U.S. patent application number 14/251981 was filed with the patent office on 2014-10-09 for compositions and methods for improving cardiovascular health.
This patent application is currently assigned to Energy Light, LLC. The applicant listed for this patent is Energy Light, LLC. Invention is credited to Nicolaas ("Mick") Emile Paulas Deutz, John P. Troup, Robert Wolfe.
Application Number | 20140303099 14/251981 |
Document ID | / |
Family ID | 40932293 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140303099 |
Kind Code |
A1 |
Wolfe; Robert ; et
al. |
October 9, 2014 |
Compositions and Methods for Improving Cardiovascular Health
Abstract
Compositions and methods for improving cardiovascular health,
especially in the elderly, by delivering a selection of essential
amino acids selected from the group of histidine, isoleucine,
leucine, valine, lysine, methionine, phenylalanine, threonine, and
arginine, which may be supplemented with a low glycemic
carbohydrate and/or a medium chain fatty acid.
Inventors: |
Wolfe; Robert; (Little Rock,
AR) ; Troup; John P.; (Plymouth, MN) ; Deutz;
Nicolaas ("Mick") Emile Paulas; (Little Rock, AR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Energy Light, LLC |
McLean |
VA |
US |
|
|
Assignee: |
Energy Light, LLC
McLean
VA
|
Family ID: |
40932293 |
Appl. No.: |
14/251981 |
Filed: |
April 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12023413 |
Jan 31, 2008 |
8716249 |
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14251981 |
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Current U.S.
Class: |
514/23 ;
514/400 |
Current CPC
Class: |
A61K 31/201 20130101;
A61K 31/201 20130101; A61K 31/352 20130101; A61K 45/06 20130101;
A61P 21/00 20180101; A61K 31/575 20130101; A61K 31/197 20130101;
A61P 9/00 20180101; A61P 9/10 20180101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/575 20130101; A61K 31/352 20130101; A61K 31/4172 20130101;
A61K 31/198 20130101; A61K 31/198 20130101 |
Class at
Publication: |
514/23 ;
514/400 |
International
Class: |
A61K 31/4172 20060101
A61K031/4172; A61K 31/197 20060101 A61K031/197; A61K 45/06 20060101
A61K045/06; A61K 31/198 20060101 A61K031/198 |
Claims
1. A composition of matter for improving cardiovascular health
comprising an amino acid blend, the blend comprising: about 0.36 g
histidine; about 0.94 g isoleucine; about 3.95 g leucine; about
1.88 g lysine; about 0.39 g methionine; about 0.51 g phenylalanine;
about 1.05 g threonine; about 0.82 g valine; and 1.10 g
arginine.
2. The composition of claim 1 further comprising a low glycemic
carbohydrate.
3. The composition of claim 1 further comprising a medium chain
fatty acid.
4. The composition of claim 2, wherein said low glycemic
carbohydrate has a combined mass of about 0.01 to about 15 g.
5. The composition of claim 3, wherein said medium chain fatty acid
has a combined mass of about 0.01 to about 15 g.
6. The composition of claim 1 further comprising supplemental
minerals.
7. The composition of claim 1 further comprising vitamins.
8. The composition of claim 1 further comprising an excipient.
9. A composition of matter for the reduction of liver fat, the
composition consisting essentially of: about 0.36 g histidine;
about 0.94 g isoleucine; about 3.95 g leucine; about 1.88 g lysine;
about 0.39 g methionine; about 0.51 g phenylalanine; about 1.05 g
threonine; about 0.82 g valine; and about 1.10 g arginine.
10. The composition of claim 9 further consisting essentially of a
low glycemic carbohydrate.
11. The composition of claim 9 further consisting essentially of a
medium chain fatty acid.
12. The composition of claim 10, wherein said low glycemic
carbohydrate has a combined mass of about 0.01 to about 15 g.
