Note: Descriptions are shown in the official language in which they were submitted.
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PATENT APPLICATION
Docket No. GASP-001-WO1
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Inventors: Bruce W. Kneller, Daniel C.
Pierce and Joseph Babick, Jr.
Attorney's Docket No.: GASP-001-WO1
STILBENE-BASED COMPOSITIONS AND METHODS OF USE THEREFOR
BACKGROUND OF THE INVENTION
It is well known by those skilled in the art that
the addition of various nutrients and dietary supplements
to the diet of humans can greatly increase athletic
performance and reduce post-recovery/post-exercise time
back to baseline state. The oral use of various types of
nutrients, including carbohydrates, proteins, essential
amino acids and creatine for increasing athletic
performance, increasing protein synthesis, enhancing
tissue repair, and reducing recovery times in humans is
well known (JISSN 5(17) : 1-12 (2008) ; JISSN 3(1) :7-27
(2006). The importance of the timing of nutrient
administration (e.g., before, during and after exercise)
in both endurance exercise and resistance training has
also been acknowledged. Additional dietary supplements
that can increase the rate or quantity of absorption,
rate or quantity of nutrient partitioning, or rate or
quantity of use of various athletic performance-enhancing
nutrients (including, but not limited to, carbohydrates,
proteins, vitamins, minerals, amino acids, creatine by
skeletal muscle cells and tissues) are desirable for
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improving weight loss, increasing lean muscle mass,
and/or improving athletic performance.
Stilbenes are small (molecular weight of 210-278
g/mol), naturally-occurring compounds found in a wide
range of plant sources, aromatherapy products, and
dietary compositions. Stilbenes exist as stereoisomers
in E and Z forms, depending on where functional groups
are attached in relation to one another on either side of
the double bond. Naturally-occurring stilbenes
overwhelmingly exist in the Z (trans) form. The E and Z
forms of stilbenes have different pharmacological
activities and elicit different effects. Research has
revealed the Z form to exhibit more potent activity
compared to the E form across various anti-cancer and
anti-oxidant assays. One such study demonstrated the
stilbene trans-reseveratrol to be ten times more potent
in its ability to induce apoptosis in the HL60 leukemia
cell line compared to cis-resveratrol (J Med Chem
46:3546-54 (2003)).
Other stilbenoid compounds include, but are not
limited to, piceatannol, pinosylvin, rhapontigenin,
tamoxifen, and pterostilbene. Pterostilbene is thought
to be a key compound found predominantly in blueberries
(as well as grapes) that exhibits anti-fungal, anti-
cancer, anti-hypercholesterolemia, and anti-
hypertriglyceridemia properties, as well as the ability
to delay and reverse cognitive decline. Thus, it may be
desirable to include stilbene-based compounds in dietary
supplements to impart a variety of benefits.
SUMMARY OF THE INVENTION
Disclosed herein are compositions, formulations and
methods relating to one or more stilbene-based compounds
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for use in humans. In particular, compositions and
formulations comprising an effective amount of the
stilbene-based insulinogenic compound can improve
athletic performance, lower blood glucose levels, and
increase lean muscle mass when administered (e.g.,
orally) to a human. In a particular embodiment the
stilbene-based compound is pterostilbene.
Thus, in one embodiment the invention relates to a
method of increasing athletic performance, lowering blood
sugar level and/or increasing lean muscle mass in a human
comprising administering an effective amount of a
stilbene-based compound to said human. In one embodiment
the stilbene-based compound is pterostilbene. In one
embodiment the pterostilbene is administered orally.
In certain embodiments the effective amount of
pterostilbene is from about 3 mg to about 25 mg per dose,
from about 3 mg to about 10 mg per dose, or from about 5
mg to about 10 mg per dose.
In certain embodiments the effective amount of
pterostilbene is from about 0.03 mg/kg bodyweight of the
human to about 0.165 mg/kg bodyweight of the human per
dose.
In certain embodiments more than one dose comprising
an effective amount of pterostilbene is administered to
the human (e.g., two or more doses spaced over time, each
dose comprising an effective amount of pterostilbene).
In some embodiments the pterostilbene is co-
administered with one or more non-carbohydrate nutrients.
For example, the non-carbohydrate nutrient may be
selected from the group consisting of creatine and its
salts, esters, amides and chelates; creatinol-0-
phosphate; the amino acids leucine, isoleucine, valine,
taurine, beta-alanine, arginine, ornithine, aspartic
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acid, glutamine, glutaric acid, agmatine, citrulline,
norvaline, glycine, and cysteine and salts, esters,
amides and chelates of said amino acids; ketoisocaproate
and sodium, potassium, calcium and magnesium salts
thereof; the dipeptides carnitine, anserine and carnosine
and salts and esters thereof; and dipeptide-containing
proteins.
In some embodiments the pterostilbene is co-
administered with one or more carbohydrate nutrients.
For example, the carbohydrate nutrient may be selected
from the group consisting of: rice oligodextrin; amylose;
amylopectin; glucose; maltodextrin; maltose;
isomaltulose; leucrose; trehalulose; ribose; trehalose;
sucrose; and fructose.
In some embodiments the pterostilbene is co-
administered with one or more non-carbohydrate nutrients
and one or more carbohydrate nutrients. For example, an
effective amount of pterostilbene can be co-administered
with both a carbohydrate nutrient and creatine or a salt,
ester, amide or chelate thereof.
In some embodiments the pterostilbene is co-
administered with one or more compounds not found in a
pterostilbene natural source.
In certain embodiments the pterostilbene is co-
administered with one or more compounds selected from the
group consisting of inethylxanthines (e.g., caffeine,
theobromine, theophylline), glucuronolactone, animal
digestive enzymes (e.g., lipase, bromelain, pancreatin,
amylase, lactase), and carbohydrates not found in a
pterostilbene natural source (e.g., isomaltulose,
trehalose, leucrose, amylose, trehalulose, rice
oligodextrin).
