WO2000059522A1 - Compositions et procedes pour le traitement de diabetes - Google Patents

Compositions et procedes pour le traitement de diabetes Download PDF

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Publication number
WO2000059522A1
WO2000059522A1 PCT/US2000/008957 US0008957W WO0059522A1 WO 2000059522 A1 WO2000059522 A1 WO 2000059522A1 US 0008957 W US0008957 W US 0008957W WO 0059522 A1 WO0059522 A1 WO 0059522A1
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WO
WIPO (PCT)
Prior art keywords
insulin
diabetes
cells
brickellia
treatment
Prior art date
Application number
PCT/US2000/008957
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English (en)
Inventor
Randy H. Ziegler
Original Assignee
Ziegler Randy H
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
Application filed by Ziegler Randy H filed Critical Ziegler Randy H
Priority to EP00921679A priority Critical patent/EP1169047A1/fr
Priority to JP2000609085A priority patent/JP2002541116A/ja
Priority to CA002368215A priority patent/CA2368215A1/fr
Priority to AU41964/00A priority patent/AU780233B2/en
Priority to BR0009592-3A priority patent/BR0009592A/pt
Priority to MXPA01010037A priority patent/MXPA01010037A/es
Publication of WO2000059522A1 publication Critical patent/WO2000059522A1/fr
Priority to US09/967,030 priority patent/US20020068704A1/en
Priority to US10/863,459 priority patent/US20050181076A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5085—Supracellular entities, e.g. tissue, organisms of invertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the present application concerns the field of natural products and more specifically plant extracts and compounds useful for the treatment of diabetes.
  • Diabetes mellitus a potentially devastating, complex disorder of glucose metabolism, which is currently partially controllable by insulin injections and/or drugs, is increasing in worldwide frequency.
  • diabetes In the United States over ten million persons are estimated to have diabetes.
  • the financial cost is in the many billions of dollars reflecting treatment expense and loss of productivity while the human cost in impaired function, progression to blindness, limb amputations, kidney failure and heart and vascular disease is immeasurable.
  • Type I or Juvenile Onset Insulin Dependant Diabetes Mellitus
  • Type II or Adult Onset Non-insulin Dependant Diabetes Mellitus
  • IDDM is an immune modulated version of the disease in which insulin production is impaired whereas NDDM is a disorder in which the cells fail to respond to insulin. Diabetes is recognized in the ancient literature of Egypt, China, and India.
  • the simple sugar glucose is a primary energy source for human cells
  • Glucose is required for optimal growth, development, and for maintenance of the central nervous system.
  • the brain is an avid consumer of glucose such that any significant lowering of blood glucose results in a concomitant drop in the glucose level in the brain with resulting cessation of normal brain function (coma).
  • the entry of glucose into the cells and the metabolism of the glucose within the cells are critical to sustain life in the human body.
  • Insulin a regulatory transport hormone, controls the uptake and transport of glucose into the cells either for energy production or for storage therein.
  • Glucose enters the bloodstream from the digestive system.
  • the intracellular level of glucose is too low or the blood level of glucose is too high, insulin is released to mediate the uptake of glucose by the cells for metabolism or storage, respectively.
  • the blood level of glucose is too low, other hormones mediate the release of glucose from glycogen (a starch-like storage polymer).
  • glycogen a starch-like storage polymer
  • insulin is necessary for the glucose homeostasis found in proper body metabolism.
  • the proper concentration of insulin in the blood is critical. A lack of insulin leads to coma and death from metabolic problems caused by excessive blood sugar. On the other hand, an excess of insulin results in shock caused by excessively low blood sugar. Similarly, if the cells fail to respond properly to insulin, the homeostasis is disrupted and excessive blood sugar levels result.
  • Insulin is produced within the pancreas by 1.5 million beta cells located in clusters known as the Islets of Langerhans. Insulin is a moderate sized protein composed of two chains: an alpha chain of 21 amino acids and a beta chain of 30 amino acids linked to one another by disulfide bonds.
  • Such beta cell destruction is recognized as being due to attack by several types of immune cells including NK (natural killer) cells and double negative (CD4-[W3/25+OX19+]/ CD8- [OX8+OX19+]) T-Lymphocytes.
  • the autoimmune response results in macrophage activation by the double negative T-cells, wherein activated macrophages then attack body cells.
  • double negative T-cells escape and become potentially autoreactive clones.
  • the CD8 protein expressed by the majority of NK cells, can be modulated by administration of monoclonal antibodies to reduce the incidence of diabetes.
  • the administration of poly clonal antibodies directed towards the NK cell glycolipid AGMI also prevents autoimmune Islet destruction.
  • aldosterone from the adrenal cortex, sets in motion a set of reactions at the surface of all cells of body tissues to regulate the uptake and retention of sodium and to extrude potassium.
  • Lowered serum sodium and the high serum potassium levels enhance aldosterone secretion.
  • the adrenal glands are influenced by the neurotransmitter dopamine, an adrenal suppressor and by the neurotransmitter seratonin, an adrenal stimulator; low potassium levels impact dopamine production and, therefore, alter aldosterone and cortisol secretion.
  • other factors are involved in the negative feedback of pituitary corticotropin to cortisol.
  • Atrial natriuretic peptides or sodium excreting hormones, that inhibit secretion of aldosterone, sodium chloride, potassium, and phosphorous. It has also been recognized that there is an interference with the ongoing inhibition of prolactin by dopamine from the hypothalamus as can be seen during the invasion of the pituitary stalk by pineal tumors. These factors may be involved in the immune abnormalities leading to insulin dependent diabetes or in the abnormal insulin responses of insulin independent diabetes.