13. The composition of claim 11, wherein said medium chain fatty
acid has a combined mass of about 0.01 to about 15 g.
14. The composition of claim 10 further consisting essentially of
supplemental minerals and or vitamins.
15. A method of improving cardiovascular health comprising: having
a patient; and delivering to said patient a composition of matter
for improving cardiovascular health comprising amino acids selected
from the group of histidine, isoleucine, leucine, valine, lysine,
methionine, phenylalanine, threonine, and arginine.
16. The method of claim 15 wherein said composition further
comprises a low glycemic carbohydrate.
17. The method of claim 15 wherein said composition further
comprises a medium chain fatty acid.
18. The method of claim 15 wherein said amino acids have a combined
mass of about 11 grams; and wherein said amino acids further
comprise about 0.36 g histidine, about 0.94 g isoleucine, about
3.95 g leucine, about 1.88 g lysine, about 0.39 g methionine, about
0.51 g phenylalanine, about 1.05 g threonine, about 0.82 g valine,
and about 1.10 g arginine.
19. The method of claim 15 wherein said delivering further
comprises delivering said composition orally to said patient twice
daily.
20. The method of claim 15 wherein said patient is over sixty-five
years of age.
Description
BACKGROUND
[0001] 1. Field of the Invention
[0002] The present invention generally relates to compositions and
methods for improving cardiovascular health. In particular, to such
compositions and methods comprising delivering a selection of amino
acids, plant-derived stanols and sterols, isoflavones, and low
glycemic carbohydrates and medium chain fatty acids to the
elderly.
[0003] 2. Description of the Related Art
[0004] As the population ages, and in particular as the "baby
boomers" grow into their old age, the health problems associated
with aging grow increasingly important. This is particularly true
in a health system such as the current one where health care costs
are distributed across the population; the increased prevalence of
aging-related health problems will result in generally increased
costs. In addition, reactive health care is more expensive than
preventative health care; for example, fixing bones or replacing a
hip after a fall by a frail patient is more expensive than
preventing that fall by decreasing the patient's frailty. For these
and other reasons, it is desirable to have effective, relatively
inexpensive means for preventing and ameliorating health problems
pervasive in the aged population.
[0005] Cardiovascular disease and its related complications, such
as stroke and myocardial infarction, are believed to be the current
number one cause of mortality within the United States. The
development of cardiovascular disease is thought to be due to
atherosclerotic plaque formation within both large and small blood
vessels. Plaque formation is due to many influences, including
increased plasma lipids such as low-density lipoproteins (LDL)
cholesterol, very low-density lipoproteins (VLDL) cholesterol, and
triglycerides (TG). Recently, the metabolic syndrome of combined
hypertension, altered cholesterol, and insulin resistance has been
recognized. Studies have shown that 20-30% percent of the United
States population has this configuration of metabolic
abnormalities.
[0006] High circulating levels of cholesterol, low density
lipoprotein, and triglycerides, as well as elevated blood pressure,
are all believed to be risk factors for development of
cardiovascular disease. Increased liver fat is also related to
these parameters. These risk factors are particularly prevalent in
the elderly, including but not limited to individuals over 65 years
of age. Over 40% of individuals over 65 years of age that are
screened have been found to have elevated cholesterol levels, and
high blood pressure is believed to occur in more than 65% of
individuals over 65 and close to 80% of those over 75. Occurrence
of elevated triglyceride concentrations in the elderly is equally
common, and over 50% of the elderly have elevated liver fat. It is
therefore desirable to address these prevalent and morbid health
problems, in the elderly and in the general affiliated
population.
