of monoterpenes including limonene, naringinen, tangeritin, nobiletin, and iberene.
  • Formula 10B comprises the components of Formula X wherein the source of omega-3 fatty acids is a fish oil.
  • Formula XI which comprises:
  • Formula 11A comprises the components of Formula XI and contains the mixture of carotenoids beta-carotene, lutein, lycopene, luteolin, and apo- carotenal.
  • Formula 1 IB comprises the components of Formula XI and contains a mixture of apple and citrus pectins.
  • Formula XII comprises the components of Formulas XI, 11A or 1 IB and: hesperiden; rutin; taxifolin; morin; absorbable strontium; gamma-linoleic acid; glutamine; and dried mushroom or mushroom extract, e.g., shitake or rieshi.
  • Formula 12A comprises the components of Formula X and contains a mixture of monoterpenes including limonene, naringinen, tangeritin, nobiletin, iberene, and d-carvone.
  • Formula XIII comprises the components of Formulas XII and 12A and denonidin; chrysin; perlargonidin; caffeic acid; absorbable silicon; and glyzzeryn (or licorice extract)
  • Formula 13 A comprises the components of Formula XIII and contains a mixture of genistein and daidzein.
  • nutrient and therapeutic formulas for use in the treatment of female cancers including hormone-dependent cancers are provided.
  • Female cancers include those cancers that occur only in women or which are more prevalent in women, including breast and ovarian cancer as well as cancer of the colon.
  • Specific formulas for the treatment of female cancers include:
  • a source of proanthocyanidins and/or bioflavanoids e.g., pine bark extract, bilberry extract, etc.
  • bioflavanoids e.g., pine bark extract, bilberry extract, etc.
  • a neovascular regulator e.g., genistein, cartilage, etc.
  • vitamin C e.g., genistein, cartilage, etc.
  • vitamin E e.g., genistein, cartilage, etc.
  • vitamin A e.g., beta-carotene
  • Formula XV which comprises the components of formula XIV and selenium; folic acid; omega-3/omega-6 fatty acids (flax seeds or fish oil); and soy isolate containing phytoestrogens and/ or phytosterols (phytoestrogens can be replaced with soy isoflavones, such as genistein or daidzein).
  • Formula XVI which comprises the components of formula XV and melatonin; lycopene; and shark or bovine cartilage.
  • Formula XVII which comprises the components of formula XVI and limonene; arginine; and conjugated dienoic linoleic acid.
  • Formula XVIII which comprises the components of formula XVII and curcumin; niacin; and naringenin.
  • the nutrient and therapeutic formulas of this invention useful in ameliorating cancer can be combined in certain applications for the treatment of cancer in females with hormone replacement formulas or drugs and or formulas or drugs for the treatment of osteoporosis.
  • N-acetylcysteine zinc, estrogenic soy components (isoflavones), soy saponins, and magnesium,
  • Osteo III Oseto II with: vitamin B6, and sodium bicarbonate.
  • Osteo IV Osteo III with : sodium fluoride, 1-lysine, and vitamin K.
  • Osteo V Osteo VI with: strontium, chromium, ipriflavone, and boron.
  • the listed osteoporosis formulas can be combined with any of the cancer protective or therapeutic formulas.
  • osteoporosis formulas can themselves be employed for protection from or amelioration of the symptoms and conditions of osteoporosis.
  • Preferred osteoporosis formulas for used in the absence of the cancer formulations herein include the components listed in Osteo I-V along with a source of proanthocyanidin or bioflavonoid (pine bark extract, bilberry extract, tea polyphenols, etc.) and a source of neovascular regulatory and/or promoter of collagen synthesis (e.g., genistein, cartilage, etc.).
  • Formulas 1-18 are optionally combined with aspirin or NSAIDS (non-steroid anti-inflammatories, including but not limited to acetaminophen, ibuprofen, with the priviso that recommended dosages of NSAIDS are employed) and may optionally be combined with DHEA (dehydroepiandrosterone).
  • NSAIDS non-steroid anti-inflammatories, including but not limited to acetaminophen, ibuprofen, with the priviso that recommended dosages of NSAIDS are employed
  • DHEA dehydroepiandrosterone
  • Red Wine Extract a powerful proanthocyanidin-containing extract can also be employed in the above formulas in place of, or in addition to, other proanthocyanidins.
  • Sulforaphane, an isothiocyante that can be provided in extracts of broccoli sprouts can be combined with any of Formulas I - XVIII to provide inhibition of carcinogenesis.
