WO2002087567A2 - Polymethoxylated flavones for treating insulin resistance - Google Patents
Polymethoxylated flavones for treating insulin resistance Download PDFInfo
- Publication number
- WO2002087567A2 WO2002087567A2 PCT/CA2002/000662 CA0200662W WO02087567A2 WO 2002087567 A2 WO2002087567 A2 WO 2002087567A2 CA 0200662 W CA0200662 W CA 0200662W WO 02087567 A2 WO02087567 A2 WO 02087567A2
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- WO
- WIPO (PCT)
- Prior art keywords
- polymethoxyflavone
- tangeretin
- insulin resistance
- composition
- serum
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
Definitions
- the present invention relates to the use of polymethoxylated flavones (PMFs) for treating the effects of insulin resistance syndrome.
- PMFs polymethoxylated flavones
- Insulin resistance is defined as an impaired ability of insulin to stimulate glucose uptake and lipolysis and to modulate liver and muscle lipid metabolism.
- insulin resistance syndrome leads to compensatory hyperinsulinemia and to various defects in lipid metabolism such as enhanced secretion of atherogenic, triacylglycerol-rich very low-density lipoproteins (VLDL), increased liberation of nonesterified fatty acids (NEF A) from adipose tissue and increased accumulation of triacylglycerols in the liver 1 .
- VLDL very low-density lipoproteins
- NEF A nonesterified fatty acids
- Other metabolic defects associated with insulin resistance include impairment of endothelium-dependent vasodilation. This last abnormality is largely a consequence of reduced bioavailability of nitric oxide, an important biological mediator involved in protection against atherosclerosis .
- Insulin resistance syndrome commonly precedes type 2 diabetes and both disorders are associated with increased risk of heart disease. Dietary strategies designed to diminish this risk are currently not well established. The most common approach is the recommendation to lower intake of total calories, especially fat and sugar, and to increase intake of fiber 3 .
- polymethoxylated flavones or polymethoxyflavones, (PMFs) from citrus fruits, especially tangeretin (5,6,7,8,4'- pentamethoxyflavone) from tangerines
- Flavonoids are polyphenolic compounds that are found in plant foods, especially in oranges, grapefruits and tangerines.
- PMFs are flavonoid compounds having multiple methoxy substituents.
- beneficial effects of flavonoids are described in US patents 6,251,400 and 6,239,114 and in PCT publication number WO/01/70029, issued to the present inventors and the disclosures of which are incorporated herein by reference.
- Other beneficial effects of flavonoid derivatives are discussed in US patents 4,591,600; 5,855,892; and, 6,096,364, the disclosures of which are also incorporated herein by reference.
- tangeretin substantially reduced production of apolipoprotein B (apo B), the structural protein of VLDL and LDL. This was associated with inhibition of synthesis of cellular lipids, especially triacylglycerols and cholesteryl esters, and with decreased cellular accumulation of triacylglycerols.
- apo B-lowering effect of tangeretin was also maintained in the presence of excess of oleic acid, a NEFA known to stimulate cellular biosynthesis of neutral lipids for assembly and secretion of apo B-containing lipoproteins in the liver 4 .
- the present invention provides, in one aspect, a method of treating hyperlipidemia comprising the use of a polymethoxyflavone.
- the invention provides a use of a polymethoxyflavone as a hypolipidemic agent.
- the invention provides for tangeretin as the above mentioned polymethoxyflavone.
- Figure 1 illustrates the effect of tangeretin on apo-B responses in in vitro studies.
- Figure 2 illustrates the effect of tangeretin on serum total cholesterol in hamsters.
- Figure 3 illustrates the effect of tangeretin on HDL cholesterol responses in hamsters.
- Figure 4 illustrates the effect of tangeretin on serum trigylceride responses in hamsters.
- Figure 5 illustrates the effect of tangeretin on serum NEFA responses in hamsters.
- Figure 6 illustrates the effect of tangeretin on serum insulin responses in hamsters.
- Figure 7 illustrates the effect of tangeretin on serum nitrate/nitrite levels in hamsters.
- Figure 10 illustrates a general structure of flavonoid compounds.
- Figure 11 illustrates the effect of PMFs on alpha-glucosidase activity in vitro.
- Figure 12 illustrates the effect of experimental diets on serum cholesterol levels.