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The invention further relates to a formulation or
composition comprising an amount of pterostilbene
effective to increase athletic performance, lower blood
sugar level and/or increase lean muscle mass in a human
to whom the formulation is administered; and one or more
compounds not found in a pterostilbene natural source.
In a particular embodiment the formulation or composition
comprises creatine or a salt, ester, amide or chelate
thereof; in some embodiments the formulation comprises
from about 250 mg to about 10,000 mg of creatine or a
salt, ester, amide or chelate thereof per dose.
In some embodiments the formulation comprises from
about 3 mg to about 25 mg of pterostilbene per dose. In
some embodiments the formulation comprises greater than
about 0.002 percent pterostilbene by weight, for example
from about 0.002 to about 100 percent pterostilbene by
weight. In some embodiments the formulation comprises
one or more carbohydrate nutrients in addition to
pterostilbene. In some embodiments the formulation
comprises one or more non-carbohydrate nutrients in
addition to pterostilbene.
In some embodiments the formulation comprises, in
addition to pterostilbene, one or more compounds selected
from the group consisting of inethylxanthines (e.g.,
caffeine, theobromine, theophylline), glucuronolactone,
animal digestive enzymes (e.g., lipase, bromelain,
pancreatin, amylase, lactase), and carbohydrates not
found in pterostilbene natural sources (e.g.,
isomaltulose, trehalose, leucrose, amylose, trehalulose,
rice oligodextrin).
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BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows pterostilbene (trans-3,5-dimethoxy-4'-
hydroxystilbene), molecular formula C16H16O3r having a
molecular weight of about 256.3 g/mol (CAS#537-42-8).
FIG. 2 shows resveratrol (3,4',5-
Trihydroxystilbene), molecular formula C14H1203, having a
molecular weight of about 228.246 g/mol (CAS# 501-36-0).
DETAILED DESCRIPTION OF THE INVENTION
Insulin is a polypeptide hormone that has extensive
effects on metabolism and other body functions, such as
vascular compliance. Insulin causes cells in the liver,
muscle, and fat tissue to take up glucose and other
nutrients from the blood. Insulin causes glucose to be
stored as glycogen in the liver and muscle. Insulin also
inhibits the body's use of fat as an energy source. When
insulin is absent (or present at low levels), glucose is
not taken up by the cells of the body; the body begins to
use fat as an energy source (for example, by transfer of
lipids from adipose tissue to the liver for mobilization
as an energy source). As its level is a central metabolic
control mechanism, its status is also used as a control
signal to other body systems (such as amino acid uptake
by body cells). It has several other anabolic effects
throughout the body. When control of insulin levels
fails, diabetes mellitus results.
Action of insulin
Insulin is produced in the pancreas and released
when any of several stimuli is detected. The stimuli
include ingested protein and glucose in the blood
produced from digested food. Certain carbohydrates
produce glucose and thereby increase blood glucose
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levels. In target cells, carbohydrates initiate a signal
transduction, which has the effect of increasing glucose
uptake and storage. Ultimately insulin is degraded,
terminating the response.
The beta cells in the islets of Langerhans in the
pancreas release insulin in two phases. In the first
phase insulin release is rapidly triggered in response to
increased blood glucose levels. The second phase is a
sustained, slow release of newly formed vesicles that are
triggered independent of sugar levels. The description of
first phase release is as follows:
1. Glucose enters the beta cells through the glucose
transporter GLUT2;
2. Glucose goes into the glycolysis and the respiratory
cycle where multiple high-energy ATP molecules are
produced by oxidation;
3. Dependent on ATP levels, and hence blood glucose
levels, the ATP-controlled potassium channels (K+) close
and the cell membrane depolarizes;
4. On depolarization, voltage controlled calcium
channels (Ca2+) open and calcium flows into the cells'
5. An increased calcium level causes activation of
phospholipase C, which cleaves the membrane phospholipid
phosphatidyl inositol 4,5-bisphosphate into inositol
1,4,5-triphosphate and diacylglycerol;
6. Inositol 1,4,5-triphosphate (IP3) binds to receptor
proteins in the membrane of endoplasmic reticulum (ER).
This allows the release of Ca2+ from the ER via lP3 gated
channels, and further raises the cell concentration of
calcium;
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7. Significantly increased amounts of calcium in the
cells causes release of previously synthesized insulin,
which has been stored in secretory vesicles.
This is the main mechanism for release of insulin.
In addition some insulin release takes place generally
upon food or other nutrient intake (not limited to
glucose or carbohydrate intake), and the beta cells are
also somewhat influenced by the autonomic nervous system.
Other substances known to stimulate insulin release
include amino acids from ingested proteins, acetylcholine
released from vagus nerve endings (parasympathetic
nervous system), and glucose-dependent insulinotropic
peptide (GIP). Three amino acids (alanine, glycine and
arginine) act in a manner similar to glucose by altering
the beta cells' membrane potential. Acetylcholine
triggers insulin release through phospholipase C, while
the last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system (via Alpha2-
adrenergic stimulation as demonstrated by the agonists
clonidine or methyldopa) inhibits the release of insulin.
However, it is worth noting that circulating adrenaline
will activate Beta2-Receptors on the beta cells in the
pancreatic islets to promote insulin release. This is
important, as muscle cannot benefit from the raised blood
sugar resulting from adrenergic stimulation (increased
gluconeogenesis and glycogenolysis from the low blood
insulin: glucagon state) unless insulin is present to
allow for GLUT-4 translocation in the tissue. Therefore,
beginning with direct innervation, norepinephrine
inhibits insulin release via alpha2-receptors;
subsequently, circulating adrenaline from the adrenal
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medulla will stimulate beta2-receptors thereby promoting
insulin release.