[0007] Generally, lowering plasma levels of LDL cholesterol and TG
via lifestyle and pharmacologic means has been positively
associated with improvements in both morbidity and mortality from
cardiovascular disease. Further, a lower fat diet with conversely
more protein has been suggested to help prevent athlerosclerotic
lesions. However, lifestyle modifications including low-fat diets
in conjunction with moderate exercise appear to be difficult to
maintain in the modem United States, and the majority of patients
are unable to maintain lifestyle changes long-term. Pharmacologic
means such as treatments with niacin, fibrates and statins have all
been shown to be effective, but are not without side effects. For
example, the facial flushing induced by niacin is a major
limitation in its use; fibrates cause liver dysfunction and skin
rash; and statins are increasingly associated with myopathy. Thus,
therapeutic options that are effective, easy to maintain, and have
minimal side-effects are desirable to properly address this
epidemic of cardiovascular metabolic abnormality. Moreover, current
treatment modalities focus on each of these risk factors
independently. In order to minimize adverse interactions between
treatment modalities and simplify treatment regimens to encourage
patient compliance, it is desirable for one treatment to address
multiple facets of cardiovascular health.
[0008] More specific aspects of current treatments also have room
for improvement. Triglyceride metabolism is believed to involve
multiple tissues within the body and has several aspects.
Initially, fat is absorbed via the gut and secreted into the
splanchnic bloodstream in the form of chylomicrons. Chylomicrons
are high in TGs and have the apolipoproteins ApoB-48, ApoCII and
ApoE. Chylomicrons are circulated to peripheral tissues, and the
TGs are there broken down into free fatty acid (FFA) and glycerol
via lipoprotein lipase (LPL). The chylomicron remnants have low
levels of TG and increased concentrations of cholesterol, and are
transported to the liver. Glycerol and FFA released by the
lipoprotein lipase may also be absorbed by the liver. In the liver,
TGs and FFAs have several fates. In the fasted state, they can be
oxidized to produce ATP or released as an energy source for other
tissues. Alternatively, in the fed state, Acyl-CoA can be
reesterified into TGs, which are then either stored within
hepatocytes, or secreted in the bloodstream alone or as part of
VLDL. VLDL has ApoB-100 protein on the surface and once in
circulation, VLDL gains the proteins ApoE and ApoCIII from HDL
particles and travels to peripheral tissues, where, like
chylomicron, TGs are extracted via lipoprotein lipase. As the TG
concentration decreases and the cholesterol proportion increases,
the lipids turn into LDL.
[0009] There are believed to be multiple sites of regulation of TG
metabolism. ApoCIII has been shown to inhibit hepatic lipase and
inhibit the interaction of TG with hepatic lipoprotein receptors.
ApoCIII is thought to increase TG in the plasma of the blood by
decreasing peripheral clearance via inhibition of LPL. ApoCII is
believed to increase the peripheral clearance of TG's by simulating
LPL. Both ApoCII and ApoCIII concentrations and synthetic rates
have been closely tied to plasma TG concentrations in healthy
patients and those with hyperlipidemia.
[0010] Several of these sites of regulation have been targeted by
different drugs. Several drugs are currently used to block the
initial absorption of TG and cholesterol via the gut, such as
eztembamide. Nicotinic acid, or niacin, is believed to work via
binding to HM74 receptors in adipose tissue, and via cAMP causes a
reduced association of hormone sensitive lipase (HSL) with lipid
droplets in adipose tissue, thus causing a decrease in FFA release
from adipose tissue. Other drugs, such as the PPAR agonist
fibrates, are thought to increase the oxidation of fats within
mitochondria and peroxisomes, and thus decrease the hepatic output
of TG. Further, they increase plasma clearance by increasing ApoCII
expression and activity and decreasing the expression of ApoCIII.
They also are believed to increase the expression of APoA, a
protein specific to HDL, and thus have been demonstrated to induce
moderate increases in HDL concentrations. Statins are believed to
work by inhibiting HmgCoase within the liver, and decreasing the de
novo synthesis of cholesterol.
