WO2004064725A2 - Compositions a administration orale et methodes permettant le traitement des effets secondaires des rayons - Google Patents

Compositions a administration orale et methodes permettant le traitement des effets secondaires des rayons Download PDF

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Publication number
WO2004064725A2
WO2004064725A2 PCT/US2003/039341 US0339341W WO2004064725A2 WO 2004064725 A2 WO2004064725 A2 WO 2004064725A2 US 0339341 W US0339341 W US 0339341W WO 2004064725 A2 WO2004064725 A2 WO 2004064725A2
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Prior art keywords
radiation
acid
vitamin
flavonoid
oral composition
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PCT/US2003/039341
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English (en)
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WO2004064725A3 (fr
Inventor
Richard A. Rosenbloom
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The Quigley Corporation
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Priority to AU2003297856A priority Critical patent/AU2003297856A1/en
Publication of WO2004064725A2 publication Critical patent/WO2004064725A2/fr
Publication of WO2004064725A3 publication Critical patent/WO2004064725A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • 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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • the present invention relates to oral compositions and methods for reducing, treating, and at least partially prevent radiation injury.
  • Radiation injury may range from less serious injuries such as radiation dermatitis to more serious injuries such as those causing vomiting, bone marrow failure, intestinal death and/or • instant incineration.
  • Such injuries or damage may be caused by radiation emitted from x-rays such as those used in diagnostic equipment, ⁇ -rays such as .those emitted from radioactive materials or from numerous other sources.
  • U.S. Patent No. 5,543,140 to Nakai et al discloses a method of inhibiting or and at least partially preventing radiation injury by administering interleukin-1- ⁇ derivatives.
  • Nakai et al uses an interleukin-1- modified by replacing the Asn at the 36 position with Asp, and replacing the Cys at the 141 position with Ser.
  • the modified interleukin-1- derivative is preferably produced using recombinant DNA techniques, which, are complicated and burdensome.
  • the potential adverse side effects of the modified interleukin-1- ⁇ derivatives are not well known.
  • U.S. Patent No. 5,767,092 to Koezuka et al. discloses a composition, which may be therapeutically or prophylactically useful in promoting bone marrow cell proliferation and protecting human bone marrow cells against radiation damage.
  • the composition disclosed in Koezuka et al. contains ⁇ -galactosylceramide.
  • radiation may cause other injuries in addition to damage to bone marrow cells and thus this composition has limited applicability.
  • an oral composition that, when ingested, will reduce, treat, prevent at least one adverse effect of radiation exposure, such as radiation injury.
  • the present invention relates to an oral composition for reducing or treating radiation injury.
  • the oral composition includes at least one flavonoid, at least one non-flavonoid antioxidant, and an acceptable carrier for an oral composition.
  • the present invention relates to a method of orally administering a composition for the reduction, treatment or prevention of at least one adverse effect of ionizing radiation.
  • a composition that includes at least one flavonoid, at least one non-flavonoid antioxidant, and an acceptable carrier for an oral composition, is orally administered to a mammal at risk for radiation exposure, to a mammal being exposed to radiation, or to a mammal who has already been exposed to radiation, to reduce, treat, or at least partially prevent at least one adverse effect of ionizing radiation.
  • an " acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • the term "safe and effective amount” refers to the quantity of a component, which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • the specific "safe and effective amount” will vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
  • ionizing radiation refers to any form of radiation that has enough energy to knock electrons out of atoms or molecules, thereby creating ions.
  • ionizing radiation includes proton radiation, alpha radiation, beta radiation, x-ray radiation, gamma radiation and neutron radiation.
  • Ionizing radiation may further include cosmic radiation that penetrates the Earth's atmosphere from space and which consists mainly of protons, alpha particles, and heavier atomic nuclei. Positrons, mesons, pions, and other exotic particles can also be found in ionizing radiation.
  • Alpha and beta particles and gamma rays can come from natural sources or can be technologically-produced. Natural radiation comes from cosmic rays, naturally occurring radioactive elements found in the earth's crust (uranium, thorium, etc.), and radioactive decay products such as radon and its subsequent decay products. In addition to these natural sources, radiation can come from such wide-ranging sources as hospitals, research institutions, nuclear reactors and their support facilities, certain manufacturing processes, and facilities involved in nuclear weapons production. Radiation can further be a result of a nuclear power plant accident, a nuclear attack by a nuclear or "dirty" bomb, and/or an accidental nuclear material leakage.
  • Adverse effects of ionizing radiation may include injury or damage to any part of the human body caused by exposure to radiation.
  • Such injury or damage may include radiation dermatitis, bone marrow cell damage, intestinal damage, and symptoms or conditions such as cancer, and DNA mutation that may be caused either directly or indirectly, by radiation exposure.
  • radiation injury as it is used in this application does not include sunburn and, preferably, refers to injury caused by ionizing radiation.
  • compositions and methods of the present invention may be employed to treat radiation injury resulting from exposure to one or more of proton radiation, fluoroscopic radiation, certain forms of ultraviolet radiation, alpha radiation, beta radiation and gamma radiation.
  • the one or more adverse • effects of radiation being reduced, treated or prevented using a method and/or a composition of the present invention is caused by one or more of alpha and beta particle radiation, gamma ray radiation and x-ray radiation.
