U.S. patent application number 10/449828 was filed with the patent office on 2004-12-02 for novel composition and method for the treatment of hypertension.
Invention is credited to Ivanov, Vadim, Ivanova, Svetlana, Niedzwiecki, Aleksandra, Rath, Matthias, Roomi, Waheed M..
Application Number | 20040242504 10/449828 |
Document ID | / |
Family ID | 33451875 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242504 |
Kind Code |
A1 |
Ivanov, Vadim ; et
al. |
December 2, 2004 |
Novel composition and method for the treatment of hypertension
Abstract
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
Glycoside and Epican Forte in therapeutic proportions.
Inventors: |
Ivanov, Vadim; (Castro
Valley, CA) ; Ivanova, Svetlana; (Castro Valley,
CA) ; Roomi, Waheed M.; (Sunnyvale, CA) ;
Niedzwiecki, Aleksandra; (San Jose, CA) ; Rath,
Matthias; (San Jose, CA) |
Correspondence
Address: |
Ali Kamarei, Esq.
280 Colorado Ave.
Palo Alto
CA
94301
US
|
Family ID: |
33451875 |
Appl. No.: |
10/449828 |
Filed: |
May 30, 2003 |
Current U.S.
Class: |
514/27 ;
514/456 |
Current CPC
Class: |
A61K 31/198 20130101;
A61K 31/352 20130101; A61K 36/82 20130101; A23L 33/105 20160801;
A23L 33/175 20160801; A61K 31/375 20130101; A61K 45/06 20130101;
A23V 2002/00 20130101; A61K 31/401 20130101; A61K 33/34 20130101;
A61K 33/06 20130101; A61K 31/7048 20130101; A61K 33/32 20130101;
A61K 33/04 20130101; A61K 36/752 20130101; A61K 31/221 20130101;
A61K 31/375 20130101; A61K 36/82 20130101; A23V 2002/00 20130101;
A23V 2002/00 20130101; A61K 33/32 20130101; A61K 31/7048 20130101;
A61K 33/04 20130101; A61K 31/401 20130101; A23L 33/16 20160801;
A61K 31/05 20130101; A23V 2002/00 20130101; A61K 31/352 20130101;
A61K 31/221 20130101; A61K 31/198 20130101; A61P 9/02 20180101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A23V 2250/0634
20130101; A23V 2250/708 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A23V 2250/063 20130101; A23V 2250/161 20130101;
A61K 2300/00 20130101; A23V 2250/2116 20130101; A61K 2300/00
20130101; A23V 2250/161 20130101; A23V 2250/0606 20130101; A23V
2250/712 20130101; A23V 2250/1612 20130101; A23V 2250/06 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A23V 2250/064
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A23V 2250/1626 20130101; A23V 2250/214 20130101;
A23V 2250/0606 20130101; A23V 2250/214 20130101; A61K 2300/00
20130101; A23V 2250/0616 20130101; A23V 2250/2116 20130101; A23V
2250/1588 20130101; A23V 2250/1626 20130101; A23V 2250/1578
20130101; A23V 2250/708 20130101; A61K 2300/00 20130101; A23V
2250/708 20130101; A61K 33/06 20130101; A61K 36/752 20130101; A61K
31/05 20130101; A61K 33/34 20130101 |
Class at
Publication: |
514/027 ;
514/456 |
International
Class: |
A61K 031/7048 |
Claims
The following is claimed:
1. A method for treatment and/or prevention of hypertension
comprising the step of administering to a patient a
therapeutically-effective amount of Quercetin or Quercetin
Glycosides, and Epican Forte, in therapeutic proportions.
2. The method of claim 1 wherein Quercetin Glycoside is extracted
from a plant source selected from the group of onions and
apples.
3. The method of claim 1 wherein the dose of Quercetin is
equivalent to between approximately 100 mg and 15 grams on a daily
basis.
4. The method of claim 1 wherein the dose of Quercetin is
equivalent to between approximately 1 grams and 10 grams on a daily
basis.
5. The method of claim 1 wherein the dose of Quercetin is repeated
daily.
6. The method of claim 1, wherein the Quercetin is administered to
a human as part of foods, drinks, health bars, bread or
cereals.
7. The method of claim 1 wherein Epican Forte is administered in
daily amounts indicated in Table 1.
8. A composition for use in treatment of hypertension in a patient
susceptible or suffering from hypertension or its side effects,
comprising of Quercetin or Quercetin Glycoside and Epican Forte in
therapeutic amounts.
9. The composition of claim 8 wherein Quercetin Glycoside is
extracted from a plant source selected from the group of onions and
apples.