When the glucose level comes down to the usual
physiologic value, insulin release from the beta cells
slows or stops. If blood glucose levels drop lower than
this, especially to dangerously low levels, release of
hyperglycemic hormones (most prominently glucagon from
Islet of Langerhans' alpha cells) forces release of
glucose into the blood from cellular stores, primarily
liver cell stores of glycogen. By increasing blood
glucose, the hyperglycemic hormones prevent or correct
life-threatening hypoglycemia. Release of insulin is
strongly inhibited by the stress hormone norepinephrine
(noradrenaline), which leads to increased blood glucose
levels during stress.
There are special transporter proteins in cell membranes
through which glucose and some nutrients from the blood
can enter a cell. These transporters are, indirectly,
under blood insulin's control in certain body cell types
(e.g., muscle cells). Low levels of circulating insulin,
or its absence, will prevent glucose and some nutrients
from entering those cells (e.g., in Type 1 diabetes).
However, more commonly there is a decrease in the
sensitivity of cells to insulin (e.g., the reduced
insulin sensitivity characteristic of Type 2 diabetes),
resulting in decreased glucose and/or nutrient
absorption. In either case, there is 'cell starvation',
weight loss, catabolism, sometimes extreme. In a few
cases, there is a defect in the release of insulin from
the pancreas. Either way, the effect is,
characteristically, the same: elevated blood glucose
levels.
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Activation of insulin receptors leads to internal
cellular mechanisms that directly affect glucose and
other nutrient uptake by regulating the number and
operation of protein molecules in the cell membrane that
transport glucose ad other nutrients into the cell. The
genes that specify the proteins that make up the insulin
receptor in cell membranes have been identified and the
structure of the interior, cell membrane section, and
now, finally after more than a decade, the extra-membrane
structure of receptor
It is well known by those skilled in the art that
two types of tissues are most strongly influenced by
insulin, as far as the stimulation of glucose and other
nutrient uptake is concerned: muscle cells (myocytes) and
fat cells (adipocytes). The former are important because
of their central role in movement, breathing,
circulation, etc, and the latter because they accumulate
excess food energy against future needs. Together, they
account for about two-thirds of all cells in a typical
human body.
The actions of insulin on human metabolism include
control of cellular intake of certain substances
(including nutrients) but most prominently glucose in
muscle and adipose tissue (about two thirds of body
cells); increase of DNA replication and protein synthesis
via control of amino acid uptake; and modification of the
activity of numerous enzymes. The actions of insulin at
the cellular level include:
1. Increased glycogen synthesis - insulin forces
storage of glucose in liver (and muscle) cells in the
form of glycogen; lowered levels of insulin cause liver
cells to convert glycogen to glucose and excrete it into
the blood. This is the clinical action of insulin which
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is directly useful in reducing high blood glucose levels
as in diabetes;
2. Increased fatty acid synthesis - insulin forces
fat cells to take in blood lipids which are converted to
triglycerides; lack of insulin causes the reverse;
3. Increased esterification of fatty acids -
forces adipose tissue to make fats (i.e., triglycerides)
from fatty acid esters; lack of insulin causes the
reverse;
4. Decreased proteolysis;
5. Decreased lipolysis - forces reduction in
conversion of fat cell lipid stores into blood fatty
acids; lack of insulin causes the reverse;
6. Decreased gluconeogenesis - decreases
production of glucose from non-sugar substrates,
primarily in the liver (remember, the vast majority of
endogenous insulin arriving at the liver never leaves the
liver); lack of insulin causes glucose production from
assorted substrates - including amino acids that could be
used to increase protein synthesis in skeletal muscle
tissue - in the liver and elsewhere;
7. Decreased autophagy - decreased level of
degradation and catabolism of damaged organelles.
Postprandial levels of insulin inhibit autophagy
completely;
8. Increased amino acid and creatine uptake -
forces cells to absorb circulating amino acids and
creatine; lack of insulin inhibits absorption;
9. Increased potassium uptake - forces cells to
absorb serum potassium; lack of insulin inhibits
absorption, lowering potassium levels in blood;
10. Arterial muscle tone - forces arterial wall
muscle to relax, increasing blood flow, especially in
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micro arteries; lack of insulin reduces flow by allowing
these muscles to contract; and
11. Increase in the secretion of hydrochloric acid
by Parietal cells in the stomach.
Insulin currently cannot be taken orally. Like
nearly all other proteins introduced into the
gastrointestinal tract, it is reduced to fragments (even
single amino acid components), whereupon all 'insulin
activity' is lost. Insulin is usually administered via
subcutaneous injection by single-use syringes with
needles, an insulin pump, or by repeated-use insulin pens
with needles.
Because of the myriad of effects caused directly or
indirectly by insulin (some of which are discussed
herein), it would be desirable to develop novel oral
products that either mimic one or more of the actions of
insulin or increase the endogenous production, secretion
or activity of insulin. Such products would have utility
in treating humans who suffer from conditions resulting
from low insulin levels or activity and in increasing the
utilization of various nutrients to increase athletic
performance.
Pterostilbene
Pterostilbene is a stilbene found, for example, in
deerberry and rabbiteye blueberries, unripe Pinot noir
and Botrytis vinifera infected Chardonnay grapes, and
immature berries of Pinot and Gamay varieties (J Agric
Food Chem 52:4713-9 (2004); J Agric Food Chem 48:6103-
6105 (2000); Plant Physiol Biochem 26:603-7 (1988)).
Pterostilbene has been shown to elicit significant
anti-oxidant activity in vitro that is comparable to the
activity of resveratrol. Research has demonstrated that
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pterostilbene inhibits cintronellal thermo-oxidation by
an EQ value of 335 mM (-90.9 mg/ml), and that
pterostilbene scavenges for 2,2-diphenyl-l-picrylhydrazyl
(DPPH) radicals with an EC50 value of about 30 mM (-7.68
mg/ml) (J Nat Prod 60:609-10 (1997)). Additionally,
pterostilbene inhibits 2,2'-azo-bis(2-amidinopropane)
(ABAP)-derived peroxyl radicals with a total reactive
antioxidant potential of 237 +/- 58 mM (-60.7 mg/ml) as
compared to resveratrol at 253 +/- 53 mM (-57.7 mM/ml) (J
Agric Food Chem 50:3453-7 (2002)). Further
investigations have demonstrated that pterostilbene
protects against lipid peroxidation by reducing
thiobarbituric acid reactive substances (TBARS)
production by 61% in normal human fibroblasts (J Biol
Chem 276:22586-94 (2001)).