  • the invention is particularly useful for persons who are, or will be, engaging in activities involving high risk of radiation exposure.
  • the invention can be employed to treat persons exposed to radiation as a result of a radiation attack, a nuclear accident, radiation from diagnostic instruments and therapeutic radiation used to treat, for example, cancer.
  • the various compositions and methods of the present invention are employed to reduce,
  • the compositions and methods of the present invention may be caused by exposure to therapeutic radiation, such as, for example, radiation therapy used in cancer treatment.
  • the present invention relates to an oral composition that is administered to a mammal before, during, or after exposure to ionizing radiation.
  • the mammal is a human.
  • the safe and effective amount of the oral composition will vary depending on such factors as' the person being treated, the particular mode of administration, the activity of the particular non-carrier ingredients employed, the age, body weight, general health, sex and diet of the person, the time of administration, the rate of excretion, the particular combination of ingredients employed, the total content of the non-carrier ingredients of the oral composition, and the severity of the radiation injury or expected radiation exposure. It is within the skill of the person of ordinary skill in the art to account for these factors to provide a suitable dosage and treatment regimen based on the dosage and treatment regimen for a standard 70 kg adult, described below.
  • compositions of the present invention include at least one flavonoid.
  • Flavonoids are small organic compounds having a phenyl benzopyrone structure. They are found in the leaves, fruits, seeds, stems, or flowers of all vascular plants. Citrus fruits are a prominent source of flavonoids, over 4000 of which have been identified as deriving from plant sources. On average, the daily Western diet contains about one gram of mixed flavonoids.
  • the flavonoids may have radioprotective effects. Most flavonoids have an antioxidant effect. Also, flavonoids have the property of protecting certain cells and tissues, for example ischemic tissue and hypoxic tissue.
  • flavonoids included in the composition may be determined by factors such as therapeutic activity, toxicity, bioavailability, solubility or dispersability, among others.
  • flavonoids include, without limitati n ⁇ flavonones, flavanols, anthocyanidins, proanthocyanidins, procyanidolic oligomers, biflavans, rutinosides, hydroxyethylrutinosides, and leucoanthocyanins.
  • flavonoids include compounds derived from known flavonoids, which compounds retain at least some of the desired activity of the flavonoid from which it is derived.
  • flavonoids suitable for use in the present invention include, without limitation, 1,2,3,6-tetra-o-gallyol- ⁇ -d-glucose; 2'o-acetylacetoside; 3,3 ',4-tri- o-methyl-ellagic acid; 6,3',4'-trihydroxy-5,7,8-trimethoxyflavone; 6-hydroxy- luteolin; 6-hydroxykaempferol-3,6-dimethyl ether; 7-o-ac ⁇ tyl-8-epi-loganic acid; acacetin; acetoside; acetyl trisulfate quercetin; amentoflavone; apigenin; apiin; astragalin; avicularin; axillarin; baicalein; brazilin; brevifolin carboxylic acid; caryophyllene; chrysin-5,7-dihydroxyflavone; chrysoeriol; chrys
  • the flavonoid used in the composition of the present invention may also preferably include one or more curcu inoids.
  • curcuminoids include, without limitation, curcumin (diferuloylmethane), desmethoxycurcumin (hydroxyci ⁇ namoyl feruloylmethane), and/or bis-desmethoxycurcumin (dihydroxydicinnamoyl methane) (see Drug Analysis by Chromatography and Microscopy, p. 169, Ann Arbor Science Inc., 1973). These compounds may be purchased from commercial sources or isolated from turmeric. Methods for isolating curcuminoids from turmeric are known, (see Janaki and Bose, An Improved Method for the Isolation of Curcumin From Turmeric, J. Indian Chem.
  • curcuminoids for use in the present invention can be prepared by synthetic methods. Curcuminoids possess antioxidant properties and also have anti- inflammatory, anti-tumor and other valuable properties. More preferred flavonoids are quercetin, quercetrin, myricetin, kaempferol, rutin, green tea extract, and myrecetrin. These compounds may have some anti- inflammatory activity and/or may help stabilize cell membranes in combination with a relatively low toxicity, both of which activities may be beneficial in the treatment of radiation injury. The preferred flavonoids may provide additional beneficial effects in the composition and method of the present invention.
  • some of the flavonoids may act as radical scavengers to decrease the concentration of free radicals such as hydroxyl radicals.
  • the flavonoid quercetin may also have an antioxidative and anticlastogentic effect.
  • quercetin may partially prevent the decrease of endogenous ascorbic acid (vitamin C) in bone marrow after gamma-ray irradiation.
  • some flavonoids may enhance their radioprotective effects by acting as radical scavengers to reduce the concentration of free radicals such as hydroxyl radicals.
  • the flavonoid is used in an amount of about 5 to about 3000 mg, more preferably about 7 to about 2000 mg, and still more preferably the amount is about 10 to about 1500 mg, all amounts being on a per dose basis.
  • Quercetin when included, is used in an amount of about 400 to about 2500 mg, more preferably about 500 to about 2000 mg, and most preferably about 600 to about 1800 mg, all amounts being on a per dose basis.
