WO2004075844A2 - Formulation for use in the prevention and treatment of carbohydrate induced diseases and conditions - Google Patents
Formulation for use in the prevention and treatment of carbohydrate induced diseases and conditions Download PDFInfo
- Publication number
- WO2004075844A2 WO2004075844A2 PCT/US2004/005353 US2004005353W WO2004075844A2 WO 2004075844 A2 WO2004075844 A2 WO 2004075844A2 US 2004005353 W US2004005353 W US 2004005353W WO 2004075844 A2 WO2004075844 A2 WO 2004075844A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- free
- group
- flavan
- acacia
- isolated
- Prior art date
Links
- 0 *C(C1)C(c2ccc(*)c(*)c2)Oc2c1c(*)cc(*)c2 Chemical compound *C(C1)C(c2ccc(*)c(*)c2)Oc2c1c(*)cc(*)c2 0.000 description 3
- PFTAWBLQPZVEMU-UHFFFAOYSA-N OC(C1)C(c(cc2)cc(O)c2O)Oc2c1c(O)cc(O)c2 Chemical compound OC(C1)C(c(cc2)cc(O)c2O)Oc2c1c(O)cc(O)c2 PFTAWBLQPZVEMU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
-
- 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
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
-
- 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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61K36/11—Pteridophyta or Filicophyta (ferns)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/13—Coniferophyta (gymnosperms)
- A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- 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
- 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)
- A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/484—Glycyrrhiza (licorice)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/486—Millettia
-
- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
-
- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/539—Scutellaria (skullcap)
-
- 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)
- A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
-
- 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)
- A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
-
- 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)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9062—Alpinia, e.g. red ginger or galangal
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- This invention relates generally to the use of a composition of matter formulated for use in preventing and treating diseases and conditions resulting from high carbohydrate ingestion.
- the present invention relates to a novel composition of matter comprised of a mixture of a blend of two specific classes of compounds —Free- B-Ring flavonoids and flavans— for use in the prevention and treatment of weight gain and obesity, as well as, other diseases and conditions resulting from high carbohydrate ingestion.
- the diseases and conditions include, but are not limited to, hyperlipidemia, high cholesterol, arteriosclerosis, atherosclerosis, syndrome X (metabolic syndrome), hypertension and systemic inflammation conditions caused by obesity and diabetes.
- ATP Energy in the body is generated by the production of ATP from "food stuff.” More specifically, when food is consumed it is broken down into its constituent parts consisting primarily of simple and complex carbohydrates, fats, proteins and indigestible fiber such as cellulose. The carbohydrates, fats and proteins are then further broken down into their basic units: carbohydrates into simple sugars, proteins into amino acids and fats into fatty acids and glycerol. The body then uses these basic units to generate substances it needs for growth, maintenance and energy production. Carbohydrates, proteins and fats can all be metabolized to provide energy in the form of ATP, however, carbohydrates are the primary substrates used by the body for the generation of ATP via glycolysis and the Kreb's cycle.
- carbohydrates are classified as either simple or complex.
- Simple carbohydrates are small molecules, specifically mono- and disaccharides, such as glucose, fructose, galactose and sucrose.
- Complex carbohydrates or polysaccharides are comprised of long chains of simple carbohydrates.
- the most important polysaccharides are starch, glycogen and cellulose, which are all polymers of glucose differing only in the way the glucose molecules are linked.
- Glycogen is the energy reservoir in animals
- starch is the energy reservoir in plants
- cellulose is the major structural component of plants. While most forms of starch are digestible, humans lack the enzyme necessary to digest cellulose and therefore it becomes part of our dietary fiber.
- Starch is a mixture of amylose and amylopectin.
- Amylose is a linear polysaccharide consisting of glucose molecules covalently bonded by ⁇ -1,4 linkages.
- Amylopectin is a branched polysaccharide consisting of glucose molecules covalently bonded with one ⁇ -1,6 linkage per approximately thirty ⁇ -1,4 linkages.
- Starch is rapidly hydrolyzed by ⁇ -amylase, which is secreted by the salivary glands and the pancreas.
- amylose Upon hydrolysis, amylose is broken down into small straight chain oligosaccharides, such as maltose (two glucose molecules in a ⁇ -1,4 linkage) and maltotriose (three glucose molecules in ⁇ -1,4 linkages).
- Amylopectin is broken down into small straight chain oligosaccharides, as well as, into the branched oligosaccharide ⁇ - dextrin (several glucose molecules linked by both ⁇ -1,4 linkages and ⁇ -1,6 linkages). These sugars are further broken down into glucose monomers by the enzymes maltase and ⁇ -amylase.
- carbohydrates consumed in our diet are simple carbohydrates, such as the monosaccharides glucose and fructose and the disaccharide sucrose.
- Glucose is present in low levels in most natural foods, whereas fructose is obtained primarily from processed foods, sweeteners and to a minor extent from fruits and certain vegetables.
- Fructose is produced synthetically via the enzymatic isomerization of dextrose. (Bhosale et al. (1996) Microbiol. Rev. 60:280-300).
- Sucrose another well l ⁇ iown sweetener, is comprised of a glucose and a fructose in an ⁇ -1,2 linkage between CI of glucose and C2 of fructose.
- Sucrose is hydrolyzed by the enzyme sucrase in the intestinal mucosa to provide glucose and fructose. (Dahlqvist (1972) Acta Med. Scand. Suppl. 542:13-18).
- Insulin is a ho ⁇ none secreted by the ⁇ -cells ofthe pancreas which enables the body to use glucose for energy.
- One ofthe key metabolic actions ofthe hormone insulin is to control blood sugar levels by promoting glucose uptake into fat and muscle cells. Briefly, when glucose enters cells, stimulated by insulin, there is an up-regulation of GLUT4 glucose transporter protein, which accumulates on the surface ofthe cells, particularly muscle and fat cells. (Furtado et al. (2002) Biochem. Cell. Biol. 80:569-578). Elevated cell surface levels of GLUT4 then facilitates enhanced glucose uptake from the circulation and storage in fat and muscle tissue.
- glucose is immediately converted to glucose 6-phosphate by the enzyme, hexokinase D also l ⁇ iown as glucokinase, which adds a phosphoryl group from ATP to C6 of glucose thereby producing ADP and glucose 6-phosphate.
- Glucose 6-phosphate is then converted to fructose 6-phosphate, which is converted to fructose 1,6-diphosphate by the action of phosphofructokinase, which adds a phosphoryl group to CI from a second molecule of ATP.
- aldolase B (aldolase) then converts fructose 1,6-diphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, a substrate suitable for the final conversion to pyruvate, which is then converted to acetyl CoA upon entry into the Kreb's cycle. Additional glyceraldehyde 3-phosphate is produced from dihydroxyacetone phosphate by the action ofthe enzyme triose phosphate isomerase.
- two ATP are expended initially, but two ATP are formed later in the process, as well as one molecule of NADH per glucose molecule, which is eventually converted to provide a net production of three ATP molecules.
- Lipogenesis includes processes of fatty acid synthesis and subsequent triglyceride synthesis. Conversely, when glucose levels in the blood become to low, the process is reversed and glucose is generated from acetyl Co-A and pyruvate.
- Gluconeogenesis refers to the process of generating glucose from acetyl-CoA and pyruvate and is essentially the reverse of glycolysis. Gluconeogenesis, like lipogenesis also occurs primarily in the liver and is the means by which glucose is generated and secreted into the blood stream for use by cells in the body.
- Fructose a constituent of sucrose and the primary sweetener and preservative added to processed foods over the last twenty years (Hanover and White (1993) Am. J. Clin. Nutr. 58(Supp.):724S-732S: Park and Yeltley (1993) Am. J. Clin. Nutr. 58(Supp.):737S-747S), is also used as a major source of energy by the body, but it enters the glycolysis pathway via a different mechanism. Fructose, unlike glucose, bypasses the need for insulin and is shunted directly into the glycolysis pathway. (Elliott et al. (2002) Am. J. Clin. Nutr. 76:911-922).
- fructose As soon as fructose enters the bloodstream, the vast majority of it (approximately 70%) is absorbed by the liver through the portal vein. (Toppings and Mayes (1971) Nutr. Metab. 13:331-338; Mayes (1993) Am. J. Clin. Nutr. 58(Supp.):754S-765S). Fructose is processed primarily in the liver, via the fructose 1- phosphate pathway.
- the first step in this pathway is the phosphorylation of fructose to fructose 1 -phosphate by the action of fructokinase, which adds a phosphoryl group from ATP to CI of fructose thereby producing ADP and fructose 1 -phosphate.
- fructokinase which adds a phosphoryl group from ATP to CI of fructose thereby producing ADP and fructose 1 -phosphate.
- Fructose- 1 -phosphate is then converted to glyceraldehyde and dihydroxyacetone phosphate. This aldol cleavage is catalyzed by a specific fructose 1 -phosphate aldolase.
- the glyceraldehyde is then converted to glyceraldehyde 3-phosphate for entry into the glycolysis pathway, requiring the input of second ATP molecule. Additionally, dihydroxyacetone phosphate is converted to glyceraldehyde 3-phosphate by the action of triose phosphate isomerase for entry into the glycolysis pathway. This process requires two ATP molecules.
