Note: Descriptions are shown in the official language in which they were submitted.
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Composition And Method For Increasing The Metabolism Of
Free Fatty Acids And Facilitating A Favorable Blood Lipid Profile
Related Applications
This application is related to co-pending U.S., Patent Application:
, entitled "Composition for inducing lipolysis and increasing the
metabolism of free fatty acids via increased nitric oxide levels" filed on May
11, 2007, the contents of which are hereby incorporated by reference in their
entirety.
Field of the Invention
The present invention relates to a dietary supplement for facilitating a
more favorable blood lipid profile and increasing the metabolism of free fatty
acids via increased nitric oxide levels. More specifically, the present
invention
relates to a dietary supplement comprising a combination of Cissus
quadrangularis extract and y-butyrobetaine.
Background of the Invention
Obesity, a condition of excessive body fat, generally results from more
food being consumed than is being used. Stemming from excessive body fat,
several health-related concerns have been linked to obesity and being
overweight, such as increased morbidity, hypertension, coronary heart
disease, type 2 diabetes mellitus, stroke and even some forms of cancer
(Curioni C, Andre C, Veras R. Weight reduction for primary prevention of
stroke in adults with overweight or obesity. Cochrane Database Syst Rev.
2006 Oct 18;(4):CD006062). Obesity has become an increasingly
widespread and predominant health concern. According to the World Health
Organization (WHO) obesity is considered a multifactorial chronic disease
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which is increasing in frequency (Curioni C, Andre C, Veras R. Weight
reduction for primary prevention of stroke in adults with overweight or
obesity.
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006062).
One of the main contributing factors in obesity is overeating, which
30 results in an excess of energy being consumed in relation to the amount of
energy being expended by an individual. This excess energy is then
commonly stored as fat. A simplified determination of an individual's body
weight is essentially governed by the net effect of energy consumed versus
energy expended. Daily energy expenditure consists of three components:
35 basal metabolic rate, adaptive thermogenesis and physical activity
(Westerterp KR. Diet induced thermogenesis. Nutr Metab (Lond). 2004 Aug
18;1(1):5). All of the aforementioned components must be in a balance with
energy expenditure in an individual, that is, energy or food intake being such
that an individual does not gain nor lose body weight. Therefore, in order for
40 a person to lose body weight from a reduction in adipose tissue, more
energy
must be expended by the individual than is taken into the body.
With the unprecedented rise in obesity throughout the world, there
exists both a need and want from individuals for improved aids, methods and
interventions directed to reducing body fat and maintaining lowered levels of
45 body fat. These needs have led to intensive study of the various mechanisms
of fat metabolism. One such mechanism that has shown promise is the
arginine-nitric oxide pathway. Nitric oxide (NO), which is synthesized from
arginine by all cell types, has been shown to be a key signal molecule
involved in adipose tissue biology by influencing adipogenesis and insulin-
50 stimulated glucose uptake.
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There are four major ways in which NO has been shown to influence
energy metabolism. Firstly, NO has been shown to increase the
phosphorylation of hormone-sensitive lipase and perilipin. Perilipin is a
protein that coats lipid droplets in adipocytes and acts to protect
triglycerides
55 from hormone-sensitive lipases, which break lipids into glycerol and free
fatty
acids. When the perilipin is phosphorylated it changes conformation and
exposes stored lipids to hormone-sensitive lipase-mediated lipolysis, hence
stimulation of lipolysis.
Second, NO has been shown to stimulate the phosphorylation of
60 adenosine-3',5'-monophosphate activated protein kinase. Activation of these
kinases causes a decrease in levels of malonyl-CoA, which plays a key role in
chain elongation in fatty acid biosynthesis by providing 2-carbon units to
fatty
acids thus comitting them to fatty acid chain synthesis. Additionally,
activated
kinases decrease the expression of genes related to lipogenesis and
65 gluconeogenesis. Thirdly, NO has been shown to increase blood flow to
insulin-sensitive tissue, thus promoting substrate uptake and product removal.