10. The composition of claim 8 wherein the dose of Quercetin or
Quercetin Glycoside is equivalent to between approximately 100 mg
and 15 grams on a daily basis.
11. The composition of claim 8 wherein the dose of Quercetin or
Quercetin Glycoside is equivalent to between approximately 1 grams
and 10 grams on a daily basis.
12. The composition of claim 8 wherein the dose of Quercetin or
Quercetin Glycoside is repeated daily.
13. The composition of claim 8, wherein the Quercetin or Quercetin
Glycoside is administered to a human as part of foods, drinks,
health bars, bread or cereals.
14. The composition of claim 8 wherein Epican Forte is administered
in daily amounts indicated in Table 1.
Description
FIELD
[0001] 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
[0002] 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.
[0003] 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.
[0004] 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 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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
[0009] 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
[0010] 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.
[0011] FIG. 2 shows the effect of 0.1 U/ml Thrombin and 100 mcg/ml
of Epican Forte.
[0012] FIG. 3 shows SMC gel contraction by 1 mcM Angiotensin II and
the effect of Epican Forte.
[0013] FIGS. 4 and 5 show SMC gel contraction by Angiotensin
II.
[0014] 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++.
[0015] FIG. 9 shows SMC gel contraction by Angiotensin I and II and
the effect of 100 mcg/ml of Epican Forte.
[0016] FIG. 10 shows SMC gel contraction by Angiotensin II and the
effects of Resveratrol and Genistein.
[0017] FIG. 11 shows SMC gel contraction by Angiotensin II and the
effect of Relacor.
[0018] FIG. 12 shows SMC gel contraction by Angiotensin II and
N-Acetyl Cystein.
[0019] FIG. 13 shows SMC gel contraction by Angiotensin II at 1 mcM
and the effect of Relacor.
[0020] FIG. 14 shows SMC gel contraction by Angiotensin II at 1 mcM
and the effects of Lysine and Proline.
[0021] FIG. 15 shows SMC gel contraction by Thrombin.
[0022] FIG. 16 shows SMC gel contraction by Angiotensin II.
[0023] FIG. 17 shows SMC gel contraction by Thrombin.
[0024] FIG. 18 shows SMC gel contraction by Angiotensin II.
[0025] FIG. 19 shows SMC gel contraction.
[0026] FIG. 20 shows SMC gel contraction and the effects of
Catechins.
[0027] FIG. 21 shows SMC gel contraction and the effects of
Polyphenols.
DETAILED DESCRIPTION
[0028] 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.
[0029] 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
[0030] The following starting material and equipment were used.
[0031] 1. Cultured vascular smooth muscle cells (SMC) isolated from
human aorta. Cells are used from 4.sup.th to 8.sup.th passages.
[0032] 2. Human collagen type I.
[0033] 3. Angiotensin II.
[0034] 4. Epican Forte (composition shown in Table 1, available
from Matthias Rath, Inc., and all ingredients commercially
available)
[0035] 5. Epigallocatechin gallate (EGCG)
[0036] 6. Quercetin (chemical structure is well defined)
[0037] 7. Cell culture medium (DMEM)
[0038] 8. 24 well plastic cell culture plate pre-incubated with 2
mg/ml bovine serum albumin.
[0039] 9. Digital camera
[0040] 10. Digital image analyzing software (Scion
Corporation).
[0041] 11. Zymography gel electrophoresis assay (Novorex Corp).
[0042] 12. Relacor (composition shown in Table 2, available form
Matthias Rath, Inc., and all ingredients commercially
available)
1TABLE 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
[0043]
2TABLE 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
[0044] 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.degree. C. to allow gel to
polymerize. 0.5 mL of experimental serum-free medium contaning 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.degree. 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
[0045] 1. 3-07-03
[0046] a. ATII 1 mcM and Thrombin 0.1 U/mL no effects
[0047] b. EF 100 mcg/ml reduction in contraction from 70% to 55%
from the original.