Limited research has demonstrated that pterostilbene
has cancer chemoprotective properties in both in vitro
and in vivo experiments (Neoplasia 1:37-47 (2005); Int J
Biochem Cell Biol 37:1709-26 (2005)). Preliminary
research has also been undertaken on pterostilbene's
ability to inhibit cyclooxygenase (COX) enzymes (J Agric
Food Chem 50:3453-7 (2002)).
Pterostilbene and Pterocarpus marsupium extracts
that have been shown to contain pterostilbene have
reported anti-diabetic properties. Research demonstrated
that pterostilbene can lower the blood glucose level in
streptozotocin-induced hyperglycemic rats by 42% (J Nat
Prod 60:609-10 (1997)). Pterocarpus marsupium, which
contains pterostilbene in its heartwood, has also been
shown to have anti-hyperglycemic properties and provide
significant protection against hypertriglyceridemia and
hyperinsulinemia (Diabetes Obes Metab 7:414-20 (2005)).
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In the development of new drugs and dietary
supplements, the scientific, medical and nutritional
communities rely heavily on animal studies that provide a
framework for human trials. To assist with this, the
U.S. Department of Health & Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research
(FDA/CDER) published recommendations in July 2005 for
estimating the maximum safe starting dose in initial
clinical trials for therapeutics in adult healthy
volunteers (on the worldwide web at
fda.gov/cder/guidance/index.htm). The document, which is
incorporated herein in its entirety by reference,
outlines a process for deriving the maximum recommended
starting dose (MSRD) for first-in-human clinical trials
of new molecular entities in adult healthy volunteers and
recommends a standardized process by which the MSRD can
be selected. Some of the stated purposes of this guiding
document are to provide common conversion factors in
deriving human equivalent dose (HED) and to delineate a
strategy for selecting MSRD for healthy adult volunteers
regardless of the projected clinical use.
The recommended process for selecting MSRD requires
the determination of "no adverse effects levels" (NOAELs)
in the tested animal species; conversion of NOAELs to HED
are discussed in this guiding document. The document
states that the NOAEL should be identified for each
species and then converted to HED using the appropriate
scaling factors. For most systemically administered
therapeutics, this conversion should be based on the
normalization of doses to body surface area. The
FDA/CDER guiding document provides tables and algorithmic
processes for determining the HED. In particular, page 7
of this document provides a table based on several
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species of test animals and appropriate formulae to
convert these animal doses to HED based on body surface
area. When the test animal is a rat, the following
formulae are provided:
To convert an animal dose in mg/kg to HED
in mg/kg either divide the animal (rat)
dose by a factor of 6.2 or multiply the
animal dose (rat) by a factor of 0.16 -
this assumes the HED is for a human with a
weight of 60kg. Alternatively, if the
weight the human is not 60kg, the following
formula (Generic Formula) may be employed:
HED = animal dose in mg/kg x (animal weight
in kg/human weight in kg) 0.33
This formula has been successfully employed in
determining a HED for resveratrol, another stilbene
structurally similar to pterostilbene(FIG. 2).
Thus based on the previous studies administering
pterostilbene to rats (having a weight of -250g) at doses
ranging from 10mg/kg bodyweight up to 40mg/kg bodyweight
with no adverse effects noted in any animal (rat) in any
of the aforementioned studies it would be expected that
an HED for pterostilbene would be between 1.61 mg/kg of
bodyweight (based on pterostilbene dose of 10 mg/kg
bodyweight in the rat) and 6.45 mg/kg of bodyweight
(based on pterostilbene dose of 40 mg/kg bodyweight in
the rat) for a human with a weight of 60 kg. Using the
Generic Formula and basing HED determination on a human
with a bodyweight of -100 kg, the range for pterostilbene
would be expected to be between 1.357 mg/kg of bodyweight
(based on pterostilbene dose of 10mg/kg bodyweight in the
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rat) and 6.542 mg/kg of bodyweight (based on
pterostilbene dose of 40 mg/kg bodyweight in the rat).
Thus according the FDA/CDER formula, a human with a
bodyweight of -100kg would be able to safely use a dose
of pterostilbene of about 135 mg to about 654 mg.
However, work described herein surprisingly showed this
not to be true.
In work described herein using pterostilbene orally
in humans (supplied by Chromadex, 10005 Muirlands
Boulevard, Suite G, Irvine, CA 92618, USA) dosing of oral
pterostilbene was initially started at a lower dose than
the calculated HED, with the intent of titrating the dose
up as needed. The initial oral dose of pterostilbene
used in humans in work described herein was 30 mg in a
gelatin capsule administered in a single dose to a 35
year old healthy male volunteer who had a bodyweight of
approximately 120.53 kg (dose of about 0.248mg/kg
bodyweight).
Within fifteen minutes of oral administration at
this dose, the human test subject began to experience
symptoms of profound hypoglycemia, including shakiness,
dysphoria, and diaphoresis. Testing of the subject's
whole blood glucose level by "finger prick" methodology
using a commercial glucometer revealed that the test
subject's whole blood glucose level had dropped about 50
mg/dL during this time period. The test subject was
immediately treated with oral glucose and other
carbohydrates and recovered without other incident.