  • Creatine phosphate and eugenol have antioxidant activity and can be employed in formulas of this invention to provide additional protection against oxidative stress and cell damage.
  • Phosphatidylcholine particularly polyunsaturated phosphalidyl choline, can be added to any of the formulas herein to provide control of the blood lipid levels.
  • All of the above specific formulas can be combined with cellular antioxidants including glutathione peroxidase, superoxide dismutase and/or catalayze. All of the above specific formulas can be combined with fruit and/or grain fiber.
  • the formulas of this invention can optionally include nutrients, vitamins and minerals other than those specifically listed to supplement particular nutritional deficiencies of given individuals, for example, chromium, iron, or other mineral may be provided or its concentration increased to supplement a given deficiency. Similarly, a particular vitamin or amino acid deficiency can be supplemented.
  • a given formulation can be adapted for sensitivities or allergies of a given individual.
  • a number of the components of formulas herein can be obtained from natural sources. Isolated major active ingredients can be recombined with extract obtained from the natural source to provide minor components that may enhance function of the major ingredient, e.g., purified genistein can be combined with soybean extract for enhanced effect.
  • Components that enhance or facilitate desirable enzyme activity e.g., lysyl oxidase (an enzyme which participates in collagen synthesis); nitric oxide inhibitors, other antioxidant carotenoids or flavonoids, additional antihyperlipoproteinemics, including probucol and blood thinning agents, e.g., heparin can be combined with any of the formulas listed above.
  • Cellular antioxidants such as the enzymes: superoxide dismutase and catalyze or thiols, including glutathione peroxidase, can be included in any of specific formulas listed above.
  • L-carnitine (which may be in the form of L-acetyl carnitine or L-propionyl carnitive) can be combined with any of the specific formulas above.
  • Treatment using the compositions of this invention can be combined with hormone therapy and or hormone supplementation, including estrogenic hormone therapy or supplementation, thyroid hormone therapy or supplementation, treatment or supplementation with human growth hormone (HGH) and/or treatment or supplementation with DHEA (dehydroepiandrosterol).
  • hormone therapy and or hormone supplementation including estrogenic hormone therapy or supplementation, thyroid hormone therapy or supplementation, treatment or supplementation with human growth hormone (HGH) and/or treatment or supplementation with DHEA (dehydroepiandrosterol).
  • the formulas of this invention can also be combined with appropriate growth factors, growth factor inhibitors and growth factor binding agents including, among others, fibroblast, epidermal, interleuken transforming and platelet-derived growth factors, agents that bind hyaluronic acid and/or collagen.
  • appropriate growth factors, growth factor inhibitors and growth factor binding agents including, among others, fibroblast, epidermal, interleuken transforming and platelet-derived growth factors, agents that bind hyaluronic acid and/or collagen.
  • the formulas of this invention can be used in combination with immune suppression of T-lymphocytes.
  • antioxidants and/or preservatives such as BHT (Butylated hydroxytoluene), BHA (Butylated hydroxyanisole), ethoxiquin and diphenyl phenylenediamine.
  • BHT Butylated hydroxytoluene
  • BHA Butylated hydroxyanisole
  • ethoxiquin diphenyl phenylenediamine.
  • the amount of each component employed in the different compositions of this invention is sufficient to provide the desired therapeutic effect(s) or nutritive effect(s), as discussed herein, to an individual and avoid toxicity with continuing regular dosing. Because compositions of this invention can have multiple components with similar functionality, the effective amount of any given component needed to provide a given level of function in a given composition will depend on the quantities of other functionally similar or otherwise related components to be included in the composition.
  • Table 2 provides a summary of certain biochemical functions of components that are useful in cancer-protective and cancer-therapeutic formulas of this invention. A single component may provide more than one of the listed biological functions in a given composition. Table 2 provides a list of exemplary components of the formulas of this invention providing a preferred range of amounts of individual components that can be combined in the formulas of this invention. The amounts listed in Table 2 are average daily adult dosages. Biological functions associated with osteoporosis are not listed.
  • the cancer-preventative and therapeutic formulas of this invention comprise components that (1) have antioxidant function to control oxidative stress and prevent cell damage, (2) promote and/ or stimulate collagen synthesis to provide healthy tissue and inhibit metastasis and recurrence, are (3) neovascular regulators which control angiogenesis and function to limit blood supply to cancers, (4) regulate blood lipid, particularly lipoprotein (a), levels, (5) decrease cell/tissue acidity and promote pH balance, (6) supplement dietary deficiencies, non-absorption, cachexia or nutrient spillage, (7) inhibit or prevent aberrant methylation, (8) stimulate or enhance immune response or cell differentiation, (9) control blood glucose levels, (10) lower homocysteine levels or (11) have other antitumor or anticancer activity.
