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WO2001070029A1 - Composition et methodes de traitement, de diminution, et de prevention de maladies et troubles cardio-vasculaires avec des polymethoxyflavones - Google Patents

Composition et methodes de traitement, de diminution, et de prevention de maladies et troubles cardio-vasculaires avec des polymethoxyflavones Download PDF

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Publication number
WO2001070029A1
WO2001070029A1 PCT/US2001/008395 US0108395W WO0170029A1 WO 2001070029 A1 WO2001070029 A1 WO 2001070029A1 US 0108395 W US0108395 W US 0108395W WO 0170029 A1 WO0170029 A1 WO 0170029A1
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WO
WIPO (PCT)
Prior art keywords
quercetin
hydroxy
limocitrin
ether
mammal
Prior art date
Application number
PCT/US2001/008395
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English (en)
Inventor
Najla Guthrie
Elzbieta Maria Kurowska
John A. Manthey
Robert M. Horowitz
Original Assignee
Kgk Synergie
United States Department Of Agriculture
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/528,488 external-priority patent/US6987125B1/en
Application filed by Kgk Synergie, United States Department Of Agriculture filed Critical Kgk Synergie
Priority to EP01920415A priority Critical patent/EP1278417A1/fr
Priority to AU2001247471A priority patent/AU2001247471A1/en
Priority to CA002403548A priority patent/CA2403548A1/fr
Publication of WO2001070029A1 publication Critical patent/WO2001070029A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention relates lo compositions and methods for the prevention, reductiotA, and/or treatment of cardiovascular diseases with synthetic and naturally occurring poiymelhoxyflavone compounds derived, some of which are deiived from limocitiin and quercelin.
  • lirnocilrin and queicelin derivatives: liniocilrin-3,7, ⁇ '-lrinieth'leiher (5-hydroxy-3,7,S,3',4'-penlamelltoxy ⁇ avo ⁇ e) limocilrin-3,5,7,4'-lelramelhylether (3,5,7,8,3'4'-he>;amelhoxyflavone) limoci ( rin-3,5,7 1 4'- ( etraelhylether (S,3'-dimelhoxy-3,5,7,4'-letraelhoxyflavone) lirnocilrin 3,7 -trime(hslethcr-5-acetate quercelin telramethylelher (5-hydroxy -3,7,3', 4'-lelramelhQxyflavone) quercelin
  • bui not limited lo. of naturally occurring polymethoxyflavones for ihe purposes of the pi esent invention include: 3 ,S,6,7,8,3',4'-heptamcthoxyflavone nobileti (5,6,7,8.3',4'-hcxamethoxyfla ⁇ One) tangeretin (5,6,7,8,4'-pen.amethoxyflavone)
  • Limocitrin derivatives are a group of citrus-derived flavonoids that are naturally occurring in the plant or are chemically synthesized. 5-desmethylsinesetin is chemically synthesized form of sinensetin (Tarum. .H. et al.. Phytochemistry II, 2283-2288, 1972). . Sinensetin occurs in trace levels in mandarin orange leaves (Sugiyama, S. et a],. Chem. Pharm. Bull., Volume 4 1 , 7 14-719. 1993), and in orange and mandarin peel. Flavonoids are p ⁇ lyphenolic compounds that occur ubiquitously in foods of plant origin. The major dietary sources of flavonoids are ⁇ egetables.
  • Flavonoids have been demonstrated to be the most potent dietary a ⁇ tioxidants and in light of the large dietary consumption, flavonoids make a major contribution to the antioxidant potential of the human diet.
  • the main food sources of flavotiols and flavones are black tea, onions, apples, herbs, and spices such as cloves and black pepper (Hertog. M.G.L.. et al, J. Agric. Food Chem., Volume 40, 2379-2383 , 1992).
  • Flavonol and flavone intake was inversely associated with mortality f.om coronary heart disease and to a lesser extent with incidence of first my ocardial infarction. These effects were independent of known risk factors for coronary heart disease such as serum cholesterol, body mass index, blood pressure, smoking and intake of antioxidant vitamins, alcohol, and fat. Flavo ⁇ ol and flavone intake (mainly quercelin) was also inversely associated with stroke risk (Hertog et al., Lancet, Volume 324, 1007- 1 0 ! I , 1993 ; Kelt et al., Arch. Inter. Med., Volume 1 54, 637-642. 1 996).
  • Atherosclerosis In the United States, the complications of atherosclerosis account for about one half of all deaths and for about one third of deaths in persons between 35 and 65 years of age. Atherosclerosis, or the developments of atheromatous plaques in large and medium-sized arteries, is the most common form of arteriosclerosis. Many factors a re associated with the acceleration of atherosclerosis, regardless of the underlying primary pathogenic change, for example, age, elevated plasma cholesterol level, high arterial blood pressure, cigarette smoking, reduced high-density lipoprotei ⁇ (HDL) cholesterol level, or family history of premature coronary artery disease.