  • curcumin is preferably added in an amount of about 1 to about 50 mg, more preferably about 5 to about 35 mg, and most preferably about 10 to about 20 mg, all amounts being on a per dose basis.
  • the non-flavonoid antioxidant may be a single compound or material or may be formulated using two or more compounds and/or materials.
  • Compounds and materials which may be used as non-flavonoid antioxidants are those which exhibit antioxidant activity when administered to a patient in a safe and effective amount, and which do not react with one or more of the ingredients of the composition thereby causing a substantial loss of activity of one or more of the ingredients.
  • the non-flavonoid antioxidants are those that occur naturally in the human body and/or are materials obtained from plants or animals, or derivatives thereof.
  • the non-flavonoid antioxidant preferably exhibits additional beneficial effects such as an anti-cancer effect, protection of DNA against ionizing radiation and other chemical mutagens, and fighting bad breath, nausea and indigestion.
  • Non-flavonoid antioxidants include, but are not limited to, ascorbic acid (vitamin C), its esters, for example, ascorbyl palmitate, and other compounds having vitamin C activity such as those generally called Ester-CTM that are disclosed in U.S. Patent Nos. 4, 822, 816 and 5,070, 085; vitamin A and its esters, for example, vitamin C
  • vitamin C ascorbic acid
  • esters for example, ascorbyl palmitate
  • other compounds having vitamin C activity such as those generally called Ester-CTM that are disclosed in U.S. Patent Nos. 4, 822, 816 and 5,070, 085
  • vitamin A and its esters for example, vitamin A
  • Non-flavonoid antioxidants include vitamin A and its esters, vitamin C and its esters, vitamin E and its esters, chlorophyllin, and lipoic acid.
  • Chlorophyllin and its salts may extracted from alfalfa extract or from silkworm feces. Chlorophyllin and its salts may also be purchased from common commercial sources, such as the Aldrich Chemical Company of St. Louis, MO.
  • the non-flavonoid antioxidant component is preferably added in the amount of about 0.1 to about 2000 mg, more preferably about 1 to about 1000 mg, and most preferably about 100 to about 750 mg.
  • ascorbyl palmitate is preferably added in the amount of about 1 to about 1500 mg, more preferably about 100 to about 1000 mg, and most preferably about 250 to about 750 mg.
  • chlorophyllin is preferably added in the amount of about 1 to about 1000 mg, more preferably about 50 to about 500 mg, and most preferably about 100 to about 350 mg.
  • mixtures of two or more non-flavonoid antioxidants are employed in the composition of the present invention.
  • the non-flavonoid antioxidants may also be used in the form of their pharmaceutically acceptable salts. This form may be preferred in some cases to increase solubility or dispersability, to reduce adverse side effects, etc.
  • Structurally similar derivatives of one or more of these compounds, which exhibit antioxidant activity when administered in the oral compositions of the present invention may also be employed.
  • structurally similar derivatives is meant derivatives that exhibit antioxidant activity and contain at least one significant, common structural element with the compound or material from which it is derived.
  • the non-flavonoid antioxidant component of the composition is used in an amount effective to provide significant antioxidant activity when administered to a patient in the composition of the present invention.
  • a physician will determine the actual dosage and duration of treatment that will be most suitable for an individual and can vary with the age, weight and response of the particular individual.
  • the dosages given herein are exemplary of the average case of a standard 70 kg individual. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the non-flavonoid antioxidants used in the composition of the present invention are preferably selected not only for their antioxidant activity, but also based on other beneficial effects that particular compounds may provide.
  • a racemic mixture of ⁇ -lipoic acid not only has a strong antioxidant activity but also has a recycling effect on vitamins C and E.
  • lipoic acid can function in both lipid and non-lipid environments.
  • vitamin E and its esters may contribute to an anti-cancer effect and may have beneficial effects on the skin and is thus is also a preferred non-flavonoid antioxidant.
  • Vitamin C and its esters are not only non- flavonoid antioxidants, but also exhibit a strong combinatorial effect with vitamin E and its esters when used together.
  • vitamin E and its esters, and vitamin C and its esters can mutually reinforce one another by a mechanism in which one nonflavonoid antioxidant (reducing agent) acts as a regenerator for the oxidized form of the other.
  • Vitamin A retinol or retinyl ester
  • Vitamin A may also have anti-cancer effects.
  • vitamin A may also enhance the physiological mechanism of cell differentiation, inhibit malignant transformation, suppress tumor promotion and directly act against neoplastic cells.
  • Vitamin A is also a fat-soluble material and thus is useful due to this additional beneficial property.
  • Vitamin A may be used in its ester forms, such as vitamin A palmitate, because the ester forms of vitamin A may be less irritating to the stomach.
  • the amount of vitamin A in the oral formulation is about 6000 to about 14,000 IU, more preferably about 7000 to about 13,000 IU, and most preferably the amount of vitamin A is about 8000 to about 12,000 IU, all amount being on a per dose basis.
  • carotenoids such as ⁇ -carotene are included in the composition of the present invention as a non-flavonoid antioxidant, the have shown beneficial effects for the present application, such as enhancement of immune response, inhibition of mutagenesis and/or reduction of induced nuclear damage.
