US20070141171A1 - Novel composition and method for the treatment of hypertension - Google Patents

Novel composition and method for the treatment of hypertension Download PDF

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US20070141171A1
US20070141171A1 US11/672,268 US67226807A US2007141171A1 US 20070141171 A1 US20070141171 A1 US 20070141171A1 US 67226807 A US67226807 A US 67226807A US 2007141171 A1 US2007141171 A1 US 2007141171A1
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atii
gel
quercetin
mcm
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Vadim Ivanov
Svetlana Ivanova
Waheed Roomi
Aleksandra Niedzwiecki
Matthias Ratii
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    • 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 
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    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to a pharmacological composition and method that provides for reduction of blood pressure using natural compounds.
  • This composition is preferably used for patients susceptible to or suffering from blood pressure elevated above normal range.
  • angiotensin II i.e. inhibitors of Angiotensin Converting Enzyme (ACE) which block a conversion of angiotensin I to angiotensin II by arterial wall cells
  • ACE Angiotensin Converting Enzyme
  • Both classes of compounds are being tested in experimental conditions for their capacity to block angiotensin-dependent contraction of arterial wall either using arteries isolated from laboratory animals or a model of cultured smooth muscle cells embedded in collagen gel.
  • a capacity of a tested compound to block a is conractile activity of angitensin II in such experimental models unequivocally means that this compound will block angiotensin II activity in in vivo conditions and will reduce angiotensin-driven abnormally high blood pressure.
  • the present invention provides for a composition and method of treatment and prevention of hypertension and its resulting complications comprising the step of administering to a patient a therapeutically-effective amount of Quercetin or Quercetin Glycosides and Epican Forte in therapeutic proportions.
  • Quercetin Glycosides extracted from a plant source, including but not limiting to the group of onions and apples.
  • the dose of Quercetin is equivalent to between approximately 100 mg and 15 grams on a daily basis. More preferably, the dose of Quercetin is equivalent to between approximately 1 grams and 10 grams on a daily basis. It is understood that the dose of Quercetin is repeated daily.
  • Quercetin is optionally administered orally to a human as part of foods, drinks, health bars, bread or cereals.
  • the dosage of Epican Forte and the ingredients therein is administered in daily amounts indicated in Table 1.
  • FIG. 1 is a graph showing the effects of Angiotensin II and Thrombin on SMC Gel Contraction in control groups and in the presence Epican Forte.
  • FIG. 2 shows the effect of 0.1 U/ml Thrombin and 100 mcg/ml of Epican Forte.
  • FIG. 3 shows SMC gel contraction by 1 mcM Angiotensin II and the effect of Epican Forte.
  • FIGS. 4 and 5 show SMC gel contraction by Angiotensin II.
  • FIGS. 6, 7 , and 8 respectively compare SMC gel contraction by Angiotensin II in presence of the three groups of Epican Forte, Arginine and Ascorbate, and Ca++and Mg++.
  • FIG. 9 shows SMC gel contraction by Angiotensin I and II and the effect of 100 mcg/ml of Epican Forte.
  • FIG. 10 shows SMC gel contraction by Angiotensin II and the effects of Resveratrol and Genistein.
  • FIG. 11 shows SMC gel contraction by Angiotensin II and the effect of Relacor.
  • FIG. 12 shows SMC gel contraction by Angiotensin II and N-Acetyl Cystein.
  • FIG. 13 shows SMC gel contraction by Angiotensin II at 1 mcM and the effect of Relacor.
  • FIG. 14 shows SMC gel contraction by Angiotensin II at 1 mcM and the effects of Lysine and Proline.
  • FIG. 15 shows SMC gel contraction by Thrombin.
  • FIG. 16 shows SMC gel contraction by Angiotensin II.
  • FIG. 17 shows SMC gel contraction by Thrombin.
  • FIG. 18 shows SMC gel contraction by Angiotensin II.
  • FIG. 19 shows SMC gel contraction
  • FIG. 20 shows SMC gel contraction and the effects of Catechins.
  • FIG. 21 shows SMC gel contraction and the effects of Polyphenols.
  • Bioflavonoids have been recognized to support arterial wall structural integrity and interfere with a variety of pro-atherosclerotic stimuli.
  • SMC cultured human aortic smooth muscle cells
  • Ang II angiotensin II
  • Gel contraction was stimulated by addition of 1 micromol/L angiotensin II (Ang II) in serum-free media and the gel area was assessed by digital image analysis after 24 hours.
  • EGCG epigallocatechin gallate
  • Que quercetin
  • a therapeutically effective amount of Quercetin is defined primarily by clinical response in a patient, and ranges from about an equivalent of 100 mg to 15 grams daily on variable schedule. A more preferred range of an effective amount of Quercetin is between about an equivalent of approximately 1 grams to 10 grams daily on a variable schedule. Preferably the dose of Quercetin is repeated daily to achieve the desired effect.
  • Quercetin also can derive from Quercetin Glycosides, naturally occurring bioflavonoids, thus Quercetin Glycosides are optionally administered orally in place of Quercetin together with the ingredients of Epican Forte.
  • Cells are used from 4 th to 8 th passages.
  • L-Arginine 750 mg Vitamin C, as ascorbic acid, 1,000 mg Calcium Ascorbate, magnesium Ascorbate or Ascorbyl Palmitate Magnesium 400 mg Vitamin E 100 IU Calcium 200 mg Citrus Fruit Peel Bioflavonoids 100 mg Method
  • Cell concentration in suspension was brought to 500,000 cell per mL in serum-free DMEM.
  • Cell suspension was then mixed 1:1 with ice-cold 2 mg/ml collagen type I solution in PBS.
  • Final concentration of collagen was 1 mg/mL, final cell concentration is 250,000 per mL.
  • Collagen-SMC suspension was distributed by 300 microL to the wells of 24 well plate in such a manner to cover the entire bottom surface of the well. The plate was then incubated for one hour at 37° C. to allow gel to polymerize.
  • bioflavonoids participate in the regulation of SMC-mediated contraction and that they have a strong potential in counteracting pathophysiological effects of Angiotensin II. While not being bound by a particular mechanism, Bioflavonoid activity strongly depends on structural characteristics and it is the conception of the present inventors that it is related to extracellular matrix integrity.
  • the present invention provides a treatment, which is directed to reversing and minimizing the lack of sensitivity of arteries that lead to hypertension.
  • the present invention provides a treatment that is directed to retarding adverse effects of stimuli, which lead to contraction of smooth muscle cells, which increase blood pressure and results in chronic hypertension.
  • the present invention provides treatment of hypertension, using compounds and extracts from nature, which are less expensive than pharmaceutical compositions.