- the selective, rapid uptake and utilization of fructose by the liver is due to the presence in liver cells ofthe enzyme fructokinase, which is lacking in most other tissues (i.e., adipose and muscle). (Van den Berghe (1986) in: Metabolic Effects of Dietary Carbohydrates.
- fructose can be phosphorylated to fructose 6-phosphate by the enzyme hexokinase, which occurs primarily in the kidneys, adipose tissue and skeletal muscle. It is estimated that approximately 20% of ingested fructose is immediately processed by the Iddneys, while approximately 10% is quickly absorbed by adipose tissue and skeletal muscle. (Froesch and Ginsberg (1962) J. Biol. Chem. 237:3317-3324; Bergstrom and Hultman (1967) Acta Med. Scand. 182:93-107). Most ofthe fructose in the kidneys, adipose tissue and skeletal muscle is metabolized via fructose 6-phosphate. Consequently, at any given time, there is a very low concentration of fructose circulating in the bloodstream. (Macdonald and Turner (1968) Lancet 1:841-843; Crossley and
- Fructose corn sweeteners have become the primary food additive in the American diet over the past twenty years with soft drinks and fruit drinks accounting for 43-44% ofthe added fructose.
- Kanter 1998 "A dietary assessment ofthe US Food Supply: Comparing per capita food consumption with food guide pyramid serving recommendations," from the Food and Rural Economics Division, Economics Research Service, U.S. Department of Agriculture, Agricultural Economic Report no. 772).
- Total sugar consumption is still rising due entirely to the addition of high fructose corn syrup to processed foods.
- NFKB plays an important role in the regulation of systemic inflammation and its relationship to sugar-induced obesity and the subsequent generation of disease (Lebovitz (2003) Int. J. Clin. Pract. Suppl. L34: 18-27). Activation of NFKB is part of a stress response activated by several biological processes including growth factors, lymphokines, cytokines, UV radiation, pharmacological agents and diet. (Spencer el al. (1997) Int. Immunol. 9:1581-1588). In its inactive form, NFKB is largely contained in the cytoplasm, bound by the I ⁇ B family of inhibitor proteins.
- NFkB Dietary changes such as increased fructose uptake can activate NFkB and cause phosphorylation of IkB thus releasing NFKB which allows translocation ofthe molecule to the nucleus.
- NFkB binds with a consensus sequence (5' GGGACTTTCC-3') of various genes, activating their transcription.
- this leads to increased expression of TNF ⁇ and IL-6. This increase in these pro-inflammatory proteins then induces an increase in CRP.
- fructose does not up-regulate insulin production due to low concentrations of fructose transporter GLUT5 protein in ⁇ cells (Grant et al. (1980) Diabetologia i9:114-117; Curry (1989) Pancreas 4:2-9; Sato et al. (1996) Tissue Cell 28:637-643). This leads to elevated blood glucose over time and insulin insensitivity, the principal cause of Type II diabetes.
- the liver can use fructose to generate glycogen via an adaptive enzyme response, but at a much lower level than glucose can be converted to glycogen. (Freedland and Harper (1957) J. Biol. Chem. 228:743-751). Additionally, increased and chronic consumption of sucrose or fructose leads to an increased ability of the liver to synthesize fatty acids, thereby decreasing liver glycogen stores since glucose cannot be processed through the glycolytic pathway. (Vrana et al. (1978) Metabolism
- Hyperuricemia was first noticed in studies in which fructose was administered to normal as well as children with hereditary fructose intolerance. (Perheentup and Raivio (1967) Lancet 2:528-31). An increase in the incidence of hyperuricemia has also been detected when fructose is administered parenterally to both diabetics and to those suffering from gout. (Hallfrisch (1987) in: Metabolic Effects of Dietary Fructose (Reiser & Hallfrisch, eds), pp. 25-40, CRC Press, Boca Raton, FL).
- fructose accelerates glycation or the non-enzymatic cross-linking of macromolecules such as nucleic acids, proteins and lipoproteins with sugars (the "Maillard Reaction”).
- Glycation was first reported by Monnier, who suggested that aging processes in the body might be contributed to by the Maillard reaction. (Mom ier (1989) "Toward a Malliear reaction theory of aging, in: the Malliard Reaction in Aging, Diabetes, and Nutrition," (Baynes, JW & Monnier VM, eds.), pp. 1-22, Alan R. Liss, New York, NY).
- a sugar such as glucose and fructose
- the sugar moieties bound to the glycated proteins/amino acids are chemically modified to become molecular structures called Advanced Glycation Endproducts (AGEs).
- AGEs can interfere with the proper functioning ofthe proteins to which they are attached.
- ROS reactive oxygen species
- AGEs can covalently crosslink with adjacent protein strands.
- Diabetic patients are particularly susceptible to the effects of glycation if fructose is used as a substitute for glucose in their diets.
- fructose is generally present in low concentration in the blood, but in diabetics an equal or greater concentration of fructose versus glucose is found in the comeal lens and nerves.
- fructose has on lipid accumulation, lipogenesis and weight gain.
- low-fat, high-carbohydrate diets are prevalent owing to the extreme awareness regarding the dangers of fat and cholesterol in cardiovascular disease, endorsement of fructose as a substitute sweetener for diabetics and a lack of awareness ofthe dangers of fructose consumption.
- lipogenesis occurs.
- simple sugars particularly fructose
- fructose are ingested to the extent that they exceed the current energy demand
- lipogenesis occurs.
- simple sugars particularly fructose
- lipogenesis includes the process of fatty acid synthesis and subsequent triglyceride synthesis. Because ofthe limited capacity of higher animals to store polysaccharides, when simple sugars, such as glucose and fructose, are ingested in excess of current energy needs and storage capacity they are converted into triacyl glycerols and stored in adipose or fat tissue.
- Figure 1 illustrates the interplay between fructose and glucose in the formation of acyl glycerols, acetyl-CoA and ultimately very low density lipids (VLDL).
- VLDL very low density lipids
- fructose metabolism has a negative effect on glycolysis and glycogen deposition, inhibiting gene and protein expression of key glycolytic enzymes, removing phosphate from the liver thereby decreasing ATP production, and finally decreasing general metabolic output in fructose induced obesity.
- fructose is more lipogenic than glucose. Rats fed continuous high amounts of fructose developed increased concentrations of VLDL triglycerides in their blood. (Herman et al. (1970) Fed. Proc. 29:1302-1307; Steiner et al. (1984) Am. J. Physiol. 246:E187-E192; Kazumi et al. (1986) Am. J. Physiol. 250.-E325- E330). When fructose was ingested, there was an immediate formation of high levels of plasma triglycerides, as well as, an increase in the rate of glycerol and fatty acid formation.
- Lipogenesis has been shown to increase in the livers of rats fed chronic fructose (Christophe and Mayer (1968) Am. J. Physiol. 197:55-59) or sucrose diets (Fabry et al. (1968) Nutr. Dieta 10:81-90; Tepperman and Tepperman (1970) Fed. Proc. 29: 1284- 1293). Rats fed high fructose diets also showed increased lipid content and large increases in organ weight compared to animals on standard starch or glucose supplemented diets. (Wapnir and Devas (1995) Am. J. Clin. Nutr. 61:105-110). The kidneys were affected to a lesser extent in animals on high fructose diets.
- fructose has a definite effect on weight gain in men and women. For example, when 14 middle-aged men, four with diabetes, supplemented their diets with an additional 50-60 g of fructose per day or roughly the equivalent of two cans of soda sweetened with high fructose com syrup, they all exhibited a net weight gain. (Anderson et al. (1989) Diabetes Care 12:337- 344).
- TNF ⁇ is expressed and secreted by adipocytes and shows a direct correlation with obesity and BMI, but not necessarily with insulin insensitivity and hyperinsulinernia (Hotamisligil et al. (1993) Science 259:87-91; Romiemaa et al. (2000) J. Clin. Endocrinol. Metab. 85:2728-2732; Berberoglu (2001) J. Pediatr. Endocrinol. Metab. 14:543-547).
- Body Mass Index is a measure of body fat based on height and weight. BMI is used as a measure of overall obesity and is one of many factors related to the potential for developing a chronic disease (such as heart disease, cancer or diabetes). Other important factors in assessing ones risk for developing a chronic disease include diet, physical activity, waist circumference, blood pressure, blood sugar levels, cholesterol levels and family history of disease. BMI is calculated as follows:
- adiposity there are three types of adiposity in the body — subcutaneous, visceral and organ. (Cinti (2000) Eat Weight Disord. 5: 132-142). Liver (organ) adiposity has been shown to be highly associated with fructose consumption (Wapnir and Devas (1995) Am. J. Clin. Nutr. 61:105-110). Visceral adiposity, on the other hand, is associated with the intake of a variety of fat and carbohydrate sources, including fructose/sucrose. (Tarui et al. (1991) Int. J. Obes. 2(Suppl):l-8; Keno et al. (1991) Int. J.
- TNF ⁇ induces secretion of IL-6 from adipose tissue which causes glucorticoid induced lipolysis thereby releasing increased concentrations of circulating nonesterified fatty acids that can serve as an additional pool for de novo fat synthesis.
- IL-6 induces secretion of IL-6 from adipose tissue which causes glucorticoid induced lipolysis thereby releasing increased concentrations of circulating nonesterified fatty acids that can serve as an additional pool for de novo fat synthesis.