[0048] 2. 3-10-03
[0049] a. Thombin 0.1 U/mL reduced gel by 58% vs 9% in control
[0050] b. EF 100 mcg/ml+Thrombin gel reduction by 12%
[0051] 3. 3-11-03
[0052] a. ATII 1 mcM gel reduction to 59% of Control 100%
[0053] b. EF dose dependent decrease in gel reduction back to
control at 3.7-100 mcg/ml
[0054] 4. 3-18-03
[0055] a. ATII 1 mcM gel reduction to 23% of 100% control
[0056] b. ATII+EF 100 mcg/ml 101%
[0057] c. ATII+AsA 100 mcM reduction to 30%
[0058] d. ATII+EGCG 15 mcM reduction to 30%
[0059] e. ATII+EGCG+AsA reduction to 33%
[0060] 5. 3-20-03
[0061] a. ATII 1 mcM gel reduction to 81% of 100% control
[0062] b. ATII+EF(11-33-100 mcg/ml) 1945, 226%, 317% of 100%
ATII
[0063] c. AsA 0.5 mM+ATII gel reduction to 90% vs 100% ATII 1
mcM
[0064] d. Arginine 0.5-2 mM no significant effect on ATII-induced
gel reduction
[0065] e. ATII+Arginine+AsA 0.5 mM no significant diff. Vs
ATII+AsA
[0066] f. Ca and Mg 1-4 mM individual or comb no effects on
ATII-induced gel
[0067] 6. 3-25-03
[0068] a. ATII 110-330-1000 nM dose dependent reduction in gel
[0069] b. EF 100 mcg/ml inhibits gel contraction to less than
control at all ATII concentrations
[0070] c. ATI 330-1000 nM gel reduction at 1000 nM only
[0071] d. EF 100 inhibit gel contraction to less than control
values at all ATI concentration
[0072] e. EF 100 increased gel area by 48% vs ATII 1 mcM
[0073] f. Genistein at 30 mcM increased gel area (GA) by 34% alone
and by 11% in combination with EF vs ATII
[0074] g. Resveratrol at 15 mcM no effect alone not on EF
effect
[0075] h. Resveratrol at 30 mcM increased GA by 45% alone and by
104% with EF vs ATII
[0076] i. 15Resv+15Gen increase by 28% and by 83% with EF vs
ATII.
[0077] 7. 3-26-03
[0078] a. EF33 returned GA to 100% from 21% reduction by ATII 1
mcM
[0079] b. Relacor 3-100 mcg/ml had no effect
[0080] c. Genist15+Relacor 11 had no effect
[0081] d. Resver15+Relacor 11 had no effect
[0082] 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
[0083] f. NAC 20+Rel 11 or NAC20+EF11 had no effect on ATII
[0084] 8. 3-28-03
[0085] a. Relacor gradually increased GA reduction by ATII at
concentration from 11 to 900 mcg/ml with 27% add at 900
[0086] b. Lysine and Proline did not effect ATII GA reduction at
0.25-1 mM
[0087] 9. 4-02-03
[0088] a. Thrombin reduced GA by 30% at 1 mcM
[0089] b. AsA 200 mcM had no effect on Thrombin
[0090] c. EF100 restored GA to 163% vs 100% control
[0091] d. EGCG30 mcM restored GA to 206% vs 100% control
[0092] e. Resveratrol30 mcM restored GA to 106% vs 100% control
[0093] f. Genistein30 mcM restored GA to 78% vs 100% control from
70% Thrombin
[0094] g. Querctin30 mcM restored GA to 133% vs 100% control
[0095] h. Rutin30 mcM reduced GA to 56% vs 70% Thrombin alone from
100% control
[0096] i. Grape seed extract 25 mcg/ml increased GA to 87% from 70%
Thrombin alone
[0097] j. Picnogenol 25 mcg/ml increased GA to 103% from 70%
Thrombin alone
[0098] 10.4-02-03
[0099] a. ATII reduced GA by 24% at 1 mcM
[0100] b. AsA 200 mcM had no effect on ATII
[0101] c. EF100 restored GA to 150% vs 100% control
[0102] d. EGCG30 mcM restored GA to 150% vs 100% control
[0103] e. Resveratrol30 mcM restored GA to 88% vs 100% control
[0104] f. Genistein30 mcM restored GA to 96% vs 100% control from
76% ATII
[0105] g. Quercetin30 mcM restored GA to 167% vs 100% control
[0106] h. Rutin30 mcM restored GA to 80 vs 76% ATII alone from 100%
control
[0107] i. Grape seed extract 25 mcg/ml increased GA to 86% from 76%
ATII alone
[0108] j. Picnogenol 25 mcg/ml increased GA to 105% from 76% ATII
alone
[0109] 11.4-17-03
[0110] a. EGCG dose-dependently reduced gel contraction by ATII at
3.3-10-30 mcM
[0111] b. AsA at 500 mcM did not have effect on ATII-induced gel
reduction alone or in combination with 10 EGCG
[0112] c. EGCG30 was more effective than ECG30 more effective than
EC=C at 30 on ATII-induced gel contraction.
[0113] d. Querc30=>Genist30=>Resver30=>Rutin30 on ATII
[0114] 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.
[0115] 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.
[0116] 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.
[0117] Third, the present invention provides treatment of
hypertension, using compounds and extracts from nature, which are
less expensive than pharmaceutical compositions.
* * * * *