  • Insulin like growth factor I (RGF-I) , is a mitogenic polypeptide that regulates cell cycle progression. IGF- I and insulin are heterotetrameric proteins that possess intrinsic tyrosine kinase activity. IGF-I actions are dependent upon binding to its own specific cell surface receptors. Both insulin and IGF-I activate insulin receptor substrate -I(IRS-l), an important multisite docking protein implicated in mytogenic signaling.
  • Activation of mytogenic pathways is magnified as a consequence of mutations in the K-ras oncogene and cell cycle associated kinases, such as pl6.
  • Insulin exerts mytogenic effects on cells by activating -the IGF-I receptor, which leads to phosphorylation of IRS-1, an important regulatory protein that mediates the growth promoting effects of insulin.
  • the tyrosine kinases are thought to be truncating the sequence of production of dopamine so that a post receptor defect is caused which has no affinity for the necessary glucocorticoid, but has affinity for the DN T-cell CD4- and CD8- proteins.
  • proteoglycin to rebalance the K+ (potassium) channel to allow a gate voltage to buildup and permit secretion of adequate amounts of aldosterone. It was also believed that a valance corrected aggregated series of polypeptides assimilated into a proteoglycan would accomplish this result.
  • Diabetes is considered to be insidious, since there is no cure known at this time.
  • Various treatments have been used to ameliorate diabetes.
  • dietetic measures have been employed to balance the relative amounts of proteins, fats, and carbohydrates in a patient.
  • diabetic conditions of moderate or severe intensity are treated by the administration of insulin.
  • prescription drugs such as "Glucoside” have been employed to rejuvenate impaired insulin production in adult onset diabetics.
  • Other drugs are used to modulate the effectiveness of insulin.
  • treatment of diabetes of either juvenile or adult onset types, have achieved only partial success.
  • a novel and useful composition for treating diabetes utilizes a steam or aqueous extract of a plant known as Brickellia californica.
  • the plant is gathered, dried, and combined with boiling water. The extract is then taken orally by a patient on a periodic basis.
  • the genus Brickellia is known to be rich in flavonoids and other secondary plant products.
  • the genus is large and many species are mentioned in folk medicine including, besides B. californica-, B. ambigens, B. arguta, B. brachyphylla, B. cylindracea, B. eupatoriodes, B. glutinosa, B. grandiflora, B. laciniata, B. lemmonii, B. oblongifolia, and B. veronicaefolia.
  • Other species of the genus appear to have some or all of the active components of B. californica.
  • Brickellia californica live plants were located and harvested.
  • Brickellia is a small to mid-sized shrub with relatively small, lobed leaves.
  • Approximately four sprigs of leaves and stems were cut from the harvested plants. Each sprig was approximately -3 inches in length.
  • the sprigs were placed in one half gallon of water and heated until boiling. Boiling continued for five minutes at which time, the extract was decanted from the container and cooled. The color of the decanted liquid was light brown.
  • the cooled extract from the Brickellia californica sprigs was administered to four adult human males ranging from 30 to 40 years of age. Each of the males suffered from diabetes. The dosage to each subject was four to five glasses per day of the extract.
  • Live Brickellia californica plants were harvested and dried.
  • the dried plant material was macerated using a mortar and pestle, transferred into a 125 ml Erlenmeyer flask and extracted with a mixture of chloroform and methanol in a ratio of 1: 1.
  • the mixture was stirred for four hours with a magnetic stirrer.
  • the extract from the flask was then filtered to remove cellulosic debris and concentrated in a "rotavap" under a vacuum to yield a crude gummy residue.
  • the residue was partitioned in chloroform and methanol to yield to two fractions labeled CHC1 3 (the more hydrophobic chloroform soluble fraction) and MeOH (the more hydrophilic methanol soluble fraction).
  • the CHC1 3 and MeOH fractions were analyzed using a Hewlett Packard 6890 gas chromatograph-mass spectrometer (GC-MS) fitted with an HP-5MS capillary column (30 meters x 250 ⁇ m x 0.25 ⁇ m).
  • the analysis conditions were as follows: initial temperature was 125 °C which was held for five minutes, followed by an increase to 275 °C at a rate of 10 °C per minute with the final temperature of 275 °C being held 15 minutes.
  • the analysis by the GC-MS of CHC1 3 fraction demonstrated the presence of a group of polar flavonoids with retention times in the range of 13-15 minutes, the presence of a group of sesquiterpenes with retention times between 16-18 minutes, and a small group of aliphatic hydrocarbons with retention times between 20- 25 minutes.
  • Analysis by GC-MS of the MeOH fraction produced similar results except that the MeOH fraction was largely free of the aliphatic hydrocarbons. It is believed that the Brickellia californica extract includes the flavonoids dihydroxykaemferol, apigenin, luteolin, myricetin and quercetin.
  • Brickellia contains these, or similar flavonoids, albeit in different proportions, and should also be effective in treatment of diabetes.
  • Experiments with diabetic test animals (rats and mice) were carried out.
  • the Brickellia extract was effective in controlling blood glucose in these model systems.
  • the administration of synthetic versions of the Brickellia flavonoids were also effective at lowering glucose levels.
  • luteolin was the most effective agent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Natural Medicines & Medicinal Plants (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Food Science & Technology (AREA)
  • Toxicology (AREA)
  • Diabetes (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
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  • Emergency Medicine (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Botany (AREA)
  • Organic Chemistry (AREA)
  • Mycology (AREA)