- atherosclerotic lesions contained high levels of TNF ⁇ that induced transcription factors promoting gene expression of proteins that induce even greater lesion formation (Goetze et al. (2001) Atherosclerosis 159:93-101).
- Acute phase represents a state of injury or inflammation in which IL-6 induces gene and protein expression of specific inflammatory proteins, such as CRP and fibrinogen (Heinrich et al. (1990) Biochem. J. 265:621-636). No other cytokine performs this function in the acute phase. Although there was l ⁇ iown to be a strong correlation between increased BMI and serum fibrinogen concentrations (Krobot et al. (1991) Arterioscler. Thromb. 12:780-788), there was no clear association with IL-6 until it was discovered that abdominal fat cells produce and secrete IL-6 (Mohamed-Ali et al. (1997) J. Clin. Endocrinol. Metab. 82:4196-4200). Thus, there is a direct correlation between IL- 6 levels in the body, BMI, and visceral adiposity.
- IL-6 secretion from visceral adipocytes is taken up primarily by the portal vein, thus acting primarily on hepatocytes.
- IL-6 also promotes lipolysis in the liver, but it especially increases fibrinogen gene expression leading to high concentrations of fibrogenin in the blood and an increased incidence of cardiovascular disease.
- IL-6 Associated with its gene expression activity is IL-6's effect on increasing CRP levels in circulation. IL-6 regulates the hepatic synthesis of CRP (Heinrich et al. (1990) Biochem. J. 265:621-636; Bataille and Klein (1992) Arthritis Rheum. 35:982-983). Since there is a correlation between increased BMI and TNF ⁇ and IL-6 concentrations, researchers looked for a correlation with respect to CRP. It was discovered that there is a direct correlation between CRP serum concentrations and BMI. (Visser et al. (1999) JAMA 282:2131-2135). In fact, there is almost a linear relationship between BMI and CRP concentration.
- This cytokine cascade caused initially by an up-regulation in fructose-induced lipogenesis in the liver is responsible for the primary protein determinants in obesity, cardiovascular disease, diabetes as well as many other diseases. (McCarty (1999) Medical Hypotheses 52:465- 477). Reduction of fructose and sugar-induced weight gain is vital in preventing these inflammation based disease states.
- Starch Mockers are compounds derived from plants that partially inhibit the action of ⁇ -amylase, thus causing starch to pass through the gut underutilized as a source of glucose.
- phaseolamin an extract isolated from kidney beans has been found to be effective in blocking carbohydrate breakdown via inhibition of ⁇ -amylase. (Marshall and Lauda (1975) J. Biol. Chem. 250:8030-8037).
- Mu Huang another well known plant extract used for weight loss, also contains ephedra, an ephedrine like substance. (Boozer et al. (2002) Int. J. Obes. Relat. Metab. Disord. 26:593-604; Boozer et al. (2001) Int. J. Obes. Relat. Metab. Disord. 25:316-324). Though several short-term clinical studies have shown Mu Huang to be safe in combination with caffeine and guarana, recent reports have suggested that ephedra containing weight loss preparations have severe cardiac side effects.
- composition of matter described herein contains no ⁇ -amylase inhibitors, which effect starch breakdown and no ephedra, ephedrine, or pseudoephedrine, which effect sugar metabolism and weight gain.
- This extract decreases weight gain in high sugar diets via reduction in fructose utilization, reduces pro-inflammatory cytokines associated with obesity, and may aid in weight loss.
- Flavonoids or bioflavonoids are a widely distributed group of natural products, which have been reported to have antibacterial, anti-inflammatory, antiallergic, antimutagenic, antiviral, antineoplastic, anti-thrombic and vasodilatory activity.
- the structural unit common to this group of compounds includes two benzene rings on either side of a 3-carbon ring as illustrated by the following general structural formula:
- flavonoids include flavanols, flavones, flavan-3-ols (catechins), anthocyanins and isoflavones.
- Free-B-Ring flavones and flavonols are a specific class of flavonoids, which have no substituent groups on the aromatic B ring, as illustrated by the following general structure:
- Ri, R 2 , R 3 , R , and R 5 are independently selected from the group consisting of -H, -OH, -SH, OR, -SR, -NH 2 , -NHR, -NR 2 , -NR 3 + X " , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, but not limited to aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein R is an alkyl group having between 1-10 carbon atoms; and X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- Free-B-Ring flavonoids are relatively rare. Out of a total 9396 flavonoids synthesized or isolated from natural sources, only 231 Free-B-Ring flavonoids are known. (The Combined Chemical Dictionary, Chapman & Hall/CRC, Version 5:1 June 2001). Free-B-Ring flavonoids have been reported to have diverse biological activity. For example, galangin (3,5,7- trihydroxyflavone) acts as anti-oxidant and free radical scavenger and is believed to be a promising candidate for anti-genotoxicity and cancer chemoprevention. (Heo et al. (2001) Mutat. Res. 488(2): 135-150). It is an inhibitor of tyrosinase monophenolase (Kubo et al.
- flavonoids have been tested for activity randomly based upon their availability. Occasionally, the requirement of substitution on the B-ring has been emphasized for specific biological activity, such as the B-ring substitution required for high affinity binding to p-glycoprotein (Boumendjel et al. (2001) Bioorg. Med. Chem. Lett. l l(l):75-77): cardiotonic effect (Itoigawa et al. (1999) J. Ethnopharmacol. 65(3): 267-272), protective effect on endothelial cells against linoleic acid hydroperoxide- induced toxicity (Kaneko and Baba (1999) Biosci Biotechnol.
- the Chinese medicinal plant, Scutellaria baicalensis contains significant amounts of Free-B-Ring flavonoids, including baicalein, baicalin, wogonin and baicalenoside.
- this plant has been used to treat a number of conditions including clearing away heat, purging fire, dampness-warm and summer fever syndromes; polydipsia resulting from high fever; carbuncle, sores and other pyogenic skin infections; upper respiratory infections, such as acute tonsillitis, laryngopharyngitis and scarlet fever; viral hepatitis; nephritis; pelvitis; dysentery; hematemesis and epistaxis.
- Anti-inflammatory flavonoids are used for the control and treatment of anorectal and colonic diseases (U.S. Patent No. 5,858,371), and inhibition of lipoxygenase (U.S. Patent No. 6,217,875). These compounds are also formulated with glucosamine collagen and other ingredients for repair and maintenance of connective tissue (Bath, U.S. Pat. No. 6,333,304). Flavonoid esters constitute active ingredients in cosmetic compositions (U.S. Patent No. 6,235,294). U.S. Application Serial No.
- Flavans include compounds illustrated by the following general structure:
- Ri, R 2 , R , R and R 5 are independently selected from the group consisting of -H, - OH, -SH, -OCH 3 , -SCH 3 , -OR, -SR, -NH 2 , -NRH, -NR 2 , -NR 3 + X " , esters ofthe mentioned substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl-cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters; thereof carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to, aldopentoses, methyl aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; dimer, trimer and other polymerized flavans; wherein
- R is an alkyl group having between 1-10 carbon atoms
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, and carbonate, etc.
- Catechin is a flavan, found primarily in green tea, having the following structure.
- Catechin Catechin works both alone and in conjunction with other flavonoids found in tea, and has both antiviral and antioxidant activity. Catechin has been shown to be effective in the treatment of viral hepatitis. It also appears to prevent oxi dative damage to the heart, kidney, lungs and spleen. Catechin has also been shown to inhibit the growth of stomach cancer cells.
- Catechin and its derivatives have also been used topically to inhibit angiogenesis in mammalian tissue, such as skin cancer, psoriasis, spider veins or under eye circles (Anderson, U.S. Pat. No. 6,248,341), against UVB-induced tumorigenesis on mice (Agarwal et al. (1993) Photochem. Photobiol. 58:695-700), for inhibiting nitric oxide synthase at the level of gene expression and enzyme activity (Chan, U.S. Pat. No. 5,922,756) and as a hair-growing agent (Takahashi, U.S. Pat. No. 6,126,940).
- Catechin based compositions have also been formulated with other extracts and vitamins for treatment of acne (Murad U.S. Pat. No. 5,962,517), hardening the tissue of digestive organs (Shi, U.S. Pat. No. 5,470, 589) and for inhibiting 5 alpha-reductase activity in treating androgenic disorder related diseases and cancers (Liao, U.S. Pat. No. 5,605,929).
- Green tea extract has been formulated with seven other plant extracts for reducing inflammation by inhibiting the COX-2 enzyme, without identification of any of the specific active components (Newmark, U.S. Pat. No. 6,264,995).
- the flavans, quercetin and fisetin were shown to stimulate PDE activity in adipose tissue as opposed to inhibition of activity in stimulating lipolysis. (Kuppusamy and Das (1994) Biochem. Pharmacol. 47:521-529). Quercetin and fisetin stimulated PDE activity in a dose dependent manner, both in the presence and absence of epinephrine, causing cellular accumulation of cyclic AMP.
- the genus Acacia includes more than 1000 species belonging to the family of Leguminosae and the subfamily of Mimosoideae. Acacias are distributed worldwide in tropical and subtropical areas of Central and South America, Africa, parts of Asia, as well as, Australia, which has the largest number of endemic species. Acacias occur primarily in dry and arid regions, where the forests are often in the nature of open thorny shrubs. The genus Acacia is divided into 3 subgenera based mainly on the leaf mo ⁇ hology —Acacia, Aculiferum and Heterophyllum.