  • Carotenoids can also protect against photo-induced tissue damage. Some carotenoids, including ⁇ - carotene, quench highly reactive singlet oxygen under certain conditions and can block free radical-mediated reactions.
  • the amount of the carotenoid used in the oral formulation is about 1,000 to about 25,000 IU, more preferably the amount is about 4,000 to about 23,000 IU, and most preferably the amount-is about 5,000 to about 20,000 IU, all amounts being on a per dose basis.
  • lipoic acid preferably ⁇ -lipoic acid, most preferably DL- ⁇ -lipoic acid
  • it is used in an amount of about 50 to about 500 mg, more preferably about 75 to about 300 mg, and most preferably the amount is about 100 to about 250 mg, all amounts being on a per dose basis.
  • Vitamin E is added in an amount of about 100 to about 700 IU, more preferably about 150 to about 650 IU, and most preferably about 200 to about 600 IU, all amounts being on a per dose basis.
  • the non-flavonoid antioxidant used in the composition of the present invention may include one or more antioxidant enzymes.
  • the antioxidant enzymes useful in the present invention are those capable of scavenging radicals, promoting radical scavengers or partially preventing radical formation.
  • the preferred antioxidant enzymes useful in the present invention include superoxide dismutase, catalase, glutathione peroxidase and methionine reductase. Other antioxidant enzymes with activities similar to those mentioned explicitly above may also be used.
  • one or more of the antioxidant enzymes may act in combination with one or more of the antioxidant compounds in the composition to, for example, scavenge free radicals and/or at least partially prevent cell damage in the skin.
  • the antioxidant enzyme is preferably added in the amount of about 1 to about 3000 eg, more preferably of about 100 to about 2500 meg, and most preferably, an amount of about 375 to about 1875 meg, all amounts being on a per dose basis. These amounts apply to, for example, superoxide dismutase.
  • the oral composition includes at least one of quercetin, vitamin E (alpha tocopherol), and superoxide dismutase.
  • a preferred optional ingredient of the oral composition is green tea extract, which contains flavonoid compounds such as (-)-epigallocatechin-3-gallate, (-)- epigallocatechin-3-gallate, (-)-epigallocatechin and/or (-)-epicatechin.
  • Green tea extract also contains non-flavonoid antioxidants and other compounds that are also believed to be beneficial. Studies (see Elmets, C. A. et al, J. Am. Acad. DermatoL, 44 (3); 425-32, March, 2001) have shown that green tea extract is effective in inhibiting erythema and at least partially preventing Langerjans cells from some forms of ultraviolet radiation damage.
  • the green tea extract When green tea is added to the formulation in the form of an extract, the green tea extract is added in the amount of about 1 to about 100 mg, more preferably the amount is about 5 to about 50 mg, and most preferably the amount of green tea extract is about 10 to about 30 mg, with all amounts being on a per dose basis.
  • Particularly preferred oral compositions contain at least one of lipoic acid, preferably ⁇ -lipoic acid, most preferably DL- ⁇ -lipoic acid, and green tea.
  • the oral composition of the present invention may also optionally include those compounds that regulate cell differentiation and/or cell proliferation.
  • Such compounds may be selected from suitable compounds that have this activity.
  • Suitable compounds that regulate cell differentiation and/or cell proliferation are those that do not induce significant, adverse side effects when administered to a patient in amounts that regulate cell differentiation and/or cell proliferation, and which do not react with one or more of the ingredients of the composition resulting in a substantial loss of activity of one or more of the ingredients.
  • the compounds for regulating cell differentiation and/or cell proliferation are those that occur naturally in the human body, or derviatives thereof, and/or materials obtained from plants or animals, or derviatives thereof, which may be administered to humans without significant, adverse side effects in the amounts used.
  • the compounds that regulate cell differentiation and/or cell proliferation used in the present invention inhibit or at least partially prevent cell differentiation or cell proliferation.
  • the compounds that regulate cell differentiation and/or cell proliferation accomplish at least one of the following: maintenance of cellular homeostasis and normal cell metabolism, regulation of cell differentiation, induce certain cancer cells to differentiate into normal cells, preferably by working in combination with vitamin A, maintenance of the epidermal permeability barrier, inhibition of cancer cell differentiation, and inhibition of cancer cell proliferation.
  • ⁇ -galactosidase assay to detect inhibitors of tyrosine kinase and tyrosine phosphatase which control or regulates cellular growth, proliferation and differentiation using ⁇ -galactosidase EFC activity.
  • inactive fragments of galactosidase, enzyme acceptor (EA) and enzyme donor (ED) complement to form active enzyme. Binding of an ED-conjugated peptide to an antibody inhibits complementation, while unlabeled peptide displaces the ED-conjugate. This results in increased ⁇ -galactosidase activity that is detected subsequently either chemiluminescence or long wavelength fluorescent substrates.
  • Another exemplary method for screening compounds that regulate cell differentiation and/or cell proliferation is available from the Commercial Ventures &
  • the method can be used to screen for cancer drugs and other drugs that inhibit or promote cell growth, cell death or cell differentiation for diseases involving ERb action, including prostate, breast and ovarian cancer, neurological disorders, osteoporosis and cardiovascular disease.