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Abstract

The present invention provides for a composition and method of treatment and prevention of hypertension and its restulting complication comprising the step of administering to a patient a therapeutically-effective amount of Quercetin or Quercetin Glycoside and Epican Forte in therapeutic proportions.

Description

    FIELD
  • This invention relates to a pharmacological composition and method that provides for reduction of blood pressure using natural compounds. This composition is preferably used for patients susceptible to or suffering from blood pressure elevated above normal range.
    • BACKGROUND
  • The various pathophysiological and clinical effects of hypertension or elevated blood pressure are well documented. These effects have both short term effects resulting in poor health and bad work performance, and longer term effects which includes myocardial infarction, stroke, cardiac arrest, kidney disease, kidney failure and others. Moreover, the effect of hypertension is exacerbated in conjunction with other diseases such as diabetes, etc. In recent years it is estimated that more than 50% of deaths relating to cardiovascular disease in the United States alone was related to or resulted from high blood pressure. Additionally, high blood pressure is the most common cause of cardiac failure or other disease states requiring some amount of hospitalization.
  • There has been significant and extensive research for effective long-term treatment for hypertension. However, present treatments for such disorders are partial treatments such as administration of Angiotensin Converting Enzyme inhibitors (ACE inhibitors), and other pharmaceutical agents. These treatments have serious shortcomings in long-term effectiveness, most notable the cost associated with these treatments and significant adverse effects.
  • There is a vast number of published research done with regard to the mechanisms of pathogenesis of hypertension. It is well accepted that extensive production and extensive activity of angiotensin II are the major source of the development of hypertension, since its excess causes abnormally strong contraction of arteries, compromises process of arteries relaxation and lead therefore to elevated blood pressure. Thus, a massive effort is being undertaken to develop pharmaceutical compounds capable either to reduce formation of angiotensin II (i.e. inhibitors of Angiotensin Converting Enzyme (ACE) which block a conversion of angiotensin I to angiotensin II by arterial wall cells) or to block a biological activity of angiotensin II (i.e. agonists of angiotensin receptors). Both classes of compounds are being tested in experimental conditions for their capacity to block angiotensin-dependent contraction of arterial wall either using arteries isolated from laboratory animals or a model of cultured smooth muscle cells embedded in collagen gel. A capacity of a tested compound to block a is conractile activity of angitensin II in such experimental models unequivocally means that this compound will block angiotensin II activity in in vivo conditions and will reduce angiotensin-driven abnormally high blood pressure.
  • In view of the foregoing, there is a significant need for a pharmacological composition and method that is directed towards treating the underlying hypertension disease process, and towards preserving and restoring the sensitivity of the arteries to stimuli which would allow for proper contraction and relaxation of smooth muscle cells in the arteries.
  • It is an objective of the present invention to provide a treatment, which is directed to reversing and minimizing the lack of sensitivity of arteries, which lead to hypertension.
  • It is another objective of the present invention to provide a treatment that is directed to retarding adverse effects of stimuli, which lead to contraction of smooth muscle cells, which increase blood pressure and results in chronic hypertension.
  • It is yet another objective of the present invention treatment of hypertension, using compounds and extracts from nature which are less expensive and more safe than pharmaceutical compositions.
    • SUMMARY
  • The present invention provides for a composition and method of treatment and prevention of hypertension and its resulting complications comprising the step of administering to a patient a therapeutically-effective amount of Quercetin or Quercetin Glycosides and Epican Forte in therapeutic proportions. As an option, Quercetin Glycosides extracted from a plant source, including but not limiting to the group of onions and apples. Further as an option, the dose of Quercetin is equivalent to between approximately 100 mg and 15 grams on a daily basis. More preferably, the dose of Quercetin is equivalent to between approximately 1 grams and 10 grams on a daily basis. It is understood that the dose of Quercetin is repeated daily. As part of the invention, Quercetin is optionally administered orally to a human as part of foods, drinks, health bars, bread or cereals. The dosage of Epican Forte and the ingredients therein is administered in daily amounts indicated in Table 1.
    • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1 is a graph showing the effects of Angiotensin II and Thrombin on SMC Gel Contraction in control groups and in the presence Epican Forte.