- Figure 13 illustrates the effect of experimental diets on serum triacylglycerol
- Figure 14 illustrates the correlation between serum triacyglycerol and NEFA levels.
- Figure 15 illustrates the effect of PMFs on glucose tolerance.
- the present invention provides compositions and methods for treating metabolic defects associated with insulin resistance, otherwise referred to as insulin resistance syndrome, in mammals and, more particularly, humans.
- the compositions of the present invention comprise PMFs that are obtained from natural sources, and, therefore, are readily available and are generally non-toxic when administered in acceptable dosages as described below.
- Figure 1 illustrates a general structure for the flavonoids of the present invention.
- a polymethoxylated flavones or polymethoxyflavone (PMF) are flavones substituted with two or more methoxy groups.
- PMFs can include two to seven methoxy groups.
- PMF compounds are also substituted with one or more hydroxy groups.
- tangeretin and nobiletin fall withing the above PMF definition.
- Hesperetin and naringenin are members of the group of flavonoids referred to as flavonones.
- the amount of the PMFs of the administered to a patient will depend on various factors. Acceptable dosages of the PMFs of the invention may be up to 5000 mg/day. Preferable dosages range from 200 - 5000 mg/day, commonly 1000-2000 mg/day, and typically 500-1500 mg/day. On a patient basis, the dosage of the PMFs may be up to 70 mg/kg/day, based on the weight of the patient. Patient dosages may range from 15-70 mg/kg/day, commonly 15-30 mg/kg/day and typically 7-21 mg/kg/day. As will be understood by persons skilled in the art, the dosage administered to the patient will depend on a number of factors such as the severity of the condition being treated, the age and weight of the patient etc.
- Formulations containing the PMFs of the present invention may by administered by any acceptable means including orally, transdermally, rectally, intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, by inhalation or any other means.
- the oral administration means is preferred.
- Formulations suitable for oral administration are commonly known and include liquid solutions of the active PMF compounds dissolved in a diluent such as, for example, saline, water, PEG 400 etc.
- Solid forms of the compounds for oral administration include capsules or tablets, each comprising the active ingredients and commonly known adjuvants.
- compositions suitable for parenteral administration include aqueous and non- aqueous isotonic sterile solutions containing buffers, antioxidants, preservatives and any other known adjuvants.
- the PMFs of the invention can be administered as a single dose or in a sustained release formulation.
- the present invention comprises the use of a mixture of PMFs as the therapeutically effective active ingredient.
- the invention comprises the use of tangeretin as the sole active ingredient.
- Example 1 Effect of Tangeretin in Treating Insulin Resistance Syndrome
- tangeretin reduced pathological responses known to be associated not only with hypercholesterolemia but also with insulin resistance (hypertriglyceridemia, high plasma free fatty acids and possibly high triacylglycerols in liver cells). For this reason, its effect was investigated in cell culture and animal models of insulin resistance.
- the hypolipidemic potential of tangeretin was evaluated using HepG2 cells made insulin-resistant by long-term incubation with high concentrations of insulin 6 .
- metabolic responses to increasing doses of tangeretin were determined using hamsters made insulin resistant by feeding 60% fructose diet 7 .
- hamsters (8-10 animals each) were given semipurified, 60% fructose diet with or without 0.25%, 0.5% or 1.0% tangeretin, and the control group was fed a standard semipurified diet which did not produce insulin resistance. Diets were pair-fed to control for 2 weeks. After that time, fasting blood samples were collected by heart puncture for measurement of plasma lipids, glucose, NEFA, insulin and nitrites/nitrates (end products of nitric oxide metabolism). Total cholesterol in whole serum and in HDL fraction as well as total triglycerides and glucose were measured by enzymatic timed-endpoint methods, using the Beckman Coulter reagents and SYNCHRONTM LX System.
- VLDL + LDL cholesterol concentrations were calculated as a difference between total and HDL cholesterol.
- NEFA were determined enzymatically by NEFA C kit (Wako Chemicals USA Inc., Richmond, Va). Serum insulin was measured using Rat Insulin RIA kit from Linco Research Inc. St. Charles, Missouri. Serum nitrates/nitrites concentrations were determined using Nitrate/Nitrite Colorimetric Assay kit from Cayman Chemical Co., Ann Arbor, MI. [0038] As indicated in Table 1, the growth performance data showed no significant difference in growth rate and food consumption between the groups.