[0011] Fibrates are believed to have a slightly greater efficacy in
terms of lowering plasma TGs compared to statins, although the
percent change depends on the population being treated. It has been
shown, in elderly patients with normotryglyceridemia, that
fenofibrate treatment decreased plasma TGs within 10 days of
treatment. In patients with mixed hyperlipidemia, 80 mg of
atorvostatin daily were shown to reduce TGs by 65% and VLDL by 57%
whereas 200 mg of fenofibrate decreased TGs and VLDL by 57% and
64%, respectively. Patients with type 2 diabetes mellitus (T2DM)
were shown to experience a 27% decrease in plasma TGs following 3
months of fenofibrate therapy. Adults with hypertryglyceridemia
were shown to experience a 46% decrease in post-paradial TGs after
fenofibrate treatment. After treatment with the fibrate
gemfibrozil, TG concentrations were shown to decrease by 38% in
patients with isolated hypercholesterolemia and 45% in patients
with hypertryglyceridemia and hypercholesterolemia; the maximal
effects were seen within 4 weeks of treatments. Based on these
studies, it appears that in patients with hypertryglyceridemia, the
extent of decrease is greater than patients with
normotryglyceridemia and can be expected to range from about
25-60%. The goal of a nutritional supplement is to achieve
comparable or better results without negative side effects.
[0012] Fibrate treatments including fenofibrate (a prescription
drug) commonly induce the undesirable side effect of liver
toxicity. It is therefore desirable to achieve similar or improved
efficacy of fibrates without such side effects. The effects of a
composition of essential amino acids (EAAs) (i.e., those that
cannot be synthesized by the body) and arginine was compared to the
effect of fenofibrate in a similar population of elderly. In
contrast to the EAA+arginine, fenofibrate treatment for 60 days had
no significant effect on liver triglyceride. Plasma triglyceride
concentration fell approximately 33%, as compared to the 20%
reduction in those receiving EAAs+arginine. These results are shown
in FIG. 2. Due to these positive effects in the absence of negative
side effects, it is desirable for a composition for improving
cardiovascular health to comprise EEAs.
[0013] Alternatively or in addition to pharmaceutic interventions,
isocaloric diets with excess protein may improve plasma TGs to the
same extent as PPAR agonists and statins. A diet consisting of 22%
protein was shown to significantly lower plasma TGs by 32% after 4
weeks, compared to a diet of 12% protein. When patients with T2DM
switched 15-30% of their calories from carbohydrates to protein,
fasted TG was shown to decrease by 22%, and post-parandial glucose
decreased, but cholesterol levels did not change. Plasma TGs were
reduced by 23.+-.5% following a high protein diet in patients with
pre-existing hypercholesterolemia. However, when elderly patients
with poorly controlled T2DM ingested 8 g/day of a mix of 11 amino
acids, they were shown to experience significant decreases in
post-parandial glucose, hemoglobin A1C, insulin and insulin
resistance, but had no changes in plasma lipid parameters. Patients
with T2DM were instructed to follow a 30% protein diet rather than
a 15% protein diet and at 8 weeks, and were found to have no
changes in lipid measurements or glucose control. An
epidemiological (rather than biochemical) study of protein intakes
effect on cardiovascular health, the Nurses Health Study, tracked
over 80,000 women aged 34 to 59 years for 14 years and showed a
moderate correlation between the level of protein intake and the
occurrence of ischemic heart disease. Data also indicates that
higher levels of protein intake have protective effects on elevated
blood pressure. A variety of epidemiological studies indicate an
inverse relationship between protein intake and blood pressure. It
is therefore desirable for a composition for improving
cardiovascular health to increase the patient's protein intake.