  • FIG. 2 shows the effect of 0.1 U/ml Thrombin and 100 mcg/ml of Epican Forte.
  • FIG. 3 shows SMC gel contraction by 1 mcM Angiotensin II and the effect of Epican Forte.
  • FIGS. 4 and 5 show SMC gel contraction by Angiotensin II.
  • FIGS. 6, 7, and 8 respectively compare SMC gel contraction by Angiotensin II in presence of the three groups of Epican Forte, Arginine and Ascorbate, and Ca++and Mg++.
  • FIG. 9 shows SMC gel contraction by Angiotensin I and II and the effect of 100 mcg/ml of Epican Forte.
  • FIG. 10 shows SMC gel contraction by Angiotensin II and the effects of Resveratrol and Genistein.
  • FIG. 11 shows SMC gel contraction by Angiotensin II and the effect of Relacor.
  • FIG. 12 shows SMC gel contraction by Angiotensin II and N-Acetyl Cystein.
  • FIG. 13 shows SMC gel contraction by Angiotensin II at 1 mcM and the effect of Relacor.
  • FIG. 14 shows SMC gel contraction by Angiotensin II at 1 mcM and the effects of Lysine and Proline.
  • FIG. 15 shows SMC gel contraction by Thrombin.
  • FIG. 16 shows SMC gel contraction by Angiotensin II.
  • FIG. 17 shows SMC gel contraction by Thrombin.
  • FIG. 18 shows SMC gel contraction by Angiotensin II.
  • FIG. 19 shows SMC gel contraction.
  • FIG. 20 shows SMC gel contraction and the effects of Catechins.
  • FIG. 21 shows SMC gel contraction and the effects of Polyphenols.
    • DETAILED DESCRIPTION
  • Plant-derived bioflavonoids have been recognized to support arterial wall structural integrity and interfere with a variety of pro-atherosclerotic stimuli. We tested whether bioflavonoids have an effect on the contractile activity of cultured human aortic smooth muscle cells (SMC) embedded in a three-dimensional type I collagen (1 mg/mL) matrix. Gel contraction was stimulated by addition of 1 micromol/L angiotensin II (Ang II) in serum-free media and the gel area was assessed by digital image analysis after 24 hours. Epigallocatechin gallate (EGCG) and quercetin (Que) were the most active inhibitors of gel contraction among the various bioflavonoids tested. When added at the concentration of 30 micromol/L, EGCG and Que inhibited Ang II-induced gel contraction by 97% and 120%, respectively. In comparative analysis of structure-related activity the presence of gallic acid residues in the catechin molecule was shown to enhance its activity. In addition, glycosylation of Que dramatically reduced its capacity to inhibit gel contraction. Comparison of gel contraction inhibition by mixed bioflavonoids extracted from natural sources demonstrated that anti-contractile activity gradually increased from citrus fruits to grape seeds to pine bark to green tea. Inhibition of gel contraction by bioflavonoids did not depend on antioxidant activity, since ascorbic acid was not significantly active in this assay. However, a reduction in Ang II-stimulated gel contraction strongly correlated with a decrease in matrix metalloproteinase 2 expression by SMC assayed by zymography in cell culture media.
  • A therapeutically effective amount of Quercetin is defined primarily by clinical response in a patient, and ranges from about an equivalent of 100 mg to 15 grams daily on variable schedule. A more preferred range of an effective amount of Quercetin is between about an equivalent of approximately 1 grams to 10 grams daily on a variable schedule. Preferably the dose of Quercetin is repeated daily to achieve the desired effect. Quercetin also can derive from Quercetin Glycosides, naturally occurring bioflavonoids, thus Quercetin Glycosides are optionally administered orally in place of Quercetin together with the ingredients of Epican Forte.
  • Experimental Protocol
  • The following starting material and equipment were used.
    • 1. Cultured vascular smooth muscle cells (SMC) isolated from human aorta.
  • Cells are used from 4th to 8th passages.
    • 2. Human collagen type I.
    • 3. Angiotensin II.
    • 4. Epican Forte (composition shown in Table 1, available from Matthias Rath, Inc., and all ingredients commercially available)
    • 5. Epigallocatechin gallate (EGCG)
    • 6. Quercetin (chemical structure is well defined)
    • 7. Cell culture medium (DMEM)
    • 8. 24 well plastic cell culture plate pre-incubated with 2 mg/ml bovine serum albumin.
    • 9. Digital camera
    • 10. Digital image analyzing software (Scion Corporation).
    • 11. Zymography gel electrophoresis assay (Novorex Corp).
  • 12. Relacor (composition shown in Table 2, available form Matthias Rath, Inc., and all ingredients commercially available)
    TABLE 1
    Epican Forte
    Compound Dosage per day
    L-Lysine 1,000 mg
    L-Proline 750 mg
    L-Arginine 500 mg
    Vitamin C, as ascorbic acid, 710 mg
    Calcium Ascorbate, magnesium
    Ascorbate or Ascorbyl Palmitate
    Magnesium
    50 mg
    Standardized Green Tea Extract, 1,000 mg
    80% polyphenils - 800 mg
    (decaffeinated)
    N-Acetyl-Cystein 200 mg
    Selenium
    30 mcg
    Copper
    2 mg
    Manganese
    1 mg
  • TABLE 2
    Relacor
    Compound Dosage per day
    L-Arginine 750 mg
    Vitamin C, as ascorbic acid, 1,000 mg
    Calcium Ascorbate, magnesium
    Ascorbate or Ascorbyl Palmitate
    Magnesium 400 mg
    Vitamin E
    100 IU
    Calcium
    200 mg
    Citrus Fruit Peel Bioflavonoids 100 mg