  • One or more of the functionalities listed in Table 2 can be provided in the compositions of this invention by art-known equivalents including equivalents from natural sources and/or drug equivalents.
  • compositions of this invention can be provided in a variety of nutrient and dosage forms including pills, tablets, capsules, lozenges, powders, solutions, suspensions, injection dosage forms and the like.
  • Compositions of this invention can be administered to individuals orally, intravenously, and by various forms of injection and various forms of absorption (e.g., dermal, sublingual).
  • Active ingredients of the formulas of this invention can be combined with excipients, fillers, buffering agents and the like to prepare desired dosage forms.
  • Generally preferred dosage forms are those appropriate for oral administration. In cases of use for cancer therapy, the optimum mode of administration can depend upon the type of cancer.
  • the formulas of this invention that are useful in the treatment and prevention of the various disease conditions discussed above combine a number of related ingredients.
  • the therapeutic and preventative compositions of this invention are based at least in part on the inventor's recognition of similarities in etiology of the various cancers.
  • the inventor considers that the development, growth and metastasis of malignancies, is at least in part, caused by or exacerbated by oxidative stress and tissue destruction associated with oxidative damage.
  • the inventor considers that in each of the disease conditions and symptoms, for which formulas are provided herein, that stimulating and or promoting collagen synthesis is an important factor in prevention and treatment, in this regard, the various disease conditions discussed herein also relate in part aberrant tissue growth, for example due to lack of proper growth factors or lack of growth factor inhibitors.
  • individuals with cancer also suffer from the effects of deprivation of adequate nutrient, vitamin, cofactor and mineral supplies and particularly from inadequate supplies of nutrients, cofactors and the building blocks needed for restoration of the collagen matrix which is necessary for regeneration and healing of tissue in general.
  • compositions of this invention are believed to derive unique and unexpected benefits from complementary and synergistic interactions between the various formula components acting together upon the various symptoms and conditions associated with the various diseases and disorders discussed herein.
  • the success of these compositions in the treatments described is, at least in part, attributable to the multi-factor strategy employed to balance nutrient and metabolic deficiencies and to control oxidative stress, while promoting or stimulating cell and tissue repair or healing and/or collagen matrix repair, and inhibiting angiogenesis.
  • a broad effective dose range for individual active components of the formulas of this invention.
  • the broad dose range given in the table provides guidance regarding approximate minimal effective amounts of given components from any source and guidance for dosage of equivalents.
  • the maximum dosages listed are estimates based generally upon what is known in the art concerning the individual components listed. The maxima listed may merely be based on an estimate of maximum amount that can be practically provided in a daily oral dosage form. Dosages can be readily adapted by those of ordinary skill in the art for use of alternate forms or sources of the components listed or for use of functional equivalents. Dosages can be readily adapted for desired dosing schedules and to match individual needs or problems of a given patient by those of ordinary skill in the art.
  • U.S. Patent application 08/018,273, filed February 4, 1998, which is incorporated in its entirety by reference herein relates to nutrient and therapeutic formulations for treatment of cardiovascular disease and the complications of diabetes.
  • the formulas therein combine antioxidants, neovascular regulators and other components having particular benefits for cardiovascular disease and diabetes complications.
  • This patent application provides exemplary formulations including certain of the components herein and provides additional guidance for appropriate dosage. Formulas of this invention can be adapted for treatment of diabetics having cancer using components and dosages provided in this U.S. application.
  • Table 2 provides a summary of the general biological functions of most components that are believed to be beneficial for the treatment of cancer. This listing provides the inventor's current understanding of the functions provided by components included in the preferred composition and provides guidance for the choice of alternative components with similar functionality. The inventor, however, does not wish to be bound by the specific functional correlations listed in these tables or by proposed functionality of individual activity.
  • the etiology of the diseases and conditions discussed herein is complex and a given component of a formula of this invention may have several different effects.
  • the component listed in the table is itself a mixture, for example, pine bark extract is a combination of naturally occurring compounds. In these cases, different components of the listed mixtures may contribute to different functions listed in Table 2.
  • compositions of this invention specifically ameliorate cancer.