- Acacia can be divided into two "popular" groups: the typical bipinnate leaved species and the phyllodenous species.
- a phyllode is a modified petiole expanded into a leaflike structure with no leaflets, an adaptation to xerophytic conditions.
- Acacias are very important economically, providing a source of tannins, gums, timber, fuel and fodder. Tannins, which are isolated primarily from bark, are used extensively for tanning hides and skins. Some Acacia barks are also used for flavoring local spirits. Some indigenous species like A.
- saponins are any of various plant glucosides that form soapy lathers when mixed and agitated with water. Saponins are used in detergents, foaming agents and emulsifiers.
- the flowers of some Acacia species are fragrant and used to make perfume.
- cassie perfume is obtained from A. ferrugenea.
- the heartwood of many Acacias is used for making agricultural implements and also provides a source of firewood.
- Acacia gums find extensive use in medicine and confectionary and as sizing and finishing materials in the textile industry. Lac insects can be grown on several species, including A. nilotica and A. catechu. Some species have been used for forestation of wastelands, including A. nilotica, which can withstand some water inundation and a few such areas have become bird sanctuaries.
- Flavonoids a type of water-soluble plant pigments, are the major class of compounds isolated from Acacias. Approximately 180 different flavonoids have been identified, 111 of which are flavans. Te ⁇ enoids are second largest class of compounds isolated from species of the Acacia genus, with 48 compounds having been identified. Other classes of compounds isolated from Acacia include, alkaloids (28), amino acids/peptides (20), tannins (16), carbohydrates (15), oxygen heterocycles (15) and aliphatic compounds (10). (Buckingham, The Combined Chemical Dictionary, Chapman & Hall CRC, version 5:2, Dec. 2001).
- Phenolic compounds, particularly flavans are found in moderate to high concentrations in all Acacia species. (Abdulrazak et al. (2000) Journal of Animal Sciences. 13:935-940). Historically, most ofthe plants and extracts ofthe Acacia genus have been utilized as astringents to treat gastrointestinal disorders, diarrhea and indigestion and to stop bleeding. (Vautrin (1996) Universite Bourgogne (France) European abstract 58-01C: 177; Saleem et al. (1998) Hamdard Midicus. 41:63-67). The bark and pods of A. arabica Willd. contain large quantities of tannins and have been utilized as astringents and expectorants.
- Plant extracts from A. nilotica have been reported to have spasmogenic, vasoconstrictor and anti-hypertensive activity (Amos et al. (1999) Phytotherapy Research 13:683-685; Gilani et al. (1999) Phytotherapy Research. 13:665- 669), and antiplatelet aggregatory activity (Shah et al. (1997) General Pharmacology. 29:251-255).
- Anti-inflammatory activity has been reported for i. nilotica. It was speculated that flavonoids, polysaccharides and organic acids were potential active components.
- the present invention includes methods that are effective in inhibiting sugar induced weight gain and sugar induced obesity.
- the methods for inhibiting sugar induced weight gain and inhibiting sugar induced obesity are comprised of administering a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof (this composition of matter is also referred to herein by the tradename DIAFINTM).
- the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99.9:0.1 Free-B-Ring flavonoids: flavans to 0.1 :99.9 Free-B-Ring flavonoids: flavans.
- the ratio of Free-B-Ring flavonoids: flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the present invention also includes a method for the prevention and treatment of other sugar-induced diseases and conditions.
- the method for preventing and treating sugar-induced diseases and conditions is comprised of administering to a host in need thereof an effective amount of a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants and a pharmaceutically acceptable carrier.
- the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99.9:0.1 Free-B-Ring flavonoids: flavans to 0.1:99.9 Free-B-Ring flavonoids: flavans.
- the ratio of Free-B-Ring flavonoids: flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the present invention further includes methods for the specific inhibition of a key enzyme in the fructose catalytic and glycolytic pathways, namely the inhibition of a specific fructose 1 -phosphate aldolase. With reference to Figure 1, this inhibits the conversion of fructose 1 -phosphate to glyceraldehyde and dihydroxy acetone-phosphate by aldolase. This specific inhibition prevents the conversion of dihydroxy acetone- phosphate to glycerol-3 -phosphate and then acyl glycerol resulting ultimately in the production of VLDL.
- the present invention also includes methods for genomic reduction ofthe transcription factor NFKB which induces production of TNF ⁇ and IL-6.
- TNF ⁇ and IL-6 are prime markers for obesity and other inflammatory diseases.
- the method for reduction of NFKB and subsequently TNF ⁇ and IL-6 is comprised of administering to a host in need thereof an effective amount of a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants.
- the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99.9:0.1 Free-B-Ring flavonoids: flavans to 0.1 :99.9 Free-B-Ring flavonoids: flavans.
- the ratio of Free-B-Ring flavonoids: flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- Free-B-Ring flavonoids also referred to herein as Free-B-Ring flavones and Free-B-Ring flavonols, that can be used in accordance with the following invention include compounds illustrated by the following general structure:
- Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of -H, -OH, -SH, OR, -SR, -NH 2 , -NHR, -NR 2 , -NR 3 + X " , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, but not limited to aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein
- R is an alkyl group having between 1-10 carbon atoms
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- the flavans that can be used in accordance with the following invention include compounds illustrated by the following general structure:
- Ri, R 2 , R 3 , 4 and R 5 are independently selected from the group consisting of H, - OH, -SH, -OCH , -SCH 3 , -OR, -SR, -NH 2 , -NRH, -NR 2 , -NR 3 + X " , esters ofthe mentioned substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl-cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters; thereof carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to, aldopentoses, methyl aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; dimer, trimer and other polymerized flavans; wherein
- R is an alkyl group having between 1-10 carbon atoms
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- the method of this invention can be used to treat and prevent a number of obesity associated diseases and conditions including, but not limited to hyperlipidemia, high cholesterol, arteriosclerosis, atherosclerosis, syndrome X (metabolic syndrome), systemic inflammation conditions caused by sugar-induced obesity and diabetes, and hypertension.
- the Free-B-Ring flavonoids of this invention may be obtained by synthetic methods or extracted from the family of plants including, but not limited to Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae and Zingiberacea.
- the Free-B-Ring flavonoids can be extracted, concentrated, and purified from the following genus of high plants, including but not limited to Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichysum,
- Centaurea Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Z iphora, Lindera, Actinodaphne, Acacia, Denis, Glycyrrhi ⁇ a, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus and
- the flavans of this invention may be obtained from a plant or plants selected from the genus of Acacia.
- the plant is selected from the group consisting of Acacia catechu ⁇ A. catechu), A. concinna, A. farnesiana, A. Senegal, A. speciosa, A. arabica, A. caesia, A. pennata, A. sinuata. A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia and mangium.
- compositions of this invention can be administered by any method l ⁇ iown to one of ordinary skill in the art.
- the modes of administration include, but are not limited to, enteral (oral) administration, parenteral (intravenous, subcutaneous, and intramuscular) administration and topical application.
- the method of treatment according to this invention comprises administering internally or topically to a patient in need thereof a therapeutically effective amount of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants.
- FIGURES Figure 1 depicts schematically the metabolism of fructose and glucose in the glycolytic and lipogenesis pathways in the liver.
- Figure 2 depicts graphically the effect of a mixture of Free-B-Ring flavonoids and flavans administered daily for 3 weeks, on fructose induced weight gain and fat-induced weight gain in ICR female mice fed a normal diet, a diet supplemented with 65% fructose or a diet supplemented with fat, as described in Example 1. Mice maintained on a normal diet served as a control. Two test groups were given either 65% fructose only or fat only.
- Figure 3 illustrates graphically the effect of a mixture of Free-B-Ring flavonoids and flavans administered daily on fructose versus glucose induced weight gain in ICR mice fed a normal diet (control), a diet supplemented with 65% fructose for 8 weeks and a diet supplemented with 65% glucose for 8 weeks as described in Example 3. Weights were measured weekly and the mean plotted for each group. The Standard Error ofthe Mean (SEM) is shown for each group at each week.
- SEM Standard Error ofthe Mean
- Figure 4 depicts the effect of a mixture of Free-B-Ring flavonoids and flavans (80:20) on the lipopolysaccharide (LPS)-induced level of TNF ⁇ in peripheal blood monocytes (PBMC) following exposure to the lipopolysaccharide in conjunction with different concentrations ofthe Free-B-Ring flavonoid and flavan mixture for one hour.
- LPS lipopolysaccharide
- PBMC peripheal blood monocytes
- Figure 5 depicts the effect of a mixture of Free-B-Ring flavonoids and flavans (80:20) on the lipopolysaccharide (LPS)-induced level of IL-6 in peripheal blood monocytes (PBMC) following exposure to the lipopolysaccharide in conjunction with different concentrations ofthe Free-B-Ring flavonoid and flavan mixture for six hours.
- the level of IL-6 is expressed in pg/mL. The standard deviation is shown for each data point.
- Figure 6 depicts graphically the relative degree of inhibition of NFKB gene expression by a mixture of Free-B-Ring flavonoids and flavans. Relative gene expression was measured in the presence of 0 to 100 ⁇ g/mL of extract.