[0014] The mechanism by which protein alters plasma triglyceride
concentrations is unclear. Current theories are shown in FIG. 1. It
is believed to take approximately 3 weeks for plasma lipids to be
altered following the initiation of a high protein diet. LPL is
believed to be crucial to the regulation of plasma triglyceride,
and may be altered by activity levels and diet. A diet high in fats
and/or saturated fat is believed to depress LPL activity in adipose
tissue and increase LPL activity in muscle tissue. Exercise has
also been show to increase LPL activity. ApoCII transcription is
believed to be regulated by PPAR-.alpha. and thyroid response
element gene domains on chromosome 19. These genes are believed to
be stimulated by alteration in bile acids (including
chenodeoxycholic, deoxycholic, and lithocolic acid concentrations)
PPAR-.alpha. agonists, and thyroid hormone, and down-regulated by
human ApoA-1 regulatory protein. Current medications that stimulate
the thyroid response element (TRE) are believed to significantly
lower plasma TG and cholesterol in rats. Protein likely does not
alter the gut absorption of triglyceride, since the effects of a
high protein diet are believed to be additive to those of the fat
binding resin cholestyramine. It may also be that protein
supplementation alters the secretion of TGs from the liver,
although the likely mechanism may be the reduction of carbohydrates
in the diet. A high protein diet in Zucker rats decreased hepatic
VLDL secretion, although so does a high fat diet. Obese Zucker rats
had a several fold increase in the incorporation of both protein
and palmitate into VLDL particles, indicating that the synthetic
function of both were increased in obesity. A diet high in
carbohydrate increases plasma levels of ApoCIII, leading to
decreased plasma TG clearance. A high carbohydrate diet also
increases ApoCII concentrations, and thus alters the ratio between
the ApoCIII and ApoCII.
[0015] The mechanism responsible for an effect of protein intake on
lowering blood pressure is believed to be at least in part due to
the extra intake of arginine. Blood pressure is influenced by the
diameter of blood vessels, which is partially controlled by nitric
oxide (NO). Substances that can alter the production of NO have
been shown to lower blood pressure. Arginine supplementation
enhances NO synthesis, reduced oxidative stress and modulation of
renal hemodynamics, among others. When arginine is administered to
hypertensive or healthy humans, in causes vasodilatation and
decreased blood pressure. It is therefore desirable for a
composition to improve cardiovascular health to include arginine,
in order to decrease blood pressure.
[0016] This decrease in plasma lipids profiles associated with a
high protein diet may be due to the decreased content of
carbohydrate. 3 weeks of a diet high in carbohydrates rather than
fat induced significant increases in plasma TG, due to increased
hepatic de novo synthesis of TG. The increase in plasma TG
following a high carbohydrate diet is rapid, with changes seen with
4 days of diet alteration. Further, plasma TG decreased after
either a high fat or a high protein diet, as compared to a high
carbohydrate diet. This substitution of substrate source is not
restricted to dietary substitution: peritoneal dialysis patients
receiving a 1.1% solution of amino acids instead of all glucose
were shown to experience a 13% decrease in plasma TGs within 1
month of the solution change. Other studies have found similar
results over 3 years of treatment.
[0017] Because carbohydrate intake is thus believed to induce
increases in blood lipids in individuals with preexistent
elevations, it is desirable for a composition for improving
cardiovascular health to have minimal carbohydrates. This is
especially desirable for elderly individuals who are often insulin
resistant and cannot obtain nutrition from carbohydrates. Medium
chain triglycerides are believed to be particularly suitable for
this purpose, as they can be readily oxidized for energy and do not
require the hormone insulin to be taken up by tissues. Long chain
fatty acids commonly found in food require an enzyme system
(carnitinepalmitoyltransferase) to transport the fatty acid into
the mitochondria for oxidation. Medium chain triglycerides bypass
this step because medium chain fatty acids can diffuse directly
into the mitochondria. Therefore, such medium chain fatty acids can
provide energy without the concomitant detrimental effect on blood
lipids induced by carbohydrate intake. This is of benefit to
individuals such as the elderly with insulin resistance, since
insulin sensitivity is not required for metabolism of medium chain
triglycerides.