Lastly, NO has been shown to activate the expression of peroxisome
proliferator-activated receptors leading to enhanced mitochondrial biogenesis
and oxidative phosphorylation.
70 Summary of the Invention
The present invention is directed towards a dietary supplement,
comprising at least a therapeutically effective amount of Cissus
quadrangularis extract, and a therapeutically effective amount of y-
butyrobetaine. The ingredients of the present dietary supplement act
75 substantially simultaneously to facilitate a more favorable blood lipid
profile,
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and increase the catabolism of free fatty acids via the phosphorylation of
perilipins. Both a composition and a method are provided by the present
disclosure.
Detailed Description of the Invention
80 In the following description, for the purposes of explanations, numerous
specific details are set forth in order to provide a thorough understanding of
the present invention. It will be apparent, however, to one of ordinary skill
in
the art that the present invention may be practiced without these specific
details.
85 The present invention is directed towards a dietary supplement, for
facilitating a more favorable blood lipid profile and increasing the
catabolism
of free fatty acids via the phosphorylation of perilipins, comprising a
combination of Cissus quadrangularis extract and y-butyrobetaine. An aspect
of the present invention comprises at least an extract of Cissus
90 quadrangularis and y-butyro beta i ne.
The term 'y-butyrobetaine' as used herein is understood to represent
gamma-butyrobetaine, also known as, butyrobetaine, deoxycarnitine, actinine,
4-butyrobetaine, or 4-trimethylamniobutyrate. Additionally, as used herein, 'y-
butyrobetaine' also includes derivatives of gamma-butyrobetaine such as
95 esters, amides, and salts, as well as other derivatives, including
derivatives
having pharmacoproperties upon metabolism to an active form.
The term 'more favorable blood lipid profile' as used herein is
understood to represent and be characterized or influenced by any one or
more of the following: a reduction in low-density lipoprotein (LDL), a
reduction
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100 in cholesterol, a lowering of fasting blood glucose levels, and increased
levels
of high-density lipoproteins (HDL).
Cissus quadrangularis Extract
Cissus quadrangularis is a plant indigenous to India where it is part of
traditional medicine. Extracts of Cissus quadrangularis contain sterols,
105 vitamin C, and tannins with antimicrobial in addition to antioxidant
activity
(Chidambara Murthy KN, Vanitha A, Mahadeva Swamy M, Ravishankar GA.
Antioxidant and antimicrobial activity of Cissus quadrangularis L. J Med Food,
2003. 6(2): p. 99-105). With respect to Cissus quadrangularis as a weight
reduction agent, clinical studies have shown that a group taking an extract of
110 Cissus quadrangularis for 6-weeks lost more weight, had lower cholesterol,
LDL and fasting blood glucose levels. The experimental group also displayed
increased HDL levels as compared to a placebo group (Oben JE, Mandob D,
Fomekong G, Momo C. The effect of an extract of Cissus quadrangularis
(Cylaris TM) on weight and serum lipids in obese patients in Cameroon: a
115 randomized double-blind clinical trial. Presented at Paris Anti-Obesity
Therapies. May 2006; Oben JE, Enyegue DM, Fomekong GI, Soukontoua YB,
Agbor GA. The effect of Cissus quadrangularis (CQR-300) and a Cissus
formulation (CORE) on obesity and obesity-induced oxidative stress. Lipids
Health Dis. 2007 Feb 4;6:4). The lowering levels of LDL and raising levels of
120 HDL has been associated with improved health, particularly in conjunction
with weight reduction (Dattilo AM, Kris-Etherton PM. Effects of weight
reduction on blood lipids and lipoproteins: a meta-analysis: Am J Clin Nutr,
1992. 56(2): p. 320-8).
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It is herein understood by the inventors that lowering levels of LDL and
125 cholesterol, as well as increasing levels of HDL will lead to a more
favorable
blood lipid profile, facilitating improved health via weight reduction.