  • HDL high-density lipoprotei ⁇
  • the t isk of death Horn coronary artery disease has a continuous and graded relation to total serum cholesterol levels greater than 1 80 g/dl (Stamler et al,, JAMA, Volume 256, 2823 , 1986). Approximately one third of adults in the United States have levels that exceed 240 mg/dl and, therefore, have a risk of coronary artery disease that is twice that of people with cholesterol levels lower than 180mg/dl. Acceleration of atheiosclev ⁇ sis is principally correlated with elevation of LDL.
  • LDL cholesterol levels are then classified as borderline-high risk ( 130- i 59 mg/dl) or high risk (> 160 mg/dl). Dietary treatment is recommended for those patients with high-risk els who have two or more additional risk factors. Drug treatment is recommended for all patients with LDL levels greater than 1 S9 mg/dl and for those patients with LDL cholesterol levels between 159 and 189 mg/dl who have t ⁇ vo or more additional risk factors. .
  • drugs that have been used to reduce serum cholesterol levels are cholestyrami ⁇ e, colestipol. clofibrate, gemfibrozil, and lovaslatin.
  • Flavonoids inhibit platelet aggregation and adhesion (Fran el et al., Lancet, Volu e 34 1 , 1 103- 1 104. 1993). Flavonoids antagonize tliro b ⁇ xa ⁇ e formation and increase platelet cyclic AMP levels. This is important because flavonoids additional! scavenge free radicals and theii antioxidant actions participate in their a ⁇ tithrombotic action (Gryglewski et al.. Biochem. Pharmacol., Volume 36, 3 17-322. 1987). Drug treatment is recommended for patients ith thrombosis and ischemic heart disease.
  • the medical therapy comprises pharmaceutical drugs including, but is not limited to, aspirin (anti-platelet aggregating agents) and the combined use of beta-adrenergic blocking agents (e.g.propranonol, nad ⁇ l ⁇ l, timol ⁇ l, etc.), nitrates (e.g , nitrogh ccrin) and calcium channel blockers (e.g.. verapamil. nifedipine, diltiazem. etc.).
  • aspirin anti-platelet aggregating agents
  • beta-adrenergic blocking agents e.g.propranonol, nad ⁇ l ⁇ l, timol ⁇ l, etc.
  • nitrates e.g , nitrogh ccrin
  • calcium channel blockers e.g. verapamil. nifedipine, diltiazem. etc.
  • compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases and disorders whei ein an effective amount of a composition having at least one limocitrin and/or quercetin derivative is administered to reduce, prevent or treat a mammal at high risk for or suffering from a cardiovascular disease.
  • Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one flavonoid is administered to reduce, prevent or treat a mammal at high risk for or suffering from a cardiovascular disease.
  • a further object of the present invention is to provide compositions and methods for the reduction, prev ention, and/or eatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin. quercetin derivative, tocotrienol, and mixtures thereof is administered to reduce, prev ent or treat a mammal at high risk for or suffering from a cardiovascular disease.
  • a still fui ther object of the present invention is to prov tde compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having al least one naturally occurring polymcthoxyaflavone is administered to reduce, prevent, or treat a mammal at high risk for or suffering from a cardiovascular disease.
  • Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one naturally occurring polymethoxyflavone, tocotrienols, and mixtures thereof, is administered to reduce, prevent or treat a mammal at high risk far or suffering from a cardiovascular disease.
  • a further object of the present invention is to provide compositions and methods for the i eduction, prev ention, and/or ti eatment of caidiovascular diseases or disorders wherein an effective amount of a composition having at least one a t ⁇ c ⁇ tricnol, flavonoid, and mixtures thereof, is administered to reduce, prevent, or treat a mammal at high risk for or suffering from a cardiovascular disease,
  • a still further object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin derivative, quercetin derivative, naturally occurring poiymethoxyaflavone, tocotrienol, and mixtures thereof, is administered to a mammal to lower serum cholesterol, apo-B, and/or LDL cholesterol.
  • Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin derivative, quercetin derivative, naturally occurring p ⁇ h methoxyaflav ⁇ e, tocotrienol, and mixtures thereof, in combination with a cholesterol-lowering drug, is administered to a mammal to lower serum cholesterol, apo-B, and/or LDL cholesterol
  • Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin derivative, quercetin derivative, naturally occurring poiymethoxyaflavone, tocotrienol, and mixtures thereof, in combination with a pharmaceutical drug including anti-platelets agents, beta-adrenergic blocking agents, nitrates or calcium channel blockers.
  • the present invention relates to the use of at least one of limocitrin derivative, quercelin derivative, polymethoxyflav ⁇ ne. tocotrienol and mixtures thereof alone or in combination with at least one cholesterol-lowering drug for the treatment of cardiovascular diseases or disorders.
  • Limociii in occurs in the peel of lemon as limocit ⁇ i ⁇ -3-Ogluc ⁇ side, and can be produced from the 3-glycoside by enzymatic and acid hydrolysis (Horowitz et al,. J. Org. Chem., Volume 25. 21 885-21 887, 1 960) or by a chemical synthesis procedure such as reported by Dryer et al., Tetrahedron, Volume 20, 2977-2983, 1 64.
  • Administering polymethoxylatedflavone of the invention . to a mammal results in a reduction in the amount of substances in the blood which contribute to CAD. such as for example apoB, LDL, cholesterol, etc; preferably reduction of the serum, plasma, or whole blood concentration or in vivo amounts of these substances.
  • concentration or in vivo amount of these substances is reduced to normal lev els typically found in such a mammal.
  • the polymethoxylatedflavone of the present invention are administered in amounts which produce little qr no cytotoxicity, more preferably where no cytotoxicity is produced.
  • a polymethoxylatedflavone is a flavone substituted with methoxy groups, preferably at least 2, more prefeiably at least 3 , more preferably at least 4, more preferably 4-8, and most preferably 4-7 methoxy groups and optionally substituted by one or oie hydroxy groups, preferably 1 -3, and more preferably 1 -2 hydroxy groups.
  • limocitrin-3 ,7,4'-trimethylether (5-hydroxy-3,7,8,3',4'-pentamethoxyflavone); limocitrin- 3,5.7,4'-telramethylether (3 ,5,7,8,3'4'-hexamethoxyflavone); and limocitrin-3,7,4'- trimethylether- -acetate.
  • tile compounds in these gioups include 5-des elhylnobilelin (5-hyd ⁇ oxy-
  • tocotrienol compounds useful in the present invention include, but are not limited to. are alpha-tocotrien ⁇ l, gamma-tocotrienol, delta-tocotrienol, and mixtures thereof.
  • cholesterol-lowering drugs for the treatment of cardiovascular diseases or disoiders include, but are not limited to, are cholestyramine, c ⁇ lestipol. cl ⁇ fibrate. gemflbr ⁇ zil or lovastati ⁇ ,
  • the methods of the present invention may be administered to any mammal, Most preferably, the polymethoxylatedflavone useful in the methods of the present invention are administered to humans.
  • the polymethoxylatedflavone may be formulated into a pharmaceutical preparation by a conventional method usually employed in the art,
  • compositions of the present invention may be formulated into pharmaceutical preparations for administration to mammals for reduction, prevention, and treatment of cardiovascular diseases.
  • cardiovascular disease treatable b> the compositions of the present invention include hypercholesterolei ⁇ ia, hyperlipidemia. atherosclerosis, thrombosis, m ocardial infarction, etc
  • the polv methoxylatedflavone can be administered by a variety of routes, including oral, transdermal. rectal, intrarticular, intravenous, and intramuscular introduction.
  • routes including oral, transdermal. rectal, intrarticular, intravenous, and intramuscular introduction.
  • the amount of the polymethoxylatedflavone actually administered ought to be determined in light of various relavent factors including the condition to be treated, the chosen route of administration, the age and weight of the individual paiieni. and the seventy of the patient ' s condition, and therefore, the doses given herein should not be construed to limit the scope of the invention in any way.
  • the polymethoxylatedflavone useful in the present invention may be administered in a pharmaceutically or physiologically acceptable carrier.
  • the pharmaceutically or physiologically acceptable carrier is any solvent with which the polymethoxylatedflavone is compatible and which is non-toxic to individuals treated at the amounts administered.
  • a variety of delivery systems for pharmacological compositions may be employed including, but not limited to, liposomes and emulsions.