- Figure 7 depicts graphically the relative degree of inhibition of TNF ⁇ gene expression by a mixture of Free-B-Ring flavonoids and flavans. Relative gene expression was measured in the presence of 0 to 100 ⁇ g/mL of extract.
- Figure 8 illustrates graphically the effect of a mixture of Free-B-Ring flavonoids and flavans have on the function of a fructose 1 -phosphate specific aldolase, which catalyzes the conversion of fructose 1 -phosphate to glyceraldehyde and dihydroxyacetone phosphate. Dose specific inhibition of this key enzyme is shown over a period of 10 minutes.
- Figure 9 illustrates shows the effect ofthe Free-B-Ring flavonoid and flavan extract on weight loss in 13 individuals orally administered 250 mg per day over a 90-day period. Individual weights (initial and final) are shown above each measurement for each human subject.
- Figure 10 illustrates the effect ofthe Free-B-Ring flavonoid and flavan extract on weight loss in 13 individuals orally administered 500 mg per day over a 90-day period. Individual weights (initial and final) are shown above each measurement for each human subject.
- Figure 11 depicts the effect on weight loss in 13 individuals orally administered a placebo over a 90-day period. Individual weights (initial and final) are shown above each measurement for each human subject.
- Figure 12 illustrates the effect of the Free-B-Ring flavonoid and flavan extract on Body Mass Index (BMI) in individuals orally administered 250 and 500 mg per day versus placebo at 30 and 90 days. The SEM is also shown for each group.
- Figure 13 illustrates the effect ofthe Free-B-Ring flavonoid and flavan extract on changes in blood glucose in individuals orally administered 250 and 500 mg per day versus placebo (baseline) at 0, 30 and 90 days.
- Figure 14 illustrates the High Pressure Liquid Chromatography (HPLC) chromatogram ofthe mixture of Free-B-Ring flavonoids and flavans carried out under the conditions as described in Example 8. Using the described conditions the Free-B-Ring flavonoids eluted between 11 to 14 minutes and the flavans eluted between 3 to 5 minutes
- Figure 15 depicts an HPLC chromatogram ofthe mixture of Free-B-Ring flavonoids and flavans carried out under the conditions as described in Example 9.
- the two flavans catechins and epicatechins
- the Free-B-Ring flavonoids bacalein and bacalin
- the separation is based upon differences in molar absorbtivity ofthe Free-B-Ring flavonoids and flavans.
- the present invention relates to a novel composition of matter comprised of a mixture of a blend of two specific classes of compounds —Free-B-Ring flavonoids and flavans— for use in the prevention and treatment of weight gain and obesity, as well as, other diseases and conditions resulting from high carbohydrate ingestion.
- the diseases and conditions include, but are not limited to, hyperlipidemia, high cholesterol, arteriosclerosis, atherosclerosis, syndrome X (metabolic syndrome), systemic inflammation conditions caused by obesity and diabetes, and hypertension.
- Free-B-Ring Flavonoids as used herein are a specific class of flavonoids, which have no substituent groups on the aromatic B ring, as illustrated by the following general structure:
- Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of -H, -OH, -SH, OR, -SR, -NH 2 , -NHR, -NR 2 , -NR 3 + X " , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, but not limited to aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein
- R is an alkyl group having between 1-10 carbon atoms
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- Flavonoids as used herein refer to a specific class of flavonoids, which are generally represented by the following general structure:
- Ri, R 2 , R 3 , R t and R 5 are independently selected from the group consisting of H, OH, -SH, -OCH 3 , -SCH 3 , -OR, -SR, -NH 2 , -NRH, -NR 2 , -NR 3 + X " , esters of substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl-cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters; thereof carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to, aldopentoses, methyl aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; dimer, trimer and other polymerized flavans; wherein
- R is an alkyl group having between 1-10 carbon atoms
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- fructose-induced lipogenesis refers to the specific pathway of lipid formation from fructose that occurs through the production ofthe intermediate dihydroxy-acetone-phosphate followed by its conversion to glycerol-3 -phosphate and subsequent esterification to acyl glycerols as illustrated schematically in Figure 1.
- De novo lipogenesis refers to the specific pathway of lipid formation from glucose that occurs through the production ofthe intermediate pyruvate, followed by its conversion to acetyl-CoA in a carboxylation reaction, which is converted to malonyl-CoA, which is then converted to acyl-CoA followed by esterification to acyl glycerols as illustrated schematically in Figure 1.
- Sud-induced lipogenesis refers to both fructose-induced and de novo lipogenesis.
- “Sugar” as used herein refers to both simple and complex carbohydrates including, but not limited to monosaccharides, disaccharides and polysaccharides.
- a monosaccharide is a simple sugar, including, but not limited to glucose, fructose and galactose.
- a disaccharide is a double sugar or a sugar that contains two molecules of a simple sugar, such as sucrose.
- Sugar as used herein also refers to the carbohydrates resulting from the break down or degradation of complex carbohydrates.
- a complex carbohydrate or polysaccharide is a carbohydrate that contains three or more molecules of a simple sugar.
- Complex carbohydrates include starch and glycogen.
- Sugars formed as a result ofthe degradation of complex carbohydrates include, but are not limited to, maltotriose, ⁇ -dextrin, maltose and other metabolically active disaccharides.
- “Therapeutic” as used herein, includes treatment and/or prophylaxis.
- therapeutic refers to humans, as well as, other animals.
- “Pharmaceutically or therapeutically effective dose or amount” refers to a dosage level sufficient to induce a desired biological result. That result may be the alleviation ofthe signs, symptoms or causes of a disease or any other desired alteration of a biological system.
- “Placebo” refers to the substitution ofthe pharmaceutically or therapeutically effective dose or amount sufficient to induce a desired biological that may alleviate the signs, symptoms or causes of a disease with a non-active substance.
- a "host” is a living subject, human or animal, into which the compositions described herein are administered. Note, that throughout this application various citations are provided. Each citation is specifically inco ⁇ orated herein in its entirety by reference.
- the present invention includes methods that are effective in inhibiting sugar induced weight gain and sugar induced obesity.
- the methods for inhibiting sugar induced weight gain and inhibiting sugar induced obesity are comprised of administering a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
- the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99.9:0.1 Free-B-Ring flavonoids: flavans to 0.1:99.9 Free-B-Ring flavonoids: flavans.
- the ratio of Free-B-ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the present invention also includes a method for the prevention and treatment of sugar induced diseases and conditions.
- the method for preventing and treating sugar induced diseases and conditions is comprised of administering to a host in need thereof an effective amount of a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants and a phamiaceutically acceptable carrier.
- the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99.9:0.1 Free-B-Ring flavo ⁇ oids:flavans to 0.1:99.9 Free-B-Ring flavonoids:flavans.
- the ratio of Free-B- ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B-Ring flavonoids: flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the present invention further includes methods for genomic reduction NFKB and subsequent decrease in TNF ⁇ and IL-6 levels, which are prime markers for obesity and other inflammatory diseases.
- the method for genomic reduction of NFKB and subsequent decrease in TNF ⁇ and IL-6 levels is comprised of administering to a host in need thereof an effective amount of a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants.
- the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99.9:0.1 Free-B-Ring flavonoids: flavans to 0.1 :99.9 Free-B-Ring flavonoids: flavans.
- the ratio of Free-B-ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the Free-B-Ring flavonoids that can be used in accordance with the following include compounds illustrated by the general structure set forth above.
- the Free-B-Ring flavonoids of this invention may be obtained by synthetic methods or may be isolated from the family of plants including, but not limited to Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae, and
- the Free-B-Ring flavonoids can be extracted, concentrated, and purified from the following genus of high plants, including but not limited to Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Derris, Glycyrrhiza, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus, and Alpinia.
- the flavonoids can be found in different parts of plants, including but not limited to stems, stem barks, twigs, tubers, roots, root barks, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.
- Methods for the isolation and purification of Free-B-Ring flavonoids are described in U.S. Application Serial No. 10/091,362, filed March 1, 2002, entitled “Identification of Free-B-Ring Flavonoids as Potent COX-2 Inhibitors," which is incorporated herein by reference in its entirety.
- the flavans that can be used in accordance with the method of this invention include compounds illustrated by the general structure set forth above.
- the flavans of this invention are isolated from a plant or plants selected from the Acacia genus of plants.
- the plant is selected from the group consisting of Acacia catechu, Acacia concinna, Acacia farnesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata. A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia and A. m ⁇ ngium.
- the flavans can be found in different parts of plants, including but not limited to stems, stem barks, trunks, trunk barks, twigs, tubers, roots, root barks, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.
- Methods for the isolation and purification of flavans are described in U.S. Application Serial No. 10/104,477, filed March 22, 2002, entitled “Isolation of a Dual Cox-2 and 5- Lipoxygenase Inhibitor from Acacia,” which is inco ⁇ orated herein by reference in its entirety.
- the method of this invention can be used to treat and prevent a number of obesity associated diseases and conditions including, but not limited to, hyperlipidemia, high cholesterol, arteriosclerosis, atherosclerosis, syndrome X (metabolic syndrome), systemic inflammation conditions caused by obesity and diabetes, and hypertension.