An embodiment of the present invention comprises Cissus
quadrangularis extract. A serving of the nutritional supplement contains from
about 0.05 g to about 0.50 g of Cissus quadrangularis extract.
130 y-butyrobetaine (GBB) and Derivatives
y-butyrobetaine is an intermediate in carnitine biosynthesis in
mammals. It is synthesized, from trimethyl lysine, in almost all cell types
and
then excreted into the blood to be reabsorbed by the kidney and liver. After
reabsorption, GBB is converted to carnitine by y-butyrobetaine dioxygenase.
135 This conversion to carnitine is extremely efficient and so the presence of
y-
butyrobetaine in urine is very small (Vaz FM, Wanders RJA. Carnitine
biosynthesis in mammals. Biochem J. 2002;361:417-429).
Since y-butyrobetaine is a precursor to carnitine, its administration has
been studied as a way to increase carnitine levels in the body. Carnitine acts
140 as a carrier molecule for fatty acids across the inner mitochondrial
membrane.
In order for free fatty acids to be catabolized, they must first enter the
mitochondria of a cell such that a-oxidation may take place to produce energy.
Fatty acids are first activated with the addition of coenzyme A(CoA), then
bound to carnitine and transferred across the mitochondrial inner membrane,
145 after which the carnitine is removed.
As an additional effect, administration of y-butyrobetaine to rats
(Sjakste N, Kleschyov JL, Baumane L, Dzintare M, Meirena D, Sjakste J,
Sydow K, Munzel T, Kalvinsh I. Endothelium- and nitric oxide-dependent
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vasorelaxing activities of gamma-butyrobetaine esters: possible link to the
150 antiischemic acitivites of mildronate. Eur J Pharmacol. 2004 Jul 8;
495(1):67-
73 (Abstract)), showed elevated vasodilating activities. These vasodilating
activities were attributed to increases in nitric oxide concentrations in
blood.
Since nitric oxide has been shown to increase energy metabolism, it is herein
understood by the inventors that increases in NO levels will lead to increased
155 catabolism of fatty acids, which will increase the utilization of
adipocytes
leading to reduced fat content in the body, by mechanisms that were
previously discussed.
An embodiment of the present invention comprises y-butyrobetaine or
derivatives thereof. A serving of the nutritional supplement contains from
160 about 0.005 g to about 0.050 g of y-butyrobetaine or derivatives thereof.
In an embodiment of the present invention, which is set forth in greater
detail in Example 1, the dietary supplement comprises an extract of green tea,
y-butyrobetaine, and y-butyrobetaine ethyl ester. The dietary supplement is
provided in any acceptable and suitable oral dosage form as known in the art
165 to induce lipolysis and increase the metabolism of free fatty acids via
increased nitric oxide levels.
While, not wishing to be bound by theory, the present invention is
comprised of components that have been shown to reduce levels of LDL,
cholesterol, and fasting blood glucose as well as increase levels of HDL. The
170 facilitation of a more favorable blood lipid profile will result in
improved health
via weight reduction (Dattilo AM, Kris-Etherton PM. Effects of weight
reduction
on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr, 1992.
56(2):
p. 320-8).
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Additionally, the present invention comprises components that have
175 been shown to lead to, via increased nitric oxide levels, increased
phosphorylation of hormone-sensitive lipase and perilipin. It is herein
understood by the inventors that increased phosphorylation of perilipin will
result in greater likelihood of lipids being broken down by lipases, leading
to
increased release of free fatty acids.
180 Furthermore, increased nitric oxide levels will yield greater
phosphorylation of adenosine-3',5'-monophosphate activated protein kinase,
which will cause a decrease in levels of malonyl-CoA and decrease the
expression of genes related to lipogenesis and gluconeogenesis. It is herein
understood by the inventors that decreased malonyl-CoA will result in reduced
185 chain elongation of fatty acids and thus a decrease in fatty acid
biosynthesis.