[0018] The mechanism by which carbohydrate levels influence
cardiovascular health remains under study. Carbohydrate intake
stimulates ApoA-1, which may play a role in the appearance of
increased TG following a high carbohydrate diet. Diets high in
carbohydrate are believed to increase the proportion of bile
cholesterol, and disrupt the balance between bile acids and
cholesterol.
[0019] Increasing the proportion of plant sterols in the diet also
has been associated with decreased cardiovascular disease. Plant
sterols, or phytosterols, are found in cellular membranes of
numerous plants, and include steroids with a hydroxyl group in the
three-position of the A-ring. Sterols are long chain fatty acid
esters and are believed to bind cholesterol in the gut effectively
in the gut and prevent its absorption. The three sterols believed
to be the most effective in lowering plasma cholesterol are
B-sitosterol, campesterol, and stigmasterol. A meta-analysis of
multiple studies with plant sterols found that chronic consumption
decreased LDL by approximately 0.33-0.50 mmol/L, or a 8-13%
decrease, and that this decrease is the equivalent of a 20-25%
decrease in cardiovascular disease. Dose response curves appear to
be linear, with the minimal effective dose of 1.5 g a day inducing
a 10% decrease in total cholesterol. Based on such findings, the
National Cholesterol Education Program Adult Treatment Panel has
recommended a trial of 2 g a day of plant sterols in patients with
hypercholesterolemia, prior to initiation of medical treatment.
[0020] Plant sterols are thought to work by decreasing intestinal
cholesterol absorption. Plant sterols have been shown to be as
effective in lowering cholesterol as starting doses of first
generation statins. FIG. 3 shows the response of blood lipids to
various doses of phytosterols (e.g., PHYTROL.RTM. (a
cholesterol-lowering agent). Importantly, the effect of
phytosterols is believed to be pronounced on cholesterol, which the
EAA+arginine mixture did not significantly affect. On the other
hand, phytosterols are not believed to affect plasma triglycerides,
which EAAs+arginine is believed to do. It is therefore desirable
for a combination to lower cholesterol, the LDL/HDL ratio,
triglycerides, and liver triglyceride, as a combination of
EAA+arginine and phytosterols is believed to do.
[0021] A ratio of sterols to stanols have been shown to lower LDL
while raising HDL more effectively than stanols alone, due to the
stanols' shorter chain lengths. A sterols to stanols ratio of 2:1
yields more effective cholesterol lowering (up to 8% greater).
Additionally, the balanced use of sterols and stanols presents a
more functional ingredient which is less waxing and able to be used
in non-fat food matrices.
[0022] In a manner similar to phytosterols, isoflavones decrease
total cholesterol as well as LDL cholesterol. Isoflavones may also
be referred to as 3-phenyl-4H-1-benzopyr-4-one, and may have added
functional groups. As in the case of the EAAs+arginine, the effect
of isoflavones is greater in those with initially elevated values.
This is shown in FIG. 4. It is therefore desirable for a
composition for improving cardiovascular health to comprise
isoflavones.
SUMMARY
[0023] Because of these and other problems in the art, disclosed
herein is, among other things, a composition of matter for
improving cardiovascular health comprising amino acids, a
phytostenol, a stanol, and a isoflavone; wherein said amino acids
are selected from the group of histidine, isoleucine, leucine,
valine, lysine, methionine, phenylalanine, threonine, arginine, and
citrullene.
[0024] In an embodiment, the composition may further comprise a low
glycemic carbohydrate. In an alternative or further embodiment, the
composition may further comprise a medium chain fatty acid.
[0025] In an embodiment of the composition, said amino acids have a
combined mass of about 11 grams; and said amino acids further
comprise about 0.36 g histidine, about 0.94 g isoleucine, about
3.95 g leucine, about 1.88 g lysine, about 0.39 g methionine, about
0.51 g phenylalanine, about 1.05 g threonine, about 0.82 g valine,
and about 1.10 g arginine. In a further embodiment, said
phytostenol and said stanol are in a balanced ratio. Said
isoflavone may have a combined mass of about 30 to about 40 g. In a
further embodiment, the composition may further comprise a low
glycemic carbohydrate, wherein said low glycemic carbohydrate has a
combined mass of about 0.01 to about 15 g. The composition may also
or further comprise a medium chain fatty acid, wherein said medium
chain fatty acid has a combined mass of about 0.01 to about 15
g.