- tangeretin tended to normalize serum NEFA concentrations.
- a diet containing 1.0% tangeretin also tended to normalize serum content of insulin.
- Serum nitrate/nitrite concentrations were not affected by fructose feeding but their concentration was doubled in the group given fructose with 1% tangeretin.
- Serum glucose was not altered by fructose feeding or by supplementation with tangeretin.
- tangeretin additionally tended to normalize elevated serum levels of NEFA and insulin.
- the beneficial effect of tangeretin on serum NEFA could be associated with its ability to modulate triacylglycerol metabolism, as suggested by the significant positive correlation between serum NEFA and serum triacylglycerol levels.
- a tangeretin- induced tendency to normalize serum insulin could be linked to its ability to raise the systemic level of endothelium-derived nitric oxide.
- recent studies in rats with fructose-induced insulin resistance and in patients with type 2 diabetes postulated a functional coupling between insulin resistance and endothelial nitric oxide production 9, 10 .
- the inverse correlation was found between serum levels of insulin and nitric oxide metabolites.
- Example 2 Effect of a mixture of PMFs in Treating Insulin Resistance Syndrome
- alpha-glucosidase Type 1 from bakers yeast was incubated for 30 min, at 37°C, in the presence of substrate (p-nitrophenyl-alpha-D-glucopyranoside) and in the presence vs. absence of citrus flavonoids or coumarins at concentrations ranging from 3 to 200 ⁇ g mL (0.01 to 1.8 mM).
- substrate p-nitrophenyl-alpha-D-glucopyranoside
- the reaction was stopped by addition of 0.2 M Na 2 CO 3 and absorbance was measured at 405 nm. Background absorbance (without enzyme) was subtracted for every flavonoid or coumarins concentration used.
- the inhibitory activity was expressed as percent control and IC 50 values (concentrations of compounds required to inhibit alpha-glucosidase by 50%) were calculated.
- the additional objective was to evaluate the effect of dietary PMF on glucose tolerance and on serum concentrations of leptin.
- Hamsters (9-10 per group) were given semipurified, 60% fructose diet with or without 1% PMF, and the control group was fed a standard semipurified diet, which did not produce insulin resistance. After 17-18 days, a glucose tolerance test was performed in fasted animals injected i.p. with 1 g/kg of glucose (6- 7 hamsters/group). Serum glucose concentrations were measured before the i.p. injection and in 30 min intervals for 2 h after the injection by using a blood glucose meter.
- lipids lipids, glucose, NEFA (non-esterified fatty acids), insulin, nitrites/nitrates (end products of nitric oxide metabolism) and leptin.
- Total cholesterol in whole serum and in HDL fraction as well as total triacylglycerols and glucose were measured by enzymatic timed-endpoint methods, using the Beckman Coulter reagents and SYNCHRONTM LX System.
- VLDL + LDL cholesterol concentrations were calculated as a difference between total and HDL cholesterol.
- NEFA were determined enzymatically by NEFA C kit (Wako Chemicals USA Inc., Richmond, Va).
- Serum insulin and serum nitrates/nitrites concentrations were determined using Insulin kit and Nitrate/Nitrite Colorimetric Assay kit from Cayman Chemical Co., Ann Arbor, MI. Leptin was evaluated with the kit from Assay Designs Inc., Ann Arbor, MI.
- Results of the glucose tolerance test are depicted in Figure 15 and in Table 6. Glucose levels during the test tended to be reduced in PMF-fed animals, resulting in 21% lower area under the curve and 28% lower maximum serum glucose concentration. This suggests a reduced tendency to develop glucose intolerance (associated with insulin resistance) in hamsters fed PMF-supplemented diet.
- PMF supplementation also appears to have a beneficial effect on glucose metabolism, reducing glucose intolerance.
- the mechanism of action of PMF in insulin resistance may involve inhibition of alpha-glucosidase in the gut.
- Type 2 Diabetes Mellitus Endocr. J. 47 (2000), 77-81. [0063] 10. Oshida, Y., Tachi, Y., Morishita, Y., Kitakoshi, K., Fuku, N., Han, Y.Q., Oshawa, I. and Sato, Y. Nitric Oxide Decreases Insulin Resistance Induced By High- Fructose Feeding. Horm. Metab. Res. 32 (2000), 339-342.