Further testing of oral pterostilbene in other human test
subjects revealed that pterostilbene is effective in
significantly reducing whole blood glucose levels in
healthy, adult humans in doses as low as 0.03 mg/kg of
bodyweight (actual dose given 3 mg orally) to about 0.165
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mg/kg of bodyweight (actual dose given 20 mg orally)
without inducing clinically significant side effects
including, but not limited to, nausea, dysphoria,
diaphoresis. At oral dosing above 0.165 mg/kg (actual
dose tested 20 mg) pterostilbene is capable of inducing
profound hypoglycemia (e.g., whole blood glucose at or
below 55 mg/dL) and the side effects associated with this
condition. Accordingly, at the doses predicted by the
FDA/CDER formula, oral administration of pterostilbene to
humans would likely be fatal.
Additional work described herein addressed the
effects of combining oral pterostilbene with various
nutrients on athletic performance. Specifically, oral
pterostilbene was administered with creatine supplements,
and the effect of this combination was compared with the
effect of creatine supplements alone. In one test using
a 28 year old healthy male volunteer with a body weight
of about 102.67 kg, the addition of 5 mg of oral
pterostilbene (0.0486 mg/kgbodyweight) to a creatine-
containing liquid dietary supplement resulted in
approximately an immediate 8% increase in maximal
exertion power and approximately an immediate 12%
increase in anaerobic work capacity compared with the
creatine-containing liquid dietary supplement alone.
Work described herein indicates that 3 mg to 20 mg
of pterostilbene added to a creatine-containing
supplement improves athletic performance dramatically,
with a preferable dose being between about 5 mg and about
10 mg. The addition of exogenous dietary carbohydrates
such as glucose, isolmaltulose, leucrose, trehalose,
trehalulose, amylose, ribose, and maltodextrin to the
creatine-containing supplement allowed for even higher
pterostilbene dosing (up to 25 mg of oral pterostilbene)
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and produced an even more pronounced, immediate increase
in athletic performance without the onset of
hypoglycemia.
Our experiments revealed that the addition of
pterostilbene to other ergogenic, athletic performance-
enhancing, non-carbohydrate based, dietary nutrients
tends to induce an immediate increase in the athletic
performance-enhancing effects of these dietary nutrients
when they are orally consumed. While not wishing to be
bound by any particular theory, the inventors believe
that pterostilbene increases or otherwise effects a
change in the rate and quantity of the transfer of these
nutrients from the blood plasma into the tissues and
organs. Such dietary nutrients include, but are not
limited to, creatine and its salts esters, amides and
chelates, creatinol-0-phosphate, branched chain amino
acids (leucine, isoleucine, valine) and their salts,
esters, amides and chelates, branched chain keto-acids
including, but not limited to ketoisocaproate and its
salts, other ergogenic, performance-enhancing amino acids
including, but not limited to, taurine, beta-alanine,
arginine, ornithine, aspartic acid, glutamine, glutaric
acid, agmatine, citrulline, norvaline, glycine, cysteine
and their salts, ester, amides and chelates, performance
enhancing dipeptides including, but not limited to,
carnitine, anserine and carnosine and their salts and
esters and proteins that are known to contain dipeptides
such as whey or soy or egg protein isolates or
concentrates or any combination of these non-carbohydrate
based dietary nutrients.
Further, the addition and oral consumption of one or
more exogenous dietary carbohydrates, including but not
limited to rice oligodextrin, amylose, amylopectin,
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glucose, maltodextrin, maltose, isolmaltulose, leucrose,
trehalulose, ribose, trehalose, and/or fructose in
conjunction with pterostilbene and a non-carbohydrate
based dietary nutrient or nutrients simultaneously
further increases the athletic performance-enhancing
effects of pterostilbene and the non-carbohydrate dietary
nutrient(s) by up to 50% and also increases the
tolerability of pterostilbene in humans by up to 50%.
The compositions and methods of the present
invention may provide significant increase or improvement
in athletic performance, e.g., muscle size, and/or muscle
strength, and/or muscle endurance in individuals. As used
herein, "athletic performance" and/or "athletic
functions" refers to the sum of physical attributes which
can be dependent to any degree on skeletal muscle
contraction. For example, athletic performance and/or
athletic functions include, but are not limited to,
maximal muscle power, muscular endurance, running speed
and endurance, swimming speed and endurance, throwing
power, lifting and pulling power. The compositions of
the invention can function as insulinogenic agents or
insulin mimetics.
While it is expected that the compositions and
methods of the present invention will be of particular
importance to bodybuilders and other athletes, the
usefulness of compositions and methods of the invention
is not limited to those groups. Rather, any individual
(i.e., human) may beneficially use the compositions and
methods of the invention.
The compositions according to the present invention
may be employed in methods for supplementing the diet of
an individual, e.g., an athlete, and/or for enhancing an
individual's muscle mass and/or muscle size and/or
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strength, and/or endurance. Accordingly, the present
invention provides methods of supplementing the dietary
intake of an individual comprising administering to the
individual an effective amount of a composition (e.g.,
pterostilbene or a nutritional supplement comprising
pterostilbene) according to the present invention to
increase athletic performance or athletic function is
said individual. The invention also relates to methods of
improving athletic performance and/or athletic function
in an individual comprising administering an effective
amount of a pterostilbene (alone or in combination with
other agents, e.g., in a dietary supplements or
nutrients) to the individual.
Accordingly, the invention relates in one embodiment
to compositions, formulations and methods relating to one
or more stilbene-based compounds for use in humans. In
particular, compositions and formulations comprising,
consisting of or consisting essentially of an effective
amount of the stilbene-based insulinogenic compound can
improve athletic performance, lower blood glucose levels,
and increase lean muscle mass when administered (e.g.,
orally) to a human. In a particular embodiment the
stilbene-based compound is pterostilbene.