  • the effect of any compound on ER-beta regulated cell growth/cell death/cell cycle arrest is determined by adding the compound to culture cells expressing the ⁇ eceptor and measuring alteration in expression levels of ER-beta regulated genes.
  • Exemplary compounds that regulate cell differentiation and/or cell proliferation are vitamin D 3 , vitamin D 3 analogs, compounds that may be converted or metabolized into vitamin D 3 in the human body, and metabolites thereof.
  • Exemplary compounds that may be converted or metabolized into vitamin D 3 include common cholesterols illustrated below.
  • the cholesterol illustrated below may be converted into Provitamin D when a hydrogen is removed from the number 7 carbon, which then forms a double bond with the number 8 carbon, in the second, or 'B' ring of the cholesterol molecule.
  • the cholesterol is 'oxidized' (that is, an electron is removed with the hydrogen atom), so that the double bond is a consequence of 2 mutually shared electrons between carbons 7 and 8.
  • Provitamin D maybe converted to Vitamin D 3 by the action of ultraviolet light through human skin.
  • the B ring of the sterol molecule is opened.
  • Cholecalciferol which is Vitamin D 3
  • Exemplary vitamin D 3 analogs include 1(S), 3(R)-dihydroxy-20(R)-(l-ethoxy- 5-ethyl-5-hydroxy-2-heptyn-l-yl)-9, 10-seco-pregna-5(Z), 7(E), 10 (19)-triene.
  • Exemplary vitamin D 3 metabolites include 1, 25-dihydroxyvitamin D 3 .
  • pharmaceutically acceptable salts of the compounds that regulate cell differentiation and/or cell proliferation may be employed.
  • the compound that regulates cell differentiation and/or cell proliferation is vitamin D 3 .
  • the compound that regulates cell differentiation and/or cell proliferation is used in an amount effective to regulate cell differentiation and/or cell proliferation when orally administered to a patient in the oral composition of the present invention.
  • the amount of vitamm D 3 used in the oral formulation is about 50 to about 2500 IU, more preferably about 250 to about 2000 IU, and most preferably the amount of vitamm D 3 used is about 500 to about 1500 IU, all amounts being on a per dose basis.
  • Preferred oral compositions contain one or more of vitamin A, vitamin E acetate, vitamin D 3 and ascorbyl palmitate.
  • the composition includes both vitamins A and D 3 , they are preferably fo ⁇ nulated together in a com oil dispersion.
  • each cubic centimeter (cc) or milliliter (mL) of the corn oil dispersion contains about 500,000 to about 2,000,000 IU of vitamin A and about 50,000 to about 200,000 IU of vitamin D 3 .
  • every milliliter of the corn oil contains about 800,000 to about 1,200,000 IU of vitamin A and about 80,000 IU to about 120,000 IU of vitamin D 3 .
  • the composition used in the invention contains about 1,000,000 IU and about 100,000 IU of vitamins A and D 3 , respectively.
  • the composition of the present invention may further include selenium and/or a compound containing selenium.
  • Selenium is known to be able to prolong the lifespan of a person exposed a severe dose of harmful radiation, e.g. as a result of the Chernobyl accident, and to reduce the potential occurrence of leukemia and other malignancies in that person.
  • Selenium may be included in the composition of the present invention in such an amount that when the composition is administered to a human according to a method ' of the present invention, the daily dosage should be between 5 micrograms and 200 micrograms.
  • selenium may be included in the composition in such an amount that when the composition is administered to a human according to a method of the present invention, the daily dosage should be between 10 micrograms and 100 micrograms.
  • An excessive amount of selenium and/or selenium compound in the composition of the present invention may render the composition toxic.
  • the oral compositions of the present invention may further include an organic germanium compound such as carboxy ethyl sesquioxide of germanium or spirogermanuium.
  • Organic germaniums are known to protect human cells from radiation damage. For example, controlled experiments haye also shown that Ge-132 reduces mutations in E. coli due to ⁇ -radiation by twenty-fold (see Mochizuki and Kada, Antimutagenic effect of Ge-132 on y-ray-induced mutations in E. coli B/r WP2 trp-. 42(6) Int. J. Radiat. Biol, 653-59 (1982)).
  • Germanium oxide has been shown to reduce the mutation rate in Salmonella typhimurium induced by Trp-P-2 (3-amino-l- methyl-5H-pyrido(4,3-b)indole), by 40-67 folds (see Kada, Mochizuki, and Miyao, Antimutagenic Effects of Germanium- Oxide on Trp-P-2 Induced Frameshift Mutations in Salmonella Typhimurium TA98 and TA 1538, 125 Mutation Research, 145-51 (1984)).
  • One or more organic germaniums may be included in the composition of the present invention in such an amount that when the composition is administered to a human according to a method of the present invention, the daily dosage of the germanium compound will be between 25 milligrams and 500 milligrams.
  • the organic germanium may be included in the composition in such an amount that when the composition is administered to a human according to a method of the present invention, the daily dosage of the germanium compound will be between 50 milligrams and 200 milligrams, and, most preferably, about 100 milligrams.
  • Siberian ginseng may also be added to the oral compositions of the present • invention in the form of one or more of Siberian ginseng roots, Siberian ginseng powder, or extracts thereof which may contain one or more of the active ingredients of the Siberian ginseng.