  • the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Formulations suitable for oral administration include liquid solutions of the active compound or compounds dissolved in a diluent such as, for example, saline, water, PEG 400; solid preparations such as capsules or tablets, each containing a predetermined amount of the active agent as solids, granules, gelatins, suspensions, and/or emulsions,
  • a diluent such as, for example, saline, water, PEG 400
  • solid preparations such as capsules or tablets, each containing a predetermined amount of the active agent as solids, granules, gelatins, suspensions, and/or emulsions
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions which contain buffers, antioxidants. and preservatives.
  • the formulations may be in unit dose or multi-dose containers.
  • Dosages administered are any effective amount of a polymethoxylatedflavone which will, when given for the treatment, prophylactically or therapeutically. reduce or prevent cardiovascular diseases by reducing levels of substances which contribute to cardiovascular diseases to normal or near normal levels in the blood or in vivo.
  • substances which contribute to . cardiovascular diseases include but are not limited to ap ⁇ protein B, low density lipoproteins, very low density lipoproteins, cholesterol, etc.
  • Fatient dosages for oral administration of flavonoids range from about 1 - 1000 mg/day, commonly 1 -500 mg/day, and typically 1 - 100 mg/day. Stated in terms of patient with a 70 kg body weight, usual dosages range from about 0.01-15 mg/kg/day, commonly from about 0.01 -7.0 mg/kg/day, and typically from about 0.01 -2.0 mg/kg/day,
  • Patient dosages for oral administration of synthetic flavonoid analogues range from about 2000-5000 mg/day. commonly from about 1 000-2000 mg/day. and typically from about 500-1500 mg/day.
  • Patient dosages for oral administration of limocitrin derivatives, quercetin derivatives, naturally-occurring polymethoxyflavones. and tocotrienols range from about 1 - 1000 mg/day, commonly about 1 -500 mg/day, and typically from about 1 - 100 mg/day ,
  • Patient dosages for oral administration of synthetic limocitrin derivatives range from about 200-500 mg/day, commonly about 1000-2000 mg/day, and typically from about 500- 1500 mg/day.
  • Patient dosages for oral administration of naturally-occurring polymethoxyflavones range from about 1- 1000 mg/day, commonly from about 1 -500 mg/day, and typically from about 1 - 100 mg/day. Stated in terms of patient body weight, for about 70 kg body weight, usual dosages range from about 0,01 - 15 mg/kg/day, commonly from about 0.01 -7.0 mg/kg/day, and typically from about 0.01 -2,0 mg kg/day.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the anti-prohferative and antioxidative effects of the disease being treated.
  • composition can be administered by injection directly into a tissue, often in a depot or sustained release formulation.
  • EXAMPLE 1 Limocitrin derivatives, quercetin derivatives, naturally occurring polymethoxyflavones, and tocotrienols were tested for cholesterol lowering activity in HepG2 cells.
  • Confluent HepG2 cells were preincubatcd for 24 hours in a lipoprotein-free medium (Minimum Essential Medium (MEM), Life Technologies, Burlington, Canada) in which the fetal bovine serum (Life Technologies, Burlington, Canada) was replaced by bovine sei um albumin (BSA, Life Technologies, Bui li gton. Canada ) to inhibit cell proliferation and to stimulate synthesis of cholesterol-containing lipoproteins.
  • MEM Minimum Essential Medium
  • BSA bovine sei um albumin
  • limocitrin derivatives quercetin derivatives, naturally occurring polv methoxv flavones, or tocotrienols (See Table 1) al the highest concentrations sustaining about 100% ⁇ 10% cell viability, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphen.vltetrazolium bromide (MTT) viability assay.
  • the lest compounds were added to the cell culture medium after solubilization in dimethyl sulfoxide (DMSO) and filter sterilized.
  • DMSO dimethyl sulfoxide
  • the final concentration of DMSO in culture media did not exceed 0.3% by volume, to prevent anv effects of DMSO on apo B metabolism.
  • concentrations' of solvent were added to all treatment media and to a control medium (without tested compounds).
  • concentration of the LDL structural protein, apo-B was measured by ELISA.
  • the competitive Elisa assay kit for determination of human apo B (Ortho Diagostics, LaJoIIa, CA) measures medium apo B concentrations w ithi-n the range 0.4-0,0 1 ⁇ g/mL.