Compositions and forumations of the invention can
preferably be dietary supplements, dietary formulations,
or nutraceuticals. As used herein, the terms "nutrient"
and "dietary supplement" and "nutraceutical" are used
interchangeably to refer to any substance that is a food
or part of a food and provides medical or health
benefits, including the prevention and treatment of
disease. Hence, compositions falling under the label
"nutrient" and "dietary supplement" may range from
isolated nutrients, nutritional or dietary supplements,
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and specific diets, to genetically engineered designer
foods, herbal products, and processed foods such as
cereals, soups, and beverages. In a more technical sense,
the term has been used to refer to a product isolated or
purified from foods, and generally sold in medicinal
forms not usually associated with foods and demonstrated
to have a physiological benefit or provide protection
against chronic disease.
Compositions and formulations of the invention will
comprise an effective amount of pterostilbene; in some
embodiments compositions and formulations of the
invention will further comprise at least one (i.e., one
or more) compounds or compositions which are not found in
a natural source of pterostilbene. In certain
embodiments the composition or compound which is not
found in a natural source of pterostilbene is an active
agent (i.e., is an agent which has a physiological effect
either alone or in combination with pterostilbene).
Pterostilbene can be obtained as known in the art by
chemical synthesis methods (see, for example, US Patent
7,253,324) or by isolation or extraction from one or more
natural sources (see, for example, US Patent Application
Publications 20080032372 and 20080124414). In some
embodiments the pterostilbene of the invention is
administered or exists in a composition or formulation
separated from one or more (e.g., from all) compounds
with which it exists in a natural source.
As used herein, an "effective amount" in
compositions of the present invention is defined as an
amount effective, at dosages and for periods of time
necessary, to achieve the desired result. For example,
the amount of pterostilbene may be effective to increase
athletic performance, lower blood sugar levels and/or
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increase lean muscle mass in a human to whom the
formulation is administered. The effective amount of
compositions of the invention may vary according to
factors such as age, sex, and weight of the individual.
Dosage regime may be adjusted to provide the optimum
response. Several divided doses may be administered
daily, or the dose may be proportionally reduced as
indicated by the exigencies of an individual's situation.
As will be readily appreciated, a composition in
accordance with the present invention may be administered
in a single serving or in multiple servings spaced
throughout the day. As will be understood by those
skilled in the art, servings need not be limited to daily
administration, and may be on an every second or third
day or other convenient effective basis. The
administration on a given day may be in a single serving
or in multiple servings spaced throughout the day
depending on the exigencies of the situation. Preferably
each dose will comprise an effective amount of
pterostilbene.
The invention relates, for example, to a formulation
comprising an amount of pterostilbene effective to
increase athletic performance in a human to whom the
formulation is administered, and creatine or a salt,
ester, amide or chelate thereof. The invention also
relates to a formulation comprising an amount of
pterostilbene effective to reduce blood sugar levels or
to increase lean muscle mass in a human to whom it is
administered. In some embodiments the effective amount
is from about 3 mg to about 25 mg of pterostilbene per
dose, more particularly from about 5 mg to about 10 mg of
pterostilbene per dose. In other embodiments the
formulation comprises from about 250 mg to about 10,000
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mg of creatine or a salt, ester, amide or chelate thereof
per dose. The formulations and compositions of the
invention may, for example, comprise from about 0.002 to
about 100 percent pterostilbene by weight. Preferably
compositions and formulations of the invention will
comprise at least about 0.002 percent pterostilbene by
weight.
In some embodiments the formulation comprises one or
more carbohydrate nutrients in addition to comprising
pterostilbene. For example, the carbohydrate nutrient
can be one or more of rice oligodextrin; amylose;
amylopectin; glucose; maltodextrin; maltose;
isomaltulose; leucrose; trehalulose; ribose; trehalose;
sucrose; and fructose.
In other embodiments the formulation comprises one
or more non-carbohydrate nutrients in addition to
comprising pterostilbene. For example, the non-
carbohydrate nutrient may be one or more of creatine and
its salts, esters, amides and chelates; creatinol-0-
phosphate; the amino acids leucine, isoleucine, valine,
taurine, beta-alanine, arginine, ornithine, aspartic
acid, glutamine, glutaric acid, agmatine, citrulline,
norvaline, glycine, and cysteine and salts, esters,
amides and chelates of said amino acids; ketoisocaproate
and sodium, potassium, calcium and magnesium salts
thereof; the dipeptides carnitine, anserine and carnosine
and salts and esters thereof; and dipeptide-containing
proteins.
In some embodiments the formulation or compositions
of the invention comprise one or more compounds or
compositions which are not found in a natural source of
pterostilbene, and in a preferred embodiment the one or
more compounds or compositions are active agents.
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In some embodiments of the invention the composition
is formulated as a tablet, capsule, caplet, powder,
suspension, gel preparation, aqueous solution, solid food
form (e.g., chewable bar or wafer), or liquid dosage form
such as elixirs, syrups, dispersed powders, granules or
emulsions. In one embodiment the composition is
particularly formulated for oral use. Although work
described herein focused on oral administration, it is
clear that compositions and formulations of the invention
may be administered effectively by other routes
including, but not limited to, parenteral, buccal,
sublingual, rectal, and transdermal. In preferred
embodiments the route of administration is oral, and
suitable means are especially tablets, caplets, capules,
pulls, suspensions, solutions (e.g., drinks), elixirs
that can be produced in ways that are commonly used and
familiar to one skilled in the art, with the additives
and vehicles that are commonly used. As non-limiting
examples, extended release or time release formulations
are among technologies known to the skilled artisan and
suitable for use with the invention.