  • Siberian ginseng (Eleutherococcus senticosus) has been shown to have restorative effects on the functions of bone marrow damaged by exposure to radiation.
  • the active ingredients of Siberian ginseng generally include eleufherosides A, B, Bl, C, D and E; triterpenoid saponins; eleutherans A, B, C, D, E, F and G; and equivalents thereof.
  • Siberian ginseng extract may be included in the composition of the present invention in such an amount that when the composition is administered to a human according to a method of the present invention, the daily dosage of the Siberian ginseng extract will be between 25 milligrams and 500 milligrams.
  • Siberian ginseng extract may be included in the composition in such an amount that when the composition is administered to a human according- to a method of the present . invention, the daily dosage of Siberian ginseng extract is between 50 milligrams and 150 milligrams. In another embodiment the daily dosage of the Siberian ginseng extract will be about 100 milligrams. If Siberian ginseng is used in a different form in the composition of the present invention, a skilled person should be able to adjust the amount being used accordingly based on the dosages for the Siberian ginseng extract given above.
  • compositions of the present invention may also include Korean ginseng (panax ginseng) and/or American ginseng (panax quinquefolius), in the form of roots, powder or an extract.
  • Korean and/or American ginseng may prompt recovery of hemateikon and splenal weight and cause improvement of thrombocyte cells.
  • This product is commercially available as Korea Insam.
  • the daily dosage for Korean and/or American ginseng is the same as for Siberian ginseng.
  • a skilled person is able to adjust the dosage of the Korean and/or American ginseng for different physical forms of administration, i.e. root, powder or extract.
  • mixtures of one or more of Siberian ginseng, Korean ginseng and American ginseng and/or extracts of one or more of these ginseng types may also be employed.
  • a preferred oral formulation includes a curcuminoid. More preferably, the curcuminoid is curcumin.
  • the non-flavonoid antioxidant comprises chlorophyllin or a pharmaceutically acceptable salt thereof.
  • compositions in accordance with the present invention contain about 200 to about 1000 IU of vitamin E in the form of alpha-tocopherol; about 100 to about 200 mg of lipoic acid; about 600 to about 1800 mg of quercetin; about 250 to about 750 mg of ascorbyl palmitate; about 10 to about 20 mg of curcumin; about 10 to about 30 mg of green tea (C&P); about 375 to about 1875 meg of superoxide dismutase; and optionally contain about 8,000 to about 12,000 IU of vitamin A palmitate; about 5,000 to about 25,000 IU of beta carotene; about 500 to about 1000 IU vitamin D 3 ; and about 100 to about 300 mg of chlorophyllin, all amounts being on a per dose basis.
  • the oral composition in accordance with the present invention may provide one or more of the following beneficial effects to a patient when orally administered in an effective amount: antioxidant properties, free radical scavenging, transition metal chelation, nitric oxide stabilization, anti-inflammatory activity, relief of pain, burning, tingling, electrical sensations and/or hyperalgesia, increased microcirculation, nitric oxide stabilization, promotion of healing of skin ulcers and lesions, protein kinase C inhibition, decreased oxidative stress, anti-inflammation, protection against radiation damage, blockage of the formation of leukotrienes, stabilization of cell membranes, and regulation of cell differentiation, cell proliferation protection of mitochondrial membranes, reduction of cell damage, especially damage to DNA molecules, and a role in the repair and regeneration process of damages cells.
  • compositions of the present invention may be formulated in any acceptable oral dosage forms including, but not limited to, capsules, tablets, lozenges, troches, hard candies, powders, sprays, elixirs, syrups, and suspensions or solutions.
  • the oral compositions of the present invention may be formulated with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable oral carrier may include, but is not limited to: (a) carbohydrates including fructose, sucrose, sugar, dextrose, starch, lactose, maltose, maltodextrins, corn syrup solids, honey solids, commercial tablet compositions including EmdexTM, Mor-RexTM, Royal-TTM, Di-PacTM, Sugar-TabTM, Sweet-RexTM, New-TabTM, (b) sugar alcohols including mannitol, sorbitol, xylitol, and (c) various relatively insoluble excipients including dicalcium phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose and other pharmaceutical tableting ingredients.
  • the pharmaceutically acceptable oral carrier may further include lactose and corn starch.
  • Lubricating agents may also be added to the tablets, including, for example, magnesium stearate, sodium lauryl sulfate and talc. Tablets may also contain excipients such as sodium citrate, calcium carbonate and calcium phosphate. Disintegrants such as starch, alginic acid and complex silicates, may also be employed. Tablets may also include binding agents such as polyvinylpyrrolidone, gelatin, PEG-8000 and gum acacia.
  • the common pharmaceutically acceptable oral carrier may further include a binder such as PEG-8000.
  • a binder such as PEG-8000.
  • lozenges are made in a 0.1 to 15 grams size to allow a suitable dissolution rate for lozenges. More preferably lozenges are made in a 1 to 6 gram size to allow a suitable dissolution rate for lozenges.
  • Dissolution time should be about 15 minutes in water bath testers at 37°C. degrees or about 30 minutes when orally dissolved as lozenges for treating a sore throat, congestion, laryngitis and mucous membrane inflammation.