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Abstract

L'invention concerne des compositions et des méthodes de traitement, de diminution et/ou de prévention de maladies et de troubles cardio-vasculaires. Des individus présentant un risque élevé de développer ou d'avoir une maladie ou un trouble cardio-vasculaire peuvent être traités au moyen d'une dose efficace d'un polyméthoxyflavone, notamment des dérivés de limocitrine, des dérivés de quercétine, des polyméthoxyflavones se produisant naturellement, des tocotriénols et des mélanges correspondants de ces composés.
PCT/US2001/008395 2000-03-17 2001-03-16 Composition et methodes de traitement, de diminution, et de prevention de maladies et troubles cardio-vasculaires avec des polymethoxyflavones WO2001070029A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP01920415A EP1278417A1 (fr) 2000-03-17 2001-03-16 Composition et methodes de traitement, de diminution, et de prevention de maladies et troubles cardio-vasculaires avec des polymethoxyflavones
AU2001247471A AU2001247471A1 (en) 2000-03-17 2001-03-16 Compositions and methods of treating, reducing, and preventing cardiovascular diseases and disorders with polymethoxyflavones
CA002403548A CA2403548A1 (fr) 2000-03-17 2001-03-16 Composition et methodes de traitement, de diminution, et de prevention de maladies et troubles cardio-vasculaires avec des polymethoxyflavones

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US09/528,488 US6987125B1 (en) 1998-10-06 2000-03-17 Compositions and methods of treating, reducing and preventing cardiovascular diseases and disorders with polymethoxyflavones
US09/528,488 2000-03-17