    Method
  • Confluent culture of SMC and suspended from culture flask by trypsinization and washed with phosphate-buffered saline (PBS) from serum-containing medium. Cell concentration in suspension was brought to 500,000 cell per mL in serum-free DMEM. Cell suspension was then mixed 1:1 with ice-cold 2 mg/ml collagen type I solution in PBS. Final concentration of collagen was 1 mg/mL, final cell concentration is 250,000 per mL. Collagen-SMC suspension was distributed by 300 microL to the wells of 24 well plate in such a manner to cover the entire bottom surface of the well. The plate was then incubated for one hour at 37° C. to allow gel to polymerize. 0.5 mL of experimental serum-free medium containing no additions (control), or 1 micromol/L angiotensin II with or without tested bioflavonoid was added to polymerized gel, plate was then gently tapped on the side to detach gel from the bottom of plastic well, and plate was then placed to incubator with the controlled atmosphere containing 5%CO2 at 37° C. for incubation. After 24 hour incubation plate was taken from the incubator and plate image with floating gels was taken using digital camera. Gel flat surface area is measured with digital image analyzing software. Sample of cell culture media was taken for analysis of matrix metalloproteinases activity by zymography (Novorex Corp). Experiments were performed in triplicates and results are presented as a mean +/−SD.
  • Summary
    • 1. Mar. 7, 2003
      • a. ATII 1 mcM and Thrombin 0.1 U/mL no effects
      • b. EF 100 mcg/ml reduction in contraction from 70% to 55% from the original.
    • 2. Mar. 10, 2003
      • a. Thombin 0.1 U/mL reduced gel by 58% vs 9% in control
      • b. EF 100 mcg/ml+Thrombin gel reduction by 12%
    • 3. Mar. 11, 2003
      • a. ATII 1 mcM gel reduction to 59% of Control 100%
      • b. EF dose dependent decrease in gel reduction back to control at 3.7-100 mcg/ml
    • 4. Mar. 18, 2003
      • a. ATII 1 mcM gel reduction to 23% of 100% control
      • b. ATII+EF 100 mcg/ml 101%
      • c. ATII+AsA 100 mcM reduction to 30%
      • d. ATII+EGCG 15 mcM reduction to 30%
      • e. ATII+EGCG+AsA reduction to 33%
    • 5. Mar. 20, 2003
      • a. ATII 1 mcM gel reduction to 81% of 100% control
      • b. ATII+EF(11-33-100 mcg/ml) 1945,226%, 317% of 100% ATII
      • c. AsA 0.5 mM+ATII gel reduction to 90% vs 100% ATII 1 mcM
      • d. Arginine 0.5−2 mM no significant effect on ATII-induced gel reduction
      • e. ATII+Arginine+AsA 0.5 mM no significant diff. Vs ATII+AsA
      • f. Ca and Mg 1-4 mM individual or comb no effects on ATII-induced gel
    • 6. Mar. 25, 2003
      • a. ATII 110-330-1000 nM dose dependent reduction in gel
      • b. EF 100 mcg/ml inhibits gel contraction to less than control at all ATII concentrations
      • c. ATI 330-1000 nM gel reduction at 1000 nM only
      • d. EF 100 inhibit gel contraction to less than control values at all ATI concentration
      • e. EF 100 increased gel area by 48% vs ATII 1 mcM
      • f. Genistein at 30 mcM increased gel area (GA) by 34% alone and by 11% in combination with EF vs ATII
      • g. Resveratrol at 15 mcM no effect alone not on EF effect
      • h. Resveratrol at 30 mcM increased GA by 45% alone and by 104% with EF vs ATII
      • i. 15Resv+15Gen increase by 28% and by 83% with EF vs ATII.
    • 7. Mar. 26, 2003