  • diagnosis and symptoms of various cancer conditions are understood in the medical arts and a variety of methods are known in the art to evaluate the severity and extent of the conditions.
  • Exemplary sources of certain components of the formulas herein are as follows:
  • Bilberry extract as a dry hydroalcohol extract containing anthocyanosides corresponding to 25% (by weight)of anthocyanidines obtained from Indena (Milan, Italy).
  • Grape Seed Extract (Leucocyanidins) (90-100%) OPCs) can be obtained from Indena (Milan, Italy).
  • Pine Bark Extract (OPC 90%) can be obtained from Euromed (Barcelona, Spain).
  • Green tea polyphenols (95%, min. 75% catechins, low caffeine) can be obtained from TSI, International, Inc. (New York, NY).
  • N-Acetyl-1-cysteine (99%), L-carnitive base (Product No. 18-1870-00), CoQIO (ubidecarenone), l-(+)-ascorbic acid, riboflavin (USP, FCC, Water CAS 7732-18-5 max 1.5%), pyridoxine hydrochloride (USP, FCC), and vitamin B 12 (USP) were obtained from
  • Vitamin B12 cyanocobalamine can be diluted in inactive filler to give a 1% by weight mixture.
  • Acetyl-R-carnitive is available from several manufacturers.
  • Taurine (98.5% min.) and folic acid (USP) were obtained from Seltzer Chemicals, Inc. (Carlsbad, CA). Homotaurine is available from several manufacturers.
  • Linoleic Acid (High Purity, 99% min) can be obtained from Spectrum Quality Products (Gardena, CA). Lipoic Acid (99.8%) and protamine sulphate (USP) were obtained from Maypro
  • Lutein is provided in a nutrient composition "FloraGlo" Lutien (Trademark, Kemin Industries, Des Moines, IA) comprising 5% by weight lutein and 0.22% zeaxanthin.
  • This material is in beadlet form and also comprises vegetable oil, natural vitamin E (as a preservative), rosemary, natural citric acid, gelatin, sucrose and starch. See U.S. Patent
  • Chondroitin sulphate as the sodium salt produced by the Strandberg method from beef trachea can be obtained from Weinstein Nutritional Products (Irvine, CA).
  • Chromium picolinate “Chromax” can be obtained from Nutrition 21 (San Diego, CA). Calcium (Krebs)22%, Zinc (Krebs) 30% and Magnesium (Krebs) were obtained from Nutrition 21 (San Diego, CA).
  • Potassium citrate (NF granular) complying with USP, FCC and FAO/WHO Food additive specifications can be obtained from Archer Daniels Midland.
  • Isolated soy protein (“Supro” HD90, Trademark) can be obtained from Protein Technologies International (St. Louis, MO). Isolate soy protein products from this source are reported to typically contain (in mg/g protein) 0.15 to 0.72 mg daidzein, 0.48 to 1.51 mg genistein, 0.05 to 0.26 glycitein with a total isoflavone content of 0.68 to 2.49 mg (aglucone units adjusted for molecular weight).
  • Vitamin E d-alpha-tocopheryl acetate (natural source, powder) can be obtained from
  • Flax seed powder containing about 23 mg of alpha-linolenic acid (omega-3-fatty acid) per 100 grams powder can be obtained from Honeyville Grain Inc. (Salt Lake City, UT).
  • Fenugreek seed powder can be obtained from Botanicals International (Long Beach, CA).
  • Ginkgo biloba L. powder extract about 26% flavonglycosides and Gymnema sylvestre powder can be obtained from Motherland International Inc. (Chino, CA).

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Abstract

La présente invention concerne des compositions nutritives et thérapeutiques destinées au traitement des symptômes et des pathologies du cancer. Les compostions de cette invention renferment un mélange d'antioxydants, des composants qui améliorent la qualité et la synthèse du collagène, des composants qui régulent les lipides sanguins, du glucose et/ou de l'insuline, ainsi que des taux faibles d'homocystéine. Par ailleurs, ces compositions fournissent une supplémentation en nutriments (vitamines, minéraux et cofacteurs) pour parer aux déficits et permettre ainsi de rétablir et de maintenir une fonction biochimique normale. Le formulations anticancéreuses, en particulier celles qui sont élaborées pour traiter les cancers féminins, peuvent être associées à d'autres composants présentant un avantage contre l'ostéoporose.
EP99938977A 1998-08-04 1999-08-03 Compositions nutritives et therapeutiques pour le traitement du cancer Withdrawn EP1100517A1 (fr)

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