In addition, the compositions can be administered or
formulated alone or can be formulated with or
administered before, concurrent with or after other
optional components such as other active ingredients. In
some embodiments the composition or formulation
comprising pterostilbene contains one or more of the
following ingredients, preferably as an active
ingredient:
= Carbohydrates including, but not limited to,
isomaltulose, trehalose, maltodextrin, glucose, sucrose,
fructose, lactose, amylose, and/or ribose;
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Water soluble vitamins including, but not
limited to, Vitamin C, Vitamin B1, Vitamin B2, Vitamin
B3, Vitamin B6, Vitamin B12, and/or Vitamin K (and
derivatives);
= Minerals including, but not limited to,
calcium, sodium, potassium, chromium, vanadium,
magnesium, and/or iron (and derivatives)(preferably in
amounts less than the RDA);
= Amino acids including, but not limited to, L-
arginine, L-ornithine, L-glutamine, L-tyrosine, L-
taurine, L-leucine, L-isoleucine, and/or L-valine (and
derivatives);
= Nutraceutically acceptable stimulants
including, but not limited to, methylxanthines (e.g. -
caffeine) and/or glucuronolactone (and derivatives);
= Nutraceutically acceptable hypoglycemic agents
including, but not limited to, alpha-lipoic acid and its
derivatives, cinnamon bark, bitter melon extracts,
Gymnema Sylvestre extracts, 4-hydroxy-isoleucine,
corosolic acid, and/or D-pinitol (and derivatives);
= Creatine and its salts (e.g., creatine
monohydrate), esters (e.g., creatine ethyl ester),
chelates, amides, ethers (and derivatives);
= Adenosine triphosphate and its disodium salt;
= Glycerol and glycerol monostearate;
= Mannitol;
= Sorbitol; and
= Dextran.
The compositions may contain pharmaceutically, e.g.,
nutraceutically, acceptable excipients, according to
methods and procedures well known in the art. As used
herein, "excipient" refers to substances that are
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typically of little or no therapeutic value, but are
useful in the manufacture and compounding of various
pharmaceutical preparations and which generally form the
medium of the composition. These substances include, but
are not limited to, coloring, flavoring, and diluting
agents; emulsifying, dispersing and suspending agents,
ointments, bases, pharmaceutical solvents; antioxidants
and preservatives; and miscellaneous agents. Suitable
excipients are described, for example, in Remington's
Pharmaceutical Sciences.
The compositions and formulations according to the
present invention can further comprise one or more
acceptable carriers. A wide number of acceptable carriers
are known in the nutritional supplement arts, and the
carrier can be any suitable carrier. The carrier need
only be suitable for administration to animals, including
humans, and be able to act as a carrier without
substantially affecting the desired activity of the
composition. Also, the carrier(s) may be selected based
upon the desired administration route and dosage form of
the composition. For example, the nutritional supplement
compositions according to the present invention are
suitable for use in a variety of dosage forms, such as
liquid form and solid form (e.g., a chewable bar or
wafer). In desirable embodiments the compositions and
formulations comprise a solid dosage form, such as a
tablet or capsule. Examples of suitable carriers for use
in tablet and capsule compositions include, but are not
limited to, organic and inorganic inert carrier materials
such as gelatin, starch, magnesium stearate, talc, gums,
silicon dioxide, stearic acid, cellulose, and the like.
Desirably, the carrier is substantially inert, but it
should be noted that the nutritional supplement
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compositions of the present invention may contain further
active ingredients in addition to pterostilbene.
The invention also relates to a method of increasing
athletic performance, lowering blood sugar level and/or
increasing lean muscle mass in a human comprising
administering an effective amount of a stilbene-based
compound to said human. In one embodiment the stilbene-
based compound is pterostilbene. In one embodiment the
pterostilbene is administered orally.
As used herein, "athletic functions" refers to the
sum of physical attributes which can be dependent to any
degree on skeletal muscle contraction. For example,
athletic functions include, but are not limited to,
maximal muscular strength, muscular endurance, running
speed and endurance, swimming speed and endurance,
throwing power, lifting and pulling power. As used
herein, improving or increasing athletic performance or
function includes enhancing an individual's muscle mass
and/or muscle size and/or strength, and/or endurance.
In certain embodiments the effective amount of
pterostilbene is from about 3 mg to about 25 mg per dose,
from about 3 mg to about 10 mg per dose, or from about 5
mg to about 10 mg per dose. In certain embodiments the
effective amount of pterostilbene is from about 0.03
mg/kg bodyweight of the human to about 0.165 mg/kg
bodyweight of the human per dose.
In certain embodiments more than one dose comprising
an effective amount of pterostilbene is administered to
the human (e.g., two or more doses spaced over time, each
dose comprising an effective amount of pterostilbene).
The pterostilbene can be co-administered with one or more
non-carbohydrate nutrients. For example, the non-
carbohydrate nutrient may be selected from the group
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consisting of creatine and its salts, esters, amides and
chelates; creatinol-0-phosphate; the amino acids leucine,
isoleucine, valine, taurine, beta-alanine, arginine,
ornithine, aspartic acid, glutamine, glutaric acid,
agmatine, citrulline, norvaline, glycine, and cysteine
and salts, esters, amides and chelates of said amino
acids; ketoisocaproate and sodium, potassium, calcium and
magnesium salts thereof; the dipeptides carnitine,
anserine and carnosine and salts and esters thereof; and
dipeptide-containing proteins.
In some embodiments the pterostilbene is co-
administered with one or more carbohydrate nutrients.
For example, the carbohydrate nutrient may be selected
from the group consisting of: rice oligodextrin; amylose;
amylopectin; glucose; maltodextrin; maltose;
isomaltulose; leucrose; trehalulose; ribose; trehalose;
sucrose; and fructose.
In some embodiments the pterostilbene is co-
administered with both one or more non-carbohydrate
nutrients and one or more carbohydrate nutrients. For
example, an effective amount of pterostilbene can be co-
administered with both a carbohydrate nutrient and
creatine or a salt, ester, amide or chelate thereof.
In some embodiments the pterostilbene is co-
administered with one or more compounds not found in a
pterostilbene natural source. In some embodiments the
pterostilbene is co-administered with one or more
compounds selected from the group consisting of
methylxanthines (e.g., caffeine, theobromine,
theophylline), glucuronolactone, animal digestive enzymes
(e.g., lipase, bromelain, pancreatin, amylase, lactase),
and carbohydrates not found in a pterostilbene natural
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source (e.g., isomaltulose, trehalose, leucrose, amylose,
trehalulose, rice oligodextrin).