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002087567A3 (fr) * 2001-05-02 2002-12-27 Kgk Synergize Inc Utilisation de flavones polymethoxylees afin de traiter l'insulinoresistance
US7201928B1 (en) 1999-09-21 2007-04-10 Rutgers, The State University Of New Jersey Extracts of orange peel for prevention and treatment of cancer
EP1748774A4 (fr) * 2004-05-26 2007-12-19 Kgk Synergize Inc Compositions contenant des flavonoides et des tocotrienols et methodes associees
JP2008513349A (ja) * 2005-05-24 2008-05-01 ケージーケー シナジャイズ インコーポレイテッド フラボノイドとトコトリエノールを含む機能性食品及びその方法
EP1748773A4 (fr) * 2004-05-26 2008-11-12 Kgk Synergize Inc Aliments fonctionnels comprenant des flavonoides et des tocotrienols et procedes associes
EP2010194A4 (fr) * 2006-03-15 2010-03-03 Univ Rutgers Compositions de polyméthoxyflavones hydroxylées
US7683095B2 (en) 1998-10-06 2010-03-23 The United States Of America As Represented By The Secretary Of Agriculture Compositions and methods of treating, reducing and preventing cardiovascular diseases and disorders with polymethoxyflavones
US7887852B2 (en) 2005-06-03 2011-02-15 Soft Gel Technologies, Inc. Soft gel capsules containing polymethoxylated flavones and palm oil tocotrienols
KR101340675B1 (ko) 2011-12-05 2013-12-12 대구한의대학교산학협력단 탄제레틴을 포함하는 심혈관계 질환의 예방 또는 치료용 약학 조성물
WO2014203059A1 (fr) * 2013-06-17 2014-12-24 Kgk Synergize, Inc. Compositions comprenant au moins une flavone polyméthoxylée, un flavonoïde, une liminoïde et/ou un tocotriénol utiles dans les polythérapies pour le traitement du diabète

Citations (1)

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US3867541A (en) * 1972-05-03 1975-02-18 Ralph C Robbins Compositions and methods for disaggregating blood cells

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US3867541A (en) * 1972-05-03 1975-02-18 Ralph C Robbins Compositions and methods for disaggregating blood cells

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DREYER ET AL.: "Flavonoids of citrus-VIII synthesis of limocitrol, limocitrin and spinacetin", TETRAHEDRON., vol. 20, 1964, pages 2977 - 2983, XP002944449 *
KUHNAU J.: "The flavonoids. A class of semi-essential food components: their role in human nutrition", WORLD REVIEW OF NUTRITION AND DIET, vol. 24, 1976, pages 117 - 191, XP002944495 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7683095B2 (en) 1998-10-06 2010-03-23 The United States Of America As Represented By The Secretary Of Agriculture Compositions and methods of treating, reducing and preventing cardiovascular diseases and disorders with polymethoxyflavones
US7201928B1 (en) 1999-09-21 2007-04-10 Rutgers, The State University Of New Jersey Extracts of orange peel for prevention and treatment of cancer
WO2002087567A3 (fr) * 2001-05-02 2002-12-27 Kgk Synergize Inc Utilisation de flavones polymethoxylees afin de traiter l'insulinoresistance
EP1748774A4 (fr) * 2004-05-26 2007-12-19 Kgk Synergize Inc Compositions contenant des flavonoides et des tocotrienols et methodes associees
EP1748773A4 (fr) * 2004-05-26 2008-11-12 Kgk Synergize Inc Aliments fonctionnels comprenant des flavonoides et des tocotrienols et procedes associes
JP2008513349A (ja) * 2005-05-24 2008-05-01 ケージーケー シナジャイズ インコーポレイテッド フラボノイドとトコトリエノールを含む機能性食品及びその方法
US7887852B2 (en) 2005-06-03 2011-02-15 Soft Gel Technologies, Inc. Soft gel capsules containing polymethoxylated flavones and palm oil tocotrienols
EP2010194A4 (fr) * 2006-03-15 2010-03-03 Univ Rutgers Compositions de polyméthoxyflavones hydroxylées
KR101340675B1 (ko) 2011-12-05 2013-12-12 대구한의대학교산학협력단 탄제레틴을 포함하는 심혈관계 질환의 예방 또는 치료용 약학 조성물
WO2014203059A1 (fr) * 2013-06-17 2014-12-24 Kgk Synergize, Inc. Compositions comprenant au moins une flavone polyméthoxylée, un flavonoïde, une liminoïde et/ou un tocotriénol utiles dans les polythérapies pour le traitement du diabète
US9132117B2 (en) 2013-06-17 2015-09-15 Kgk Synergize, Inc Compositions and methods for glycemic control of subjects with impaired fasting glucose
US9610276B2 (en) 2013-06-17 2017-04-04 Kgk Synergize, Inc. Compositions and methods for glycemic control of subjects with impaired fasting glucose

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AU2001247471A1 (en) 2001-10-03
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