  • the active ingredients may be added to PEG-8000 processed fructose; or they may be added to crystalline fructose and commercially available, sweet, direct compression products such as Mendell's Sugartab TM , SweetrexTM, or EmdexTM Other sweeteners, such as saccharin, may be included, and other optional ingredients include flavors, glidants, such as silica gel, and lubricants, such as magnesium stearate.
  • the mixture is generally kept dry and tableted soon after mixing, using conventional pharmaceutical mixing and tableting equipment.
  • the compressive force is preferably sufficient to produce maximum hardness throughout the lozenges, to preserve the dissolution rate, and to maximize the efficacy of lozenges.
  • Dissolution should occur over a sustained period of time of about 5 to about 60 minutes, and preferably about 20 to about 30 minutes.
  • the composition is preferably stored in an airtight container and in a cool dark place. Tablets and troches can be manufactured using procedures similar to those described above with minor changes in the optional ingredients.
  • the oral composition of the present invention may be formulated in liquid form, such as syrups, mouthwashes or sprays, with a solvent or dispersant such as water, or other liquids in a pharmaceutically acceptable oral carrier for delivery of the composition to a patient.
  • a solvent or dispersant such as water, or other liquids in a pharmaceutically acceptable oral carrier for delivery of the composition to a patient.
  • the oral composition may also be formulated in chewable compositions such as soft candy, gum drops, liquid filled candies, chewing gum bases and dental supplies, such as toothpastes and mouthwashes by further including fructose, sucrose, or saccharin in the composition, as needed.
  • chewable compositions such as soft candy, gum drops, liquid filled candies, chewing gum bases and dental supplies, such as toothpastes and mouthwashes by further including fructose, sucrose, or saccharin in the composition, as needed.
  • the oral composition of the invention may be formulated in capsule form with or without diluents.
  • useful diluents include lactose and dried cornstarch.
  • emulsifying and/or suspending agents may be employed in the suspensions.
  • solid compositions including one or more of the ingredients of the lozenges described above may be employed in soft and hard gelatin capsules.
  • compositions of the present invention may also be formulated into a nasal aerosol or inhalant.
  • suitable carriers may include the following ingredients: saline with one or more preservatives, absorption promoters to enhance bioavailability, fluoro carbons and/or other conventional solubilizing or dispersion agents.
  • compositions of the present invention include inositol, other B-complex vitamins, and anti- inflammatories.
  • ingredients such as sweeteners, flavorants, coloring agents, dyes, and diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof, may be included in the oral composition of the present invention.
  • the optional sweeteners which may be used in the oral composition of the present invention include, but are not limited to, saccharin, aspartame, cyclamates, acesulfame K, neohesperidin dihydrochalcone, other super sweeteners, and mixtures thereof, which may be added to the carrier in amounts sufficiently low so as not to chemically interact with the non-carrier ingredients of the oral composition.
  • the optional flavorants which may be used in the oral composition of the present invention include, but are not limited to, peppermint, peppermint-menthol, eucalyptol, wintergreen, licorice, clove, cinnamon, spearmint, cherry, lemon, orange, lime, menthol and various combinations thereof.
  • the non-carrier ingredients described above which may include the compound that regulates cell differentiation and/or proliferation, the flavonoids, nonflavonoid antioxidants, antioxidants, preferably, the flavonoids, and optionally selenium, organic germanium, Korean ginseng, American ginseng and Siberian ginseng make up from about 0.5-50% by weight of the total composition.
  • the non-carrier ingredients will make up about 1-20% by weight of the total composition. More preferably, the non-carrier ingredients make up about 2-10% by weight of the total composition.
  • the present invention relates to a method of preventing, reducing or treating at least one adverse effect of radiation by the oral administration of an amount of a composition, which includes at least one flavonoid, at least one non-flavonoid anti-oxidant, and an acceptable carrier for an oral composition.
  • the method of the present invention involves the oral administration of a composition in accordance with the present invention to a mammal that may be potentially exposed to ionizing radiation, is in the process of being exposed to ionizing radiation, or has already been exposed to ionizing radiation.
  • the mammal is a human.
  • the oral composition may be administered 1 to 10 times per day, as needed, more preferably, 2 to 6 times per day, as needed, or most preferably, 3 times per day, to a person before, during and/or after radiation expos ire.
  • 1 to 5 tablets, capsules, lozenges, or equivalents thereof are ingested by the person.
  • 1 to 2 tablets, capsules, lozenges or equivalents thereof are ingested by the person during each administration of a dose.
  • the tablets, capsules or lozenges or equivalents thereof are ingested with a fluid such as water, juice, milk, or other suitable fluids.
  • An oral composition of the present invention is described in Table 1 below. These ingredients may be mixed with a suitable amount of a pharmaceutically acceptable oral carrier as described above to form, for example, tablets for oral administration.
  • Another embodiment of the present invention provides an oral composition of as described in Table 2 below. These ingredients may be mixed with a suitable amount of a pharmaceutically acceptable oral carrier described as above to form, for example, tablets for oral administration.
  • Table 2
  • compositions of Examples 1-2 can be administered 1 to 5 times daily for the reduction, treatment or prevention of at least one adverse effect of ionizing radiation, prior to, during or after radiation exposure.