Abstract

L'invention concerne des produits extraits de Brickellia californica et des flavonoïdes isolés, dont l'apigénine, la lutéoline, la quercétine et dihydroxykaemférol, purifiés provenant de Brickellia californica, qui sont utiles pour le traitement de diabètes. Les produits extraits et des flavonoïdes peuvent être utilisés en alternance dans le traitement des diabètes insulinodépendant et non insulinodépendant car ces substances entraînent la baisse sensible du glucose.
PCT/US2000/008957 1999-04-05 2000-04-04 Compositions et procedes pour le traitement de diabetes WO2000059522A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP00921679A EP1169047A1 (fr) 1999-04-05 2000-04-04 Compositions et procedes pour le traitement de diabetes
JP2000609085A JP2002541116A (ja) 1999-04-05 2000-04-04 糖尿病の治療のための組成物及び方法
CA002368215A CA2368215A1 (fr) 1999-04-05 2000-04-04 Compositions et procedes pour le traitement de diabetes
AU41964/00A AU780233B2 (en) 1999-04-05 2000-04-04 Compositions and methods for treatment of diabetes
BR0009592-3A BR0009592A (pt) 1999-04-05 2000-04-04 Composição anti-diabética, e, método para tratamento de diabetes mellitus
MXPA01010037A MXPA01010037A (es) 1999-04-05 2000-04-04 Compuestos y metodos para el tratamiento de la diabetes.
US09/967,030 US20020068704A1 (en) 1999-04-05 2001-09-27 Compositions and methods for treatment of diabetes
US10/863,459 US20050181076A1 (en) 1999-04-05 2004-06-07 Compositions and methods for treatment of diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12782499P 1999-04-05 1999-04-05
US60/127,824 1999-04-05

Related Child Applications (1)

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US09/967,030 Continuation-In-Part US20020068704A1 (en) 1999-04-05 2001-09-27 Compositions and methods for treatment of diabetes

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WO2000059522A1 true WO2000059522A1 (fr) 2000-10-12

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PCT/US2000/008957 WO2000059522A1 (fr) 1999-04-05 2000-04-04 Compositions et procedes pour le traitement de diabetes

Country Status (7)