- Values are means ⁇ SD.
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Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ529243A NZ529243A (en) | 2001-05-02 | 2002-05-02 | Use of polymethoxylated flavones for treating insulin resistance |
MXPA03010080A MXPA03010080A (en) | 2001-05-02 | 2002-05-02 | Use of polymethoxylated flavones for treating insulin resistance. |
AU2002308324A AU2002308324B2 (en) | 2001-05-02 | 2002-05-02 | Polymethoxylated flavones for treating insulin resistance |
CA002445963A CA2445963A1 (en) | 2001-05-02 | 2002-05-02 | Polymethoxylated flavones for treating insulin resistance |
US10/697,563 US20040152641A1 (en) | 2001-05-02 | 2003-10-31 | Use of polymethoxylated flavones for treating insulin resistance |
Applications Claiming Priority (2)
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US28770301P | 2001-05-02 | 2001-05-02 | |
US60/287,703 | 2001-05-02 |
Related Child Applications (1)
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US10/697,563 Continuation US20040152641A1 (en) | 2001-05-02 | 2003-10-31 | Use of polymethoxylated flavones for treating insulin resistance |
Publications (2)
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WO2002087567A2 true WO2002087567A2 (en) | 2002-11-07 |
WO2002087567A3 WO2002087567A3 (en) | 2002-12-27 |
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PCT/CA2002/000662 WO2002087567A2 (en) | 2001-05-02 | 2002-05-02 | Polymethoxylated flavones for treating insulin resistance |
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US (1) | US20040152641A1 (en) |
AU (1) | AU2002308324B2 (en) |
CA (1) | CA2445963A1 (en) |
MX (1) | MXPA03010080A (en) |
NZ (1) | NZ529243A (en) |
WO (1) | WO2002087567A2 (en) |
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WO2006077972A1 (en) * | 2005-01-21 | 2006-07-27 | Arkray, Inc. | Metabolic syndrome-improving agent and medicine, supplement, functional food and food additive containing the same |
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WO2007132893A1 (en) * | 2006-05-17 | 2007-11-22 | Arkray, Inc. | Suppressor of expression of mcp-1, and ameliorating agent for inflammatory disease, pharmaceutical, supplement, food, beverage or food additive using the suppressor |
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US9610276B2 (en) | 2013-06-17 | 2017-04-04 | Kgk Synergize, Inc. | Compositions and methods for glycemic control of subjects with impaired fasting glucose |
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US6987125B1 (en) * | 1998-10-06 | 2006-01-17 | The United States Of America As Represented By The Secretary Of Agriculture | Compositions and methods of treating, reducing and preventing cardiovascular diseases and disorders with polymethoxyflavones |
US20060013861A1 (en) * | 2004-05-26 | 2006-01-19 | Kgk Synergize Inc. | Functional foods comprising flavonoids and tocotrienols and methods thereof |
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US7887852B2 (en) * | 2005-06-03 | 2011-02-15 | Soft Gel Technologies, Inc. | Soft gel capsules containing polymethoxylated flavones and palm oil tocotrienols |
US20050249803A1 (en) * | 2005-06-03 | 2005-11-10 | Udell Ronald G | Soft gel capsules containing polymethoxylated flavones and palm oil tocotrienols |
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US20180296523A1 (en) * | 2017-03-07 | 2018-10-18 | The Board Of Regents Of The University Of Texas System | Use of polymethoxylated flavones to ameliorate circadian rhythm disorders |
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- 2002-05-02 CA CA002445963A patent/CA2445963A1/en not_active Abandoned
- 2002-05-02 WO PCT/CA2002/000662 patent/WO2002087567A2/en active Application Filing
- 2002-05-02 AU AU2002308324A patent/AU2002308324B2/en not_active Ceased
- 2002-05-02 NZ NZ529243A patent/NZ529243A/en unknown
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Also Published As
Publication number | Publication date |
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MXPA03010080A (en) | 2006-04-05 |
WO2002087567A3 (en) | 2002-12-27 |
CA2445963A1 (en) | 2002-11-07 |
US20040152641A1 (en) | 2004-08-05 |
AU2002308324B2 (en) | 2008-04-03 |
NZ529243A (en) | 2007-11-30 |
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