      • a. EF33 returned GA to 100% from 21% reduction by ATII 1 mcM
      • b. Relacor 3-100 mcg/ml had no effect
      • c. Genist15+Relacor 11 had no effect
      • d. Resver15+Relacor 11 had no effect
      • e. NAC at 2 mcM returned GA to control 100% vs 21% reduction with ATII, but did not have any effect at higher concentration up to 60 mcM
      • f. NAC 20+Rel 11 or NAC20+EF11 had no effect on ATII
    • 8. Mar. 28, 2003
      • a. Relacor gradually increased GA reduction by ATII at concentration from 11 to 900 mcg/ml with 27% add at 900
      • b. Lysine and Proline did not effect ATII GA reduction at 0.25-1 mM
    • 9. Apr. 2, 2003
      • a. Thrombin reduced GA by 30% at 1 mcM
      • b. AsA 200 mcM had no effect on Thrombin
      • c. EF100 restored GA to 163% vs 100% control
      • d. EGCG30 mcM restored GA to 206% vs 100% control
      • e. Resveratrol30 mcM restored GA to 106% vs 100% control
      • f. Genistein30 mcM restored GA to 78% vs 100% control from 70% Thrombin
      • g. Querctin30 mcM restored GA to 133% vs 100% control
      • h. Rutin30 mcM reduced GA to 56% vs 70% Thrombin alone from 100% control
      • i. Grape seed extract 25 mcg/ml increased GA to 87% from 70% Thrombin alone
      • j. Picnogenol 25 mcg/ml increased GA to 103% from 70% Thrombin alone
    • 10. Apr. 2, 2003
      • a. ATII reduced GA by 24% at 1 mcM
      • b. AsA 200 mcM had no effect on ATII
      • c. EF100 restored GA to 150% vs 100% control
      • d. EGCG30 mcM restored GA to 150% vs 100% control
      • e. Resveratrol30 mcM restored GA to 88% vs 100% control
      • f. Genistein30 mcM restored GA to 96% vs 100% control from 76% ATII
      • g. Quercetin30 mcM restored GA to 167% vs 100% control
      • h. Rutin30 mcM restored GA to 80 vs 76% ATII alone from 100% control
      • i. Grape seed extract 25 mcg/ml increased GA to 86% from 76% ATII alone
      • j. Picnogenol 25 mcg/ml increased GA to 105% from 76% ATII alone
    • 11. Apr. 17, 2003
      • a. EGCG dose-dependently reduced gel contraction by ATII at 3.3-10-30 mcM
      • b. AsA at 500 mcM did not have effect on ATII-induced gel reduction alone or in combination with 10 EGCG
      • c. EGCG30 was more effective than ECG30 more effective than EC=C at 30 on ATII-induced gel contraction.
      • d. Querc30=>Genist30=>Resver30=>Rutin30 on ATII
  • The results show that bioflavonoids participate in the regulation of SMC-mediated contraction and that they have a strong potential in counteracting pathophysiological effects of Angiotensin II. While not being bound by a particular mechanism, Bioflavonoid activity strongly depends on structural characteristics and it is the conception of the present inventors that it is related to extracellular matrix integrity.
  • It is therefore evident how the objective of the present invention is satisfied. First, the present invention provides a treatment, which is directed to reversing and minimizing the lack of sensitivity of arteries that lead to hypertension.
  • Second the present invention provides a treatment that is directed to retarding adverse effects of stimuli, which lead to contraction of smooth muscle cells, which increase blood pressure and results in chronic hypertension.
  • Third, the present invention provides treatment of hypertension, using compounds and extracts from nature, which are less expensive than pharmaceutical compositions.