[0026] In embodiments of the composition, the composition may
further comprise supplemental minerals, vitamins, and/or an
excipient.
[0027] Also disclosed herein is a method of improving
cardiovascular health comprising having a patient; and delivering
to said patient a composition of matter for improving
cardiovascular health comprising amino acids, a phytostenol, a
stanol, and a isoflavone; wherein said amino acids are selected
from the group of histidine, isoleucine, leucine, valine, lysine,
methionine, phenylalanine, threonine, arginine, and citrullene.
[0028] In an embodiment of the method, said composition further
comprises a low glycemic carbohydrate. In an alternative or further
embodiment, said composition further comprises a medium chain fatty
acid.
[0029] In an alternative or further embodiment, said amino acids
have a combined mass of about 11 grams; and said amino acids
further comprise about 0.36 g histidine, about 0.94 g isoleucine,
about 3.95 g leucine, about 1.88 g lysine, about 0.39 g methionine,
about 0.51 g phenylalanine, about 1.05 g threonine, about 0.82 g
valine, and about 1.10 g arginine. In a further embodiment, said
phytostenol and said stanol are in a balanced ratio. In a further
or alternative embodiment, said isoflavone has a combined mass of
about 30 to about 40 g. In a further or alternative embodiment,
said delivering further comprises delivering said composition
orally to said patient twice daily. Said patient may be over
sixty-five years of age.
[0030] Also disclosed herein is a method of increasing muscle mass,
strength, and functional performance, comprising having a patient;
and delivering to said patient means for improving cardiovascular
health by delivering amino acids, a phytostenol, a stanol, and a
isoflavone; wherein said amino acids are selected from the group of
histidine, isoleucine, leucine, valine, lysine, methionine,
phenylalanine, threonine, arginine, and citrullene.
[0031] In a further embodiment of the method, said delivering
further comprises delivering a low glycemic carbohydrate. In an
alternative or further embodiment, said delivering further
comprises delivering a medium chain fatty acid. In an alternative
or further embodiment, said delivering is oral. Said patient may be
over sixty-five years of age.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 shows what is believed to be the mechanism of dietary
protein decreasing plasma triglycerides.
[0033] FIG. 2 shows a comparison of the effects of a composition of
essential amino acids and arginine, compared to a fibrate drug.
[0034] FIG. 3 shows the effect of phytostenols on blood lipids.
[0035] FIG. 4 shows the effect of isoflavones on blood lipids.
[0036] FIG. 5 shows average triglyceride concentration in response
to delivery of a composition for improving cardiovascular
health.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0037] The compositions and methods described herein comprise a
blend of components that cooperate improve blood pressure and lower
plasma concentrations of total cholesterol, LDL cholesterol, and
triglycerides, and liver fat and so together have a beneficial
effect on cardiovascular health. Also disclosed herein are modes of
delivering such a composition in order to improve cardiovascular
health. In a preferred embodiment, the compositions and delivery
methods improve the cardiovascular health of the elderly, including
but not limited to those individuals over 65 years old.
[0038] The composition may comprise amino acids, plant stanols and
sterols, isoflavones, and low glycemic carbohydrates and medium
chain fatty acids.
[0039] It is believed that only the essential amino acids (EAAs)
and arginine are needed to elicit the TG lowering effect that can
be induced by a high protein diet. It is contemplated that
additional amino acids may be desirable to accomplish other
purposes such as remedying individual deficiencies or addressing
other health problems.