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Abstract

L'invention concerne une composition administrée par voie orale et une méthode permettant la réduction, le traitement ou la prévention d'au moins un effet secondaire des rayons ionisants chez un mammifère. La composition décrite contient au moins un flavonoïde et au moins un antioxydant autre qu'un flavonoïde, dans un véhicule acceptable pour une composition à administration orale. La méthode décrite comprend l'administration par voie orale de la composition décrite, avant, pendant ou après l'exposition aux rayons, afin de prévenir, de réduire ou de traiter au moins un effet secondaire de l'exposition aux rayons.
PCT/US2003/039341 2003-01-13 2003-12-10 Compositions a administration orale et methodes permettant le traitement des effets secondaires des rayons WO2004064725A2 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100448484C (zh) * 2005-10-31 2009-01-07 张力元 医用射线防护喷剂
CN101830877A (zh) * 2010-02-08 2010-09-15 中国人民解放军军事医学科学院放射与辐射医学研究所 阿曼托双黄酮及其衍生物在预防及治疗辐射损伤中的用途
AU2006233256B2 (en) * 2006-10-30 2012-01-19 Armaron Bio Pty Ltd Improved flavonols
EP2717693A4 (fr) * 2011-06-06 2015-06-24 Us Cosmeceutechs Llc Traitements de la peau contenant des esters de pyrroloquinoléine quinone (pqq) et leurs procédés de préparation et d'utilisation
WO2016088116A1 (fr) * 2014-12-05 2016-06-09 University Health Network Utilisation d'antioxydants comme agents radioprotecteurs
CN106581019A (zh) * 2016-12-13 2017-04-26 新疆维吾尔自治区维吾尔医药研究所 类叶升麻苷在制备抗焦虑药物中的用途
US10183026B2 (en) * 2016-04-08 2019-01-22 The Secretary, Department Of Atomic Energy Method of adjuvant treatment with chlorophyllin containing therapeutic preparation including for radioprotection of normal tissues during radiation therapy and kit therefor
WO2021072555A1 (fr) * 2019-10-18 2021-04-22 Lifelock Solutions Inc. Compositions et procédés pour le traitement et/ou la prophylaxie du diabète et d'autres maladies
CN113633759A (zh) * 2020-09-29 2021-11-12 中国农业大学 用于提高超氧化物歧化酶的活性和/或热稳定性的制剂及其应用
CN115209892A (zh) * 2019-10-28 2022-10-18 科拉医疗股份有限公司 用于减轻或预防氧化应激损伤的制剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5709868A (en) * 1995-09-20 1998-01-20 Perricone; Nicholas V. Lipoic acid in topical compositions
US6051602A (en) * 1998-03-16 2000-04-18 The Procter & Gamble Company Methods for regulating skin appearance

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5709868A (en) * 1995-09-20 1998-01-20 Perricone; Nicholas V. Lipoic acid in topical compositions
US6051602A (en) * 1998-03-16 2000-04-18 The Procter & Gamble Company Methods for regulating skin appearance

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100448484C (zh) * 2005-10-31 2009-01-07 张力元 医用射线防护喷剂
AU2006233256B2 (en) * 2006-10-30 2012-01-19 Armaron Bio Pty Ltd Improved flavonols
CN101830877A (zh) * 2010-02-08 2010-09-15 中国人民解放军军事医学科学院放射与辐射医学研究所 阿曼托双黄酮及其衍生物在预防及治疗辐射损伤中的用途
EP2717693A4 (fr) * 2011-06-06 2015-06-24 Us Cosmeceutechs Llc Traitements de la peau contenant des esters de pyrroloquinoléine quinone (pqq) et leurs procédés de préparation et d'utilisation
AU2012268427B2 (en) * 2011-06-06 2016-02-04 Dermaforce Holdings, LLC Skin treatments containing pyrroloquinoline quinone (PQQ) esters and methods of preparation and use thereof
US10799441B2 (en) 2011-06-06 2020-10-13 Pcr Technology Holdings, Lc Skin treatments containing pyrroloquinoline quinone (PQQ) esters and methods of preparation and use thereof
WO2016088116A1 (fr) * 2014-12-05 2016-06-09 University Health Network Utilisation d'antioxydants comme agents radioprotecteurs
US10183026B2 (en) * 2016-04-08 2019-01-22 The Secretary, Department Of Atomic Energy Method of adjuvant treatment with chlorophyllin containing therapeutic preparation including for radioprotection of normal tissues during radiation therapy and kit therefor
CN106581019A (zh) * 2016-12-13 2017-04-26 新疆维吾尔自治区维吾尔医药研究所 类叶升麻苷在制备抗焦虑药物中的用途
WO2021072555A1 (fr) * 2019-10-18 2021-04-22 Lifelock Solutions Inc. Compositions et procédés pour le traitement et/ou la prophylaxie du diabète et d'autres maladies
CN115209892A (zh) * 2019-10-28 2022-10-18 科拉医疗股份有限公司 用于减轻或预防氧化应激损伤的制剂
CN113633759A (zh) * 2020-09-29 2021-11-12 中国农业大学 用于提高超氧化物歧化酶的活性和/或热稳定性的制剂及其应用

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