- obesity associated diseases and conditions including, but not limited to, hyperlipidemia, high cholesterol, arteriosclerosis, atherosclerosis, syndrome X (metabolic syndrome), systemic inflammation conditions caused by obesity and diabetes, and hypertension.
- compositions of this invention can be administered by any method known to one of ordinary skill in the art.
- the modes of administration include, but are not limited to, enteral (oral) administration, parenteral (intravenous, subcutaneous, and intramuscular) administration and topical application.
- the method of treatment according to this invention comprises administering internally or topically to a host in need thereof a therapeutically effective amount of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants.
- the composition is administered in a dosage selected from 0.01 to 200 mg/kg of body weight.
- the present invention implements a strategy that combines a series of in vivo weight measurement studies as well as in vitro biochemical, cellular, and gene expression screens to identify active plant extracts that specifically inhibit fructose metabolism as it pertains to increase in lipid and fat content in the body, enzymatic activity of metabolic enzymes, impact on mRNA gene expression and lipogenesis in general. Free B-ring flavonoids and flavans were tested for their ability to inhibit fructose-induced obesity when administered by oral gavage.
- Example 1 describes an experiment designed to determine the effect of a mixture of Free-B-Ring flavonoids and flavans on weight gain resulting from a diet supplemented with fructose or fat for three weeks. The results are set forth in Figure 2. With reference to Figure 2, it can be seen that animals that were given fat, together with the extract gained approximately the same amount of weight as those given fat only and no extract. However, mice given fructose, together with extract gained the same amount of weight as the control group, which were fed a normal diet.
- composition of matter comprised of a mixture of Free-B-Ring flavonoids (60-90% based on HPLC) and flavans (10-60% based on HPLC) was effective in preventing excess weight gain resulting from the consumption of fructose. While not limited by theory, it is presumed that this result is due to a change in fructose utilization in the lipogenesis pathway.
- Example 2 describes an experiment designed to illustrate the effect of a mixture of Free-B-Ring flavonoids and flavans on weight gain resulting from a diet supplemented with fructose and glucose for eight weeks.
- the results are set forth in Figure 3.
- animals that were given glucose, together with extract gained approximately the same amount of weight as those given glucose only and no extract.
- the mice given fructose together with extract gained significantly less weight than the mice given fructose only and no extract.
- Mice given sucrose or commercial sources of fructose syrup showed intermediate weight gain under the conditions of this experiment (data not shown).
- Example 3 illustrates the effect of a mixture of Free-B-Ring flavonoids and flavans on the secreted concentration of TNF ⁇ .
- the results are set forth in Figure 4.
- the extract decreased TNF ⁇ secreted into the cell culture supernatant substantially over a wide range of concentrations from 2 to 100 ⁇ g/mL. Since TNF ⁇ is a marker in obesity, the extract has a significant impact by decreasing this pro-inflammatory cytokine in primed inflammatory cells.
- Example 4 illustrates the effect of a mixture of Free-B-Ring flavonoids and flavans on the secreted concentration of IL-6. The results are set forth in Figure 5.
- the extract decreased IL-6 secreted into the cell culture supernatant substantially over a wide range of concentrations from 2 to 100 ⁇ g/mL. Since IL-6 is a marker in obesity, the extract has a significant impact by decreasing this pro- inflammatory cytokine in primed inflammatory cells.
- aldolase A catalyzes the conversion of fructose- 1-phophate to glyceraldehyde and dihydroxyacetone phosphate
- aldolase A catalyzes the conversion of fructose- 1,6-bis-phosphate to glyceraldehyde-3 -phosphate and dihydroxyacetone phosphate, respectively.
- Trioseisomerase catalyzes the conversion of dihydroxyacetone phosphate to glyceraldehyde-3 -phosphate, while triokinase with the expenditure of a single ATP molecule catalyzes the conversion of glyceraldehyde to glyceraldehyde-3 -phosphate, thus linking the fructose catalytic and glycolytic pathways.
- Aldolase B is not commercially available ⁇ therefore aldolase A which can also catalyze the conversion of fructose- 1,6-bis-phosphate to glyceraldehyde-3 -phosphate and dihydroxyacetone phosphate, was employed to detemiine the potential effect ofthe extract on these enzymes in vitro, as described in Example 6.
- Example 7 describes a human clinical trial initiated to test the effectiveness ofthe extract on human weight loss.
- the results are set forth in Figures 9-13.
- Figure 9 depicts the effect of the Free-B-Ring flavonoid and flavan extract on weight loss in 13 individuals orally administered 250 mg per day over a 90-day period. Individual weights (initial and final) are shown above each measurement for each subject. With reference to Figure 9, it can be seen that at dosage of 250 mg per day a significant weight loss was observed in 13 of 14 individuals remaining in the study after 90 days. Only one subject (subject 4) did not show weight loss. The weight data differences between day 0 and day 90 showed a statistical significance with p ⁇ 0.001.
- Figure 10 illustrates the effect of the Free-B-Ring flavonoid and flavan extract on weight loss in 13 individuals orally administered 500 mg per day over a 90-day period. Individual weights (initial and final) are shown above each measurement for each subject. As can be seen in Figure 10, when the dosage was increased to 500 mg per day, the weight loss showed a different pattern. Subjects with higher BMIs tended to lose more weight than those with lower BMIs. A stratification occurred in which lower weight subjects either did not lose weight or even gained in some cases (see subjects 3, 15, 43, and 47). Thirteen subjects completed the study. The statistical significance for this data showed a p ⁇ 0.011.
- Figure 11 depicts the effect on weight loss in 13 individuals orally administered a placebo over a 90-day period. Individual weights (initial and final) are shown above each measurement for each human subject. As can be seen in this figure, the placebo group showed very little change in weight for the 13 subjects that completed the trial.
- Figure 12 illustrates the effect ofthe Free-B-Ring flavonoid and flavan extract on BMI in individuals orally administered 250 and 500 mg per day versus placebo at 30 and 90 days.
- Figure 12 when the average BMI for all tliree groups was plotted, significant differences are observed.
- the p ⁇ 0.075 At a dose of 250 mg per day versus the placebo, the p ⁇ 0.075, while the 500 mg per day dose showed a p ⁇ 0.005.
- Within group analysis showed p ⁇ 0.004 for 250 mg dose versus p ⁇ 0.051 for the 500 mg per day dose.
- Figure 13 illustrates the effect ofthe Free-B-Ring flavonoid and flavan extract on changes in blood glucose in individuals orally administered 250 and 500 mg per day versus placebo at 0, 30 and 90 days.
- blood glucose levels went down in the 250 and 500 mg per day groups with the latter showing the greatest change.
- the fasting serum glucose data showed significance compared to the baseline data with a p ⁇ 0.018 for the 500 mg per day dose and p ⁇ 0.014 for the 250 mg per day dose.
- the fasting serum glucose data showed significance compared to the baseline data with a p ⁇ 0.018 for the 500 mg per day dose and p ⁇ 0.014 for the 250 mg per day dose.
- mice were fed the test articles by oral gavage with daily doses of 90 mg/kg (equivalent to the human daily dose of 500 mg), 450 mg/kg (five times the daily dose equivalent) and 900 mg/kg (ten times the daily dose equivalent). The treated mice showed no adverse effects in terms of weight gain, physical appearance and behavior.
- Free-B-Ring flavonoids and flavans Based on the ability of Free-B-Ring flavonoids and flavans to directly inhibit sugar-induced obesity, as well as, their activity in genomically reducing NFKB the key transcription factor in the regulation ofthe pro-inflammatory cytokine markers for obesity, TNF ⁇ and IL-6, the composition described herein will effectively inhibit weight gain, sugar-based lipogenesis and systemic inflammation. Additionally, the ability of Free-B- Ring flavonoids and flavans to directly inhibit aldolase, which converts fructose- 1- phosphate to glyceraldehydes and dihydroxyacetone phosphate, will result in a decrease in the amount of substrate available for synthesis of fat in both de novo and fructose-induced lipogenesis.
- Example 1 Effect of a mixture of Free-B-Ring flavonoids and flavans on weight gain resulting from a diet supplemented with fructose or fat for three weeks
- composition of matter comprised of a mixture of Free B-Ring flavonoids and flavans has weight gain
- a defined plant extract containing Free-B-Ring flavonoids isolated from Scutellaria baicalensis and flavans isolated from Acacia catechu in a ratio of 80:20 (Free-B-Ring flavonoids:flavans) was used.
- This composition of matter was formulated as described in U.S. Application Serial No. 10/427,746, filed April 30, 2003, entitled “Formulation With Dual Cox-2 And 5- Lipoxygenase Inhibitory Activity," which is incorporated herein by reference in its entirety.
- mice Six-week-old ICR female mice (ten per test group) (Harlan Laboratories) were gavaged with the extract in water at a therapeutic dose of 100 mg/kg. One group of mice were fed their normal diet and given a 65% solution of fructose as their drinking water, administered ad libitum. A second group of mice were fed a diet that was supplemented with fat and administered ad libitum. Two test groups were given either 65% fructose in their water (without extract) or their diet was supplemented with fat ad libitum (without extract). The results are set forth in Figure 2.