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EP (1) EP1169047A1 (fr)
JP (1) JP2002541116A (fr)
AU (1) AU780233B2 (fr)
BR (1) BR0009592A (fr)
CA (1) CA2368215A1 (fr)
MX (1) MXPA01010037A (fr)
WO (1) WO2000059522A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026561A2 (fr) * 2001-09-27 2003-04-03 Ziegler Randy H Compositions et methodes pour le traitement du diabete
EP1351679A2 (fr) * 2000-12-21 2003-10-15 The Quigley Corporation Methode et composition pour le traitement de neuropathies diabetiques
WO2003094928A1 (fr) 2002-05-06 2003-11-20 Diakron Pharmaceuticals, Inc. Compositions pharmaceutiques permettant de reduire la glycemie et les taux de cholesterol sanguin
JP2005504796A (ja) * 2001-09-06 2005-02-17 シノークス インコーポレイテッド ３−デオキシフラボノイドによるｔ−リンパ球活性化の阻害および関連療法
WO2005065667A2 (fr) * 2003-12-29 2005-07-21 President And Fellows Of Harvard College Compositions pour traiter ou prevenir l'obesite et les troubles de resistance a l'insuline
WO2007005453A2 (fr) * 2005-07-01 2007-01-11 President And Fellows Of Harvard College Compositions destinees au traitement ou a la prevention de l'obesite et de troubles lies a la resistance a l'insuline
US7410659B2 (en) 2002-11-06 2008-08-12 The Quigley Corporation Methods for the treatment of peripheral neural and vascular ailments
US7914823B2 (en) 2000-12-21 2011-03-29 Prophase Labs, Inc. Method and composition for the topical treatment of diabetic neuropathy
US8287677B2 (en) 2008-01-31 2012-10-16 Kimberly-Clark Worldwide, Inc. Printable elastic composite
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008007452A (ja) * 2006-06-28 2008-01-17 Ajinomoto Co Inc 膵β細胞保護剤
JP5594719B2 (ja) * 2010-01-06 2014-09-24 国立大学法人神戸大学 筋肉の糖取り込み促進剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
R. S. GOODWIN ET AL.: "INHIBITION OF ALDOSE REDUCTASE BY FLAVONOIDS FROM BRICKELLIA ARGUTA", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 22, no. 2 SUPPL, 1982, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, HAGERSTOWN, MD, US, pages 148, XP000929172, ISSN: 0146-0404 *
ROSA MARTHA PÉREZ-GUTIÉRREZ ET AL.: "ACTIVIDAD HIPOGLUCEMIANTE DE BOUVARDIA TERNIFLORA, BRICKELLIA VERONICAEFOLIA Y PARMENTIERA EDULIS", SALUD PÚBLICA DE MÉXICO, vol. 40, no. 4, July 1998 (1998-07-01) - August 1998 (1998-08-01), pages 354 - 358, XP000929245 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1351679A2 (fr) * 2000-12-21 2003-10-15 The Quigley Corporation Methode et composition pour le traitement de neuropathies diabetiques
US7914823B2 (en) 2000-12-21 2011-03-29 Prophase Labs, Inc. Method and composition for the topical treatment of diabetic neuropathy
EP1351679A4 (fr) * 2000-12-21 2007-03-21 The Quigley Corp Methode et composition pour le traitement de neuropathies diabetiques
JP2005504796A (ja) * 2001-09-06 2005-02-17 シノークス インコーポレイテッド ３−デオキシフラボノイドによるｔ−リンパ球活性化の阻害および関連療法
WO2003026561A2 (fr) * 2001-09-27 2003-04-03 Ziegler Randy H Compositions et methodes pour le traitement du diabete
WO2003026561A3 (fr) * 2001-09-27 2003-11-06 Randy H Ziegler Compositions et methodes pour le traitement du diabete
CN100341525C (zh) * 2001-09-27 2007-10-10 兰迪H·齐格勒 治疗糖尿病的组合物和方法
WO2003094928A1 (fr) 2002-05-06 2003-11-20 Diakron Pharmaceuticals, Inc. Compositions pharmaceutiques permettant de reduire la glycemie et les taux de cholesterol sanguin
US7338941B2 (en) 2002-05-06 2008-03-04 Diakron Pharmaceuticals, Inc. Pharmaceutical compositions for lowering blood glucose and blood cholesterol levels
US7410659B2 (en) 2002-11-06 2008-08-12 The Quigley Corporation Methods for the treatment of peripheral neural and vascular ailments
WO2005065667A3 (fr) * 2003-12-29 2008-01-17 Harvard College Compositions pour traiter ou prevenir l'obesite et les troubles de resistance a l'insuline
WO2005065667A2 (fr) * 2003-12-29 2005-07-21 President And Fellows Of Harvard College Compositions pour traiter ou prevenir l'obesite et les troubles de resistance a l'insuline
AU2004312072B2 (en) * 2003-12-29 2011-06-23 President And Fellows Of Harvard College Compositions for treating or preventing obesity and insulin resistance disorders
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9597347B2 (en) 2003-12-29 2017-03-21 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators
WO2007005453A3 (fr) * 2005-07-01 2007-06-14 Harvard College Compositions destinees au traitement ou a la prevention de l'obesite et de troubles lies a la resistance a l'insuline
WO2007005453A2 (fr) * 2005-07-01 2007-01-11 President And Fellows Of Harvard College Compositions destinees au traitement ou a la prevention de l'obesite et de troubles lies a la resistance a l'insuline
US8287677B2 (en) 2008-01-31 2012-10-16 Kimberly-Clark Worldwide, Inc. Printable elastic composite

Also Published As

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MXPA01010037A (es) 2003-07-14
JP2002541116A (ja) 2002-12-03
EP1169047A1 (fr) 2002-01-09
AU4196400A (en) 2000-10-23
AU780233B2 (en) 2005-03-10
BR0009592A (pt) 2002-01-08
CA2368215A1 (fr) 2000-10-12

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