In addition, the present invention comprises components that have
been shown to lead to, via increased nitric oxide levels, elevated expression
of peroxisome proliferator-activated receptors. It is herein understood by the
inventors that increased expression of peroxisome proliferator-activated
190 receptors will enhance mitochondrial biogenesis and oxidative
phosphorylation, resulting in elevated metabolism of free fatty acids.
Further to the aforementioned functions, the present invention
comprises components that have been shown to lead to, via increased nitric
oxide levels, elevated blood flow to insulin-sensitive tissue. It is herein
195 understood by the inventors that increased blood flow will promote
substrate
uptake and product removal, thus increasing the movement of free fatty acids
throughout the body.
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Additional embodiments of the present invention may also include
portions of the composition as fine-milled ingredients. U.S. Non-Provisional
200 Patent Application 11/709,526 entitled "Method for Increasing the Rate and
Consistency of Bioavailability of Supplemental Dietary Ingredients" filed Feb
21, 2007, which is herein fully incorporated by reference, discloses a method
of increasing the rate of bioavailability following oral administration of
components comprising supplemental dietary compositions by the process of
205 particle-milling.
Furthermore, additional embodiments of the present invention may be
incorporated into specific controlled-release solid dosage forms. U.S. Non-
Provisional Patent Application 11/709,525 entitled "Method for a
Supplemental Dietary Composition Having a Multi-Phase Dissolution Profile"
210 filed Feb 21, 2007, which is herein fully incorporated by reference,
discloses a
method of achieving a solid oral dosage form with multiple dissolution
characteristics for the release of active ingredients.
According to various embodiments of the present invention, the dietary
supplement may be consumed in any form. For instance, the dosage form of
215 the dietary supplement may be provided as, e.g., a powder beverage mix, a
liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid
capsule, a tablet, a capiet, or as a dietary gel. The preferred dosage forms
of
the present invention are as a caplet or as a liquid capsule.
Furthermore, the dosage form of the dietary supplement may be
220 provided in accordance with customary processing techniques for herbal and
dietary supplements in any of the forms mentioned above. Additionally, the
dietary supplement set forth in the example embodiment herein disclosed may
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contain any appropriate number and type of excipients, as is well known in the
art. By way of ingestion of the composition of the present invention, a method
225 for substantially simultaneously facilitating a more favorable blood lipid
profile
and increasing the catabolism of free fatty acids via the phosphorylation of
perilipins. The method of the present invention comprises at least the step of
administering to an individual an effective amount of the composition of the
present invention. Although the following example illustrates the practice of
230 the present invention in one of its embodiments, the example should not be
construed as limiting the scope of the invention. Other embodiments will be
apparent to one of skill in the art from consideration of the specifications
and
example.
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Examples
235 Example 1
A dietary supplement comprising the following ingredients per serving is
prepared for consumption as a capiet:
About 0.15 g of Cissus quadrangularis extract which is standardized for 2.5%
240 phytosterols, about 0.01 g of y-butyrobetaine (GBB), and about 0.025 g of
y-
butyrobetaine ethyl ester.
Example 2
A dietary supplement comprising the following ingredients per serving is
245 prepared for consumption as a caplet:
About 0.15 g of Cissus quadrangularis extract which is standardized for 2.5%
phytosterols, about 0.01 g of y-butyrobetaine (GBB), about 0.025 g of y-
butyrobetaine ethyl ester, and about 0.01 g of theobromine.
250
Example 3
A dietary supplement comprising the following ingredients per serving is
prepared for consumption as a caplet:
255 About 0.15 g of Cissus quadrangularis extract which is standardized for
2.5%
phytosterols, about 0.01 g of y-butyrobetaine (GBB), about 0.025 g of y-
butyrobetaine ethyl ester, and about 0.46 g of green tea extract green tea
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extract which is standardized for 90% polyphenols, 75% catechins, 45%
epigallocatechin gallate.
260
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Extensions and Alternatives
In the foregoing specification, the invention has been described with a
specific embodiment thereof; however, it will be evident that various
modifications and changes may be made thereto without departing from the
265 broader spirit and scope of the invention.
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