- Example 2 Effect of a mixture of Free-B-Ring flavonoids and flavans on weight gain resulting from a diet supplemented with fructose and glucose for eight weeks
- test groups received the control diet plus 65% fructose ad libitum in their water. One of these groups was gavaged daily with 100 mg/kg of extract. The final two test groups received the control diet plus 65% glucose ad libitum in their water. One of these groups was gavaged daily with 100 mg/kg of extract. After eight weeks, the average weights were plotted with the standard error ofthe mean (SEM) shown on the graph.
- SEM standard error ofthe mean
- PBMCs Peripheral blood monocytes
- LPS lipopolysaccharide
- PBMCs Peripheral blood monocytes
- LPS lipopolysaccharide
- Example 5 Effect of a mixture of Free-B-Ring flavonoids and flavans on the gene expression ofthe transcription factor NFKB and on the gene expression of TNF ⁇ PBMCs were induced with 1 mg/ml LPS for 18 hours and co-cultured with increasing amounts ofthe Free-B-Ring flavonoid:flavan extract. RNA was then isolated (Qiagen), reverse transcribed to DNA, and subjected to PCR using the TaqMan system and pre-validated primers for both NFKB and TNF ⁇ in quantitative PCR (ABI). Relative gene expression was measured in the presence of 0 to 100 ⁇ g/mL of extract. The results are set forth in Figures 6 and 7.
- Example 6 Effect of a mixture of Free-B-Ring flavonoids and flavans on the enzyme adolase A
- Aldolase A (Sigma) at 1 unit/ ⁇ L was added to a solution of 4 mM fructose- 1- phosphate in a buffer containing 100 ⁇ M EDTA and 3.5 mM hydrazine sulfate, pH 7.5
- Example 9 Quantification ofthe mixture of Free-B-Ring flavonoids and flavans by reverse phase Isocratic HPLC (Method 2)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006503820A JP2006519231A (en) | 2003-02-26 | 2004-02-24 | Formulations for the prevention and treatment of carbohydrate-induced diseases and conditions |
EP04714134A EP1596877A4 (en) | 2003-02-26 | 2004-02-24 | Formulation for use in the prevention and treatment of carbohydrate induced diseases and conditions |
CA002516710A CA2516710A1 (en) | 2003-02-26 | 2004-02-24 | Formulation for use in the prevention and treatment of carbohydrate induced diseases and conditions |
BRPI0407893-4A BRPI0407893A (en) | 2003-02-26 | 2004-02-24 | formulation for use in the prevention and treatment of carbohydrate-induced diseases and conditions |
HK06109870.0A HK1089376A1 (en) | 2003-02-26 | 2006-09-05 | Formulation for use in the prevention and treatment of carbohydrate induced ; diseases and conditions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45092203P | 2003-02-26 | 2003-02-26 | |
US60/450,922 | 2003-02-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004075844A2 true WO2004075844A2 (en) | 2004-09-10 |
WO2004075844A3 WO2004075844A3 (en) | 2005-07-07 |
Family
ID=32927688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/005353 WO2004075844A2 (en) | 2003-02-26 | 2004-02-24 | Formulation for use in the prevention and treatment of carbohydrate induced diseases and conditions |
Country Status (9)
Country | Link |
---|---|
US (1) | US7531521B2 (en) |
EP (1) | EP1596877A4 (en) |
JP (1) | JP2006519231A (en) |
KR (1) | KR20050103962A (en) |
CN (1) | CN100560076C (en) |
BR (1) | BRPI0407893A (en) |
CA (1) | CA2516710A1 (en) |
HK (1) | HK1089376A1 (en) |
WO (1) | WO2004075844A2 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1631304A1 (en) * | 2003-04-04 | 2006-03-08 | Unigen Pharmaceuticals, Inc. | Formulation of dual cycloxygenase (cox) and lipoxygenase (lox) inhibitors for mammal skin care |
JP2006232782A (en) * | 2005-02-28 | 2006-09-07 | Wood One:Kk | Anti-obestic composition comprising substance derived from bark of genus acacia |
JP2006232781A (en) * | 2005-02-28 | 2006-09-07 | Wood One:Kk | Hypoglycemic composition comprising substance derived from bark of genus acacia |
CN101175406A (en) * | 2005-03-10 | 2008-05-07 | 尤尼根制药公司 | Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent |
WO2009014315A1 (en) * | 2007-07-26 | 2009-01-29 | Korea Institute Of Science And Technology | A composition that is comprising extracts, fractions or isolated single compounds of robinia pseudo-acacia var. umbraculifera |
EP2052728A1 (en) * | 2006-08-10 | 2009-04-29 | Wood One Co., Ltd. | Hypoglycemic composition containing component originating in the bark of tree belonging to the genus acacia |
JP2009518439A (en) * | 2005-12-09 | 2009-05-07 | メタプロテオミクス,エルエルシー | Protein kinase regulation by hops and acacia products |
US8568799B2 (en) | 2002-03-22 | 2013-10-29 | Unigen, Inc. | Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from acacia |
WO2014035060A1 (en) * | 2012-08-31 | 2014-03-06 | 한국생명공학연구원 | Composition for preventing or treating cancer containing extracts of artocarpus altilis fruits, leaves, or stems, or fractions thereof as active ingredients |
US9370544B2 (en) | 2002-04-30 | 2016-06-21 | Unigen, Inc. | Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent |
US9827279B2 (en) | 2008-07-07 | 2017-11-28 | Kao Corporation | Xanthine oxidase inhibitor and uric acid production inhibitor |
EP2052729B1 (en) * | 2006-08-10 | 2018-09-12 | mimozax Co., Ltd. | Antiobesity composition containing component originating in the bark of tree belonging to the genus acacia |
ES2912350A1 (en) * | 2021-09-19 | 2022-05-25 | Fundacion Univ San Antonio Ucam | New colorectal cancer treatment (Machine-translation by Google Translate, not legally binding) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8206753B2 (en) * | 2001-06-20 | 2012-06-26 | Metaproteomics, Llc | Anti-inflammatory botanical products for the treatment of metabolic syndrome and diabetes |
US7972632B2 (en) | 2003-02-28 | 2011-07-05 | Unigen Pharmaceuticals, Inc. | Identification of Free-B-Ring flavonoids as potent COX-2 inhibitors |
US8034387B2 (en) * | 2002-04-30 | 2011-10-11 | Unigen, Inc. | Formulation of a mixture of free-B-ring flavonoids and flavans for use in the prevention and treatment of cognitive decline and age-related memory impairments |
US8945518B2 (en) * | 2002-04-30 | 2015-02-03 | Unigen, Inc. | Formulation of dual eicosanoid system and cytokine system inhibitors for use in the prevention and treatment of oral diseases and conditions |
CA2632607A1 (en) * | 2005-12-09 | 2007-06-21 | Metaproteomics, Llc | Anti-inflammatory botanical products for the treatment of metabolic syndrome and diabetes |
WO2008018142A1 (en) * | 2006-08-10 | 2008-02-14 | Wood One Co., Ltd. | Antioxidant composition containing component originating in the bark of tree belonging to the genus acacia |
KR101332531B1 (en) * | 2006-08-10 | 2013-11-22 | 가부시키가이샤 미모잭스 | Composition for preventing and/or treating itching containing component originating in the bark of tree belonging to the genus acacia |
EP2052730B1 (en) * | 2006-08-10 | 2016-03-23 | mimozax Co., Ltd. | Composition for preventing and/or treating tumor containing component originating in the bark of tree belonging to the genus acacia |
US20080139527A1 (en) * | 2006-12-08 | 2008-06-12 | Reddy Kota J | Methods for treatment of heart disease |
US7759317B2 (en) * | 2006-12-28 | 2010-07-20 | Bmb Patent Holding Corporation | Analgesic and anti-inflammatory compositions and methods with flavonoid glycoside-type compounds |
US8633252B2 (en) * | 2009-01-26 | 2014-01-21 | Taipei Medical University | Use of pterosin compounds for treating diabetes and obesity |
WO2011109353A2 (en) * | 2010-03-01 | 2011-09-09 | Natcure Sciences | Immunosuppressant extracts derived from millettia laurentii or pseudotsuga pinaceae |
US8450350B2 (en) | 2010-05-05 | 2013-05-28 | Infinity Pharmaceuticals, Inc. | Triazoles as inhibitors of fatty acid synthase |
CA2798330A1 (en) | 2010-05-05 | 2011-11-10 | Infinity Pharmaceuticals, Inc. | Tetrazolones as inhibitors of fatty acid synthase |
JP6259899B2 (en) * | 2016-12-12 | 2018-01-10 | 花王株式会社 | GLP-1 secretion promoter |
CN107296824A (en) * | 2017-06-30 | 2017-10-27 | 广西民族大学 | Comospore trifoliate jewelvine ligroin extraction and its preparation and inflammatory applications |
CN107308199A (en) * | 2017-07-13 | 2017-11-03 | 博奥生物集团有限公司 | The application of Japanese Raspberry Root or its extract in fat-reducing medicament is prepared |
CN117120043A (en) | 2020-07-30 | 2023-11-24 | 尤尼根公司 | Standardized bioflavonoid compositions for regulating host defense mechanism homeostasis |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2651132B1 (en) | 1989-08-30 | 1993-01-08 | Pacific Chem Co Ltd | PROTECTIVE AGENTS FOR CELLS AGAINST CHEMICAL SPECIES WITH ACTIVE OXYGEN AND THEIR PREPARATION. |