As used herein, "co-administration" includes, but is
not limited to, concurrent administration of multiple
compositions, either as separate compositions or in
admixture. Co-administration also includes
administration of the multiple compositions proximal in
time, as long as the co-administered compositions exhibit
the synergistic or enhanced functional effect observed
when the compositions are administered concurrently. The
synergistic effect or enhanced effect need not be of the
same scope or magnitude as observed upon concurrent
administration.
In particular, co-administration of an effective
amount of pterostilbene and a non-carbohydrate nutrient
exhibits an improved effect on athletic performance as
compared with either nutrient alone. Moreover this co-
administration exhibits an enhanced or synergistic effect
on athletic performance which is greater than the
additive effect of the nutrients. Addition of a
carbohydrate nutrient further enhances this effect.
Particularly, and without limitation, increased muscle
volumization occurs, ADP to ATP regeneration increases,
and/or glycogen synthesis in muscle increase.
The embodiments set forth in the present application
are provided only to illustrate various aspects of the
invention, and additional embodiments and advantages of
the food supplements and methods of the present invention
will be apparent to those skilled in the art. The
articles "a" and "an" as used herein, unless clearly
indicated to the contrary, should be understood to
include the plural referents. Claims or descriptions
that include "or" between one or more members of a group
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are considered satisfied if one, more than one, or all of
the group members are present in, employed in, or
otherwise relevant to a given product or process unless
indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which
exactly one member of the group is present in, employed
in, or otherwise relevant to a given product or process.
The invention also includes embodiments in which more
than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or
process. Furthermore, it is to be understood that the
invention encompasses all variations, combinations, and
permutations in which one or more limitations, elements,
clauses, descriptive terms, etc., from one or more of the
listed claims is introduced into another claim dependent
on the same base claim (or, as relevant, any other claim)
unless otherwise indicated or unless it would be evident
to one of ordinary skill in the art that a contradiction
or inconsistency would arise. Where elements are
presented as lists, (e.g., in Markush group or similar
format) it is to be understood that each subgroup of the
elements is also disclosed, and any element(s) can be
removed from the group. It should be understood that, in
general, where the invention, or aspects of the
invention, is/are referred to as comprising particular
elements, features, etc., certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements, features, etc. For
purposes of simplicity those embodiments have not in
every case been specifically set forth in so many words
herein. It should be understood that any embodiment or
aspect of disclosed invention may be freely combined with
one or more other embodiments of the invention unless
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otherwise indicated; exhaustive combinations of disclosed
embodiments have not in every instance been specifically
set forth verbatim but are intended to be encompassed by
this disclosure. It should also be understood that any
embodiment or aspect of the invention can be explicitly
excluded from the claims, regardless of whether the
specific exclusion is recited in the specification. The
teachings of all references cited herein are incorporated
herein by reference in their entirety.
Examples
Non-limiting examples of pterostilbene used with
non-carbohydrate dietary nutrients and pterostilbene used
with non-carbohydrate dietary nutrients plus exogenous
carbohydrates are provided in the examples below. The
servings set forth in these examples are designed for an
athlete with a body mass of about 70 kilograms. Daily
values can be increased or decreased, depending on the
body mass of the individual athlete and individual needs
and requirements.
EXAMPLE 1
In this example, an athlete consumes one serving of
the food supplement described herein daily; typically the
athlete will consume a serving of the food supplement
about 30-60 minutes before exercise. Each serving is
about 85.855 grams and contains the following:
Pterostilbene 0.005 grams; Creatine Monohydrate 3.00
grams; Magnesium Creatine Chelate 2.00 grams; L-Leucine
5.00 grams;Propionyl-L-Carnitine 1.00 gram;Ubiquinone
0.100 grams;L-Taurine 3.00 grams;L-Glutamine 7.50
grams;L-Tyrosine 2.00 grams;Disodium ATP 0.200
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grams;Partially Hydrolyzed Guar Gum 5.00
grams;Isomaltulose 15.00 grams; Trehalose 15.00
grams;Glucose 15.00 grams;Calcium Phosphate 3.00 grams;
Calcium Citrate 2.00 grams; Calcium Bicarbonate 5.00
grams; Carnosine 2.00 grams and Potassium R-a-Lipoic Acid
0.050 grams.
Each 85.855 gram serving is administered as a powder
dissolved into about 500-750 milliliters of water or
fruit juice to provide a liquid drink.
EXAMPLE 2
In this example, an athlete consumes two servings of
the food supplement as described herein daily; typically
the athlete will consume one serving of the food
supplement about 30-60 minutes before exercise or
athletic activity and the second serving of the food
supplement immediately after the cessation of exercise or
athletic activity. Each serving is about 99.005 grams and
contains the following:
Pterostilbene 0.010 grams; Creatine Monohydrate 3.00
grams;Maltodextrin 50.00 grams; and Whey Protein
Concentrate 46.00 grams
Each approximately 99.010 gram serving is mixed in about
500-1000 milliliters of water or fruit juice to provide a
liquid drink.
EXAMPLE 3
In this example, an athlete consumes three servings
of the food supplement as described herein daily;
typically the athlete will consume one serving of the
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food supplement about 30-60 minutes before exercise or
athletic activity, the second serving of the food
supplement immediately after the cessation of exercise or
athletic activity, and an additional serving 6-8 hours
later. Each serving is about 19.8021 grams and contains
the following:
Pterostilbene 0.0021 grams (2.100 milligrams); Leucine
3.00 grams; Isoleucine 1.500 grams; Valine 1.50 grams, b-
alanine 0.800 grams, Taurine 5.00 grams, Glutamine 5.00
grams.
Each approximately 19.8021 gram serving is mixed in about
300-500 milliliters of water or fruit juice to provide a
liquid drink.
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