[0040] Further, it is also believed that the effect of the amino
acid component of the compositions disclosed herein can be elicited
in the absence of any other dietary changes, making EEA delivery a
simple means for improving cardiovascular health without major
lifestyle changes. EEAs may reduce circulating and tissue TG
concentrations and improve insulin sensitivity in subjects with
impaired glucose tolerance, including elderly subjects. EEAs may
also improve cardiovascular health without the undesirable side
effects of pharmaceutical interventions, e.g. fibrates. Some
positive effects of a composition comprising EEAs on cardiovascular
health are shown in FIG. 2.
[0041] In an embodiment, the composition comprises the essential
amino acids (meaning that they are not produced in the body),
including histidine, isoleucine, leucine, valine, lysine,
methionine, phenylalanine, and threonine. The amino acid arginine
and/or its immediate precursor citrulline may be included in order
to have a further effect of lowering blood pressure. The amino
acids may be in free form or contained in intact protein, including
whey protein or peptides. The amino acids may be in the 1-form.
[0042] In a preferred embodiment, the composition further comprises
phytosterols and stanols, more preferably in a balanced blend, and
most preferably in a 2:1 ratio of sterols to stanols. These may be
included in order to capture the believed effect of these esters in
lowering LDL and decreasing cardiovascular disease, which is
believed to be superior to a simple EAA+arginine mixture. In a
further embodiment, the composition comprises B-sitosterol,
campesterol, stigmasterol, and/or their functional equivalents.
[0043] In an embodiment, the composition comprises isoflavones, in
order to capture the believed effect of decreasing total
cholesterol as well as LDL cholesterol shown in FIG. 4. In a
further embodiment, the isoflavone may be derived from soy or other
functionally equivalent sources.
[0044] In an embodiment, the composition comprises low glycemic
carbohydrates. The low glycemic carbohydrate may provide energy
while still accomplishing the decrease in plasma lipids profiles
believed to be associated with a diet with decreased carbohydrates.
In addition, the low glycemic carbohydrate may provide energy
without eliciting a significant insulin response. The elderly are
generally resistant to the action of insulin, so avoiding the
insulin response will be advantageous to that population. The low
glycemic carbohydrate may also be useful in improving the taste of
the composition, making it a more palatable means for improving
cardiovascular health and so improving patient compliance.
[0045] In an embodiment, the composition's principal energy
substrate may be medium chain triglycerides. One example of such a
medium chain triglyceride may be triolein, which consists of three
molecules of oleic acid bound together by a backbone of glycerol.
As explained above, such medium chain fatty acids can provide
energy without the concomitant detrimental effect on blood lipids
induced by carbohydrate intake. This is of benefit to individuals
such as the elderly with insulin resistance, since insulin
sensitivity is not required for metabolism of medium chain
triglycerides. In an embodiment, a certain amount of carbohydrate
may be required from the standpoint of nutrient production (i.e.,
taste and constituency), but it will remain a minor contributor to
the overall energy content of the composition.
[0046] In an embodiment, a dose of a composition disclosed herein
comprises at least about 11 g of amino acids. In a further
embodiment, those amino acids comprise about 0.36 g histidine,
about 0.94 g isoleucine, about 3.95 g leucine, about 1.88 g lysine,
about 0.39 g methionine, about 0.51 g phenylalanine, about 1.05 g
threonine, about 0.82 g valine, and about 1.10 g arginine. Any
proportion, quantity, and selection of EAAs that improves
cardiovascular health is contemplated. The amino acids may be in
the form of free amino acids, peptides, or intact protein.
[0047] In a further embodiment of a composition dose of at least
about 11 g of amino acids, the composition may contain about 2 g of
phytosterols, which may compromise B-sitosterol, campesterol,
stigmasterol, their functional equivalents, and any combination
thereof. In a further or alternative embodiment, the composition
may contain about 30-40 mg of isoflavones, which may be derived
from soy or any other functionally equivalent source.
[0048] The composition may contain between about 0-15 g low
glycemic carbohydrates and/