JPH03240725A (en) | 1990-02-15 | 1991-10-28 | Senjiyu Seiyaku Kk | Maillard reaction inhibitor |
US5650432A (en) | 1995-03-24 | 1997-07-22 | Jlb, Inc. | Method of treating or preventing non-viral microbial infection |
CN1043406C (en) * | 1993-12-27 | 1999-05-19 | 尚庆英 | Method for preparation of compound Qingdaisan powder |
JPH07223941A (en) | 1994-02-14 | 1995-08-22 | Nippon Ham Kk | Anticomplementary substance |
CA2175985A1 (en) * | 1995-05-10 | 1996-11-11 | Yoichi Kiyosuke | Pharmaceutical composition containing substance inhibiting hsp47 production |
JPH08301757A (en) * | 1995-05-10 | 1996-11-19 | Kureha Chem Ind Co Ltd | Hsp47 synthesis suppressing agent |
US6093403A (en) | 1997-08-01 | 2000-07-25 | Phytocell Research, Inc. | Sugar imbalance and diabetes treating herbal formulation |
US5886029A (en) * | 1997-09-05 | 1999-03-23 | Dhaliwal; Kirpal S. | Method and composition for treatment of diabetes |
JP2001507198A (en) | 1997-10-02 | 2001-05-29 | 株式会社ニッコー | A device that shields radio waves transmitted from mobile communication devices |
US6696484B2 (en) | 1997-10-31 | 2004-02-24 | University Of Chicago Office Of Technology And Intellectual Property | Method and compositions for regulation of 5-alpha reductase activity |
EP1027045A4 (en) * | 1997-10-31 | 2004-12-08 | Arch Dev Corp | Methods and compositions for regulation of 5-alpha reductase activity |
US6083921A (en) | 1998-01-12 | 2000-07-04 | Xu; Kai Jian | Pharmaceutical compositions and method of using same |
US6080401A (en) | 1998-11-19 | 2000-06-27 | Reddy; Malireddy S. | Herbal and pharmaceutical drugs enhanced with probiotics |
WO2000059523A1 (en) | 1999-04-08 | 2000-10-12 | Metagenics, Inc. | Composition and method for treatment of inflammation and pain in mammals |
US6475530B1 (en) * | 2000-05-31 | 2002-11-05 | Eric H. Kuhrts | Methods and compositions for producing weight loss |
JP4719372B2 (en) * | 2000-06-21 | 2011-07-06 | 花王株式会社 | PPAR-dependent gene transcription activator |
JP2002053484A (en) | 2000-08-07 | 2002-02-19 | Asahi Breweries Ltd | Lipase inhibitor, and food and drink containing the same |
WO2003002134A1 (en) * | 2001-06-27 | 2003-01-09 | Unigen Pharmaceuticals, Inc. | Method for generating, screening and dereplicating natural product libraries for the discovery of therapeutic agents |
US7108868B2 (en) * | 2002-03-22 | 2006-09-19 | Unigen Pharmaceuticals, Inc. | Isolation of a dual cox-2 and 5-lipoxygenase inhibitor from acacia |
BRPI0309689B1 (en) * | 2002-04-30 | 2021-06-29 | Unigen, Inc | COMPOSITIONS COMPRISING A MIXTURE OF B-RING-FREE FLAVONOIDS AND FLAVANES AND USES THEREOF |
-
2004
- 2004-02-24 US US10/785,704 patent/US7531521B2/en not_active Expired - Lifetime
- 2004-02-24 EP EP04714134A patent/EP1596877A4/en not_active Withdrawn
- 2004-02-24 JP JP2006503820A patent/JP2006519231A/en active Pending
- 2004-02-24 KR KR1020057015855A patent/KR20050103962A/en not_active Application Discontinuation
- 2004-02-24 BR BRPI0407893-4A patent/BRPI0407893A/en not_active IP Right Cessation
- 2004-02-24 WO PCT/US2004/005353 patent/WO2004075844A2/en active Application Filing
- 2004-02-24 CN CNB2004800052087A patent/CN100560076C/en not_active Expired - Fee Related
- 2004-02-24 CA CA002516710A patent/CA2516710A1/en not_active Abandoned
-
2006
- 2006-09-05 HK HK06109870.0A patent/HK1089376A1/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of EP1596877A4 * |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8568799B2 (en) | 2002-03-22 | 2013-10-29 | Unigen, Inc. | Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from acacia |
US9168242B2 (en) | 2002-03-22 | 2015-10-27 | Unigen, Inc. | Isolation of a dual COX-2 and 5-lipdxygenase inhibitor from Acacia |
US9849152B2 (en) | 2002-04-30 | 2017-12-26 | Unigen, Inc. | Formulation of a mixture of Free-B-ring flavonoids and flavans as a therapeutic agent |
US9370544B2 (en) | 2002-04-30 | 2016-06-21 | Unigen, Inc. | Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent |
EP1631304A4 (en) * | 2003-04-04 | 2007-03-21 | Unigen Pharmaceuticals Inc | Formulation of dual cycloxygenase (cox) and lipoxygenase (lox) inhibitors for mammal skin care |
US9622964B2 (en) | 2003-04-04 | 2017-04-18 | Unigen, Inc. | Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care |
EP1631304A1 (en) * | 2003-04-04 | 2006-03-08 | Unigen Pharmaceuticals, Inc. | Formulation of dual cycloxygenase (cox) and lipoxygenase (lox) inhibitors for mammal skin care |
US8790724B2 (en) | 2003-04-04 | 2014-07-29 | Unigen, Inc. | Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care |
JP2006232782A (en) * | 2005-02-28 | 2006-09-07 | Wood One:Kk | Anti-obestic composition comprising substance derived from bark of genus acacia |
JP2006232781A (en) * | 2005-02-28 | 2006-09-07 | Wood One:Kk | Hypoglycemic composition comprising substance derived from bark of genus acacia |
CN101175406A (en) * | 2005-03-10 | 2008-05-07 | 尤尼根制药公司 | Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent |
CN101175406B (en) * | 2005-03-10 | 2012-11-21 | 尤尼根公司 | Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent |
JP2009518439A (en) * | 2005-12-09 | 2009-05-07 | メタプロテオミクス,エルエルシー | Protein kinase regulation by hops and acacia products |
EP2052729B1 (en) * | 2006-08-10 | 2018-09-12 | mimozax Co., Ltd. | Antiobesity composition containing component originating in the bark of tree belonging to the genus acacia |
EP2052728A4 (en) * | 2006-08-10 | 2012-03-21 | Mimozax Co Ltd | Hypoglycemic composition containing component originating in the bark of tree belonging to the genus acacia |
EP2052728A1 (en) * | 2006-08-10 | 2009-04-29 | Wood One Co., Ltd. | Hypoglycemic composition containing component originating in the bark of tree belonging to the genus acacia |
WO2009014315A1 (en) * | 2007-07-26 | 2009-01-29 | Korea Institute Of Science And Technology | A composition that is comprising extracts, fractions or isolated single compounds of robinia pseudo-acacia var. umbraculifera |
US9827279B2 (en) | 2008-07-07 | 2017-11-28 | Kao Corporation | Xanthine oxidase inhibitor and uric acid production inhibitor |
US9486490B2 (en) | 2012-08-31 | 2016-11-08 | Korea Research Institute Of Bioscience And Biotechnology | Composition for preventing or treating cancer containing extracts of artocarpus altilis fruits, leaves, or stems, or fractions thereof as active ingredients |
WO2014035060A1 (en) * | 2012-08-31 | 2014-03-06 | 한국생명공학연구원 | Composition for preventing or treating cancer containing extracts of artocarpus altilis fruits, leaves, or stems, or fractions thereof as active ingredients |
ES2912350A1 (en) * | 2021-09-19 | 2022-05-25 | Fundacion Univ San Antonio Ucam | New colorectal cancer treatment (Machine-translation by Google Translate, not legally binding) |
Also Published As
Publication number | Publication date |
---|---|
EP1596877A2 (en) | 2005-11-23 |
JP2006519231A (en) | 2006-08-24 |
CN100560076C (en) | 2009-11-18 |
US20040186062A1 (en) | 2004-09-23 |
KR20050103962A (en) | 2005-11-01 |
HK1089376A1 (en) | 2006-12-01 |
CN1753681A (en) | 2006-03-29 |
BRPI0407893A (en) | 2006-03-01 |
EP1596877A4 (en) | 2007-07-25 |
US7531521B2 (en) | 2009-05-12 |
WO2004075844A3 (en) | 2005-07-07 |
CA2516710A1 (en) | 2004-09-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7531521B2 (en) | Formulation for use in the prevention and treatment of carbohydrate induced diseases and conditions | |
US9849152B2 (en) | Formulation of a mixture of Free-B-ring flavonoids and flavans as a therapeutic agent | |
US9622964B2 (en) | Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care | |
CN101083981B (en) | Flavonoid composition for treating oral diseases | |
KR20070030160A (en) | Formulation of a mixture of free-b-ring flavonoids and flavans for use in the prevention and treatment of cognitive decline and age-related memory impairments | |
Mehta et al. | Research and Reviews: Journal of Medical and Health Sciences |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2516710 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004714134 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020057015855 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006503820 Country of ref document: JP Ref document number: 20048052087 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 1020057015855 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2004714134 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0407893 Country of ref document: BR |