Claims (4)

1. A composition for use in treatment of hypertension in a patient suffering from hypertension or its side effect, the composition consisting of one or more pharmaceutical excipients and a therapeutically˜effective amount of Quercetin or a glycoside derivative thereof, L-Lysine, 1-Proline, L-Arginine, vitanin C, magnesium standard green tea extract containing 80% polyphenols, N-acetyl-cysteine, selenium, copper, and manganese.
2. The composition of claim 1 wherein the amount of Quercetin or Quercetin glycoside derivative is in the range from about 100 mg to about 15 grams.
3. The composition of claim 1 wherein the amount of Quercetin or Quercetin glycoside derivative is in the range from about 1 gram to about 10 grams.
4. The composition of claim 1 wherein the amount of L-Lysine is 1000 mg, the amount of L-Proline is 750 mg, the amount of L-Arginine is 500 mg, the amount of vitamin C is 710 mg, the amount of magnesium is 50 mg, the amount of standard green tea extract containing 80% polyphenols is 1000 mg, tile amount of N-acetyl-cysteine is 200 mg the amount of selenium is 30 mcg(micrograms), the amount of copper is 2 mg, and the amount of manganese is 1 mg.
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US4840966A (en) * 1987-03-03 1989-06-20 Mitsui Norin Co., Ltd. Method of treating hypertension
US6054128A (en) * 1997-09-29 2000-04-25 Wakat; Diane Dietary supplements for the cardiovascular system

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Publication number Priority date Publication date Assignee Title
US4840966A (en) * 1987-03-03 1989-06-20 Mitsui Norin Co., Ltd. Method of treating hypertension
US6054128A (en) * 1997-09-29 2000-04-25 Wakat; Diane Dietary supplements for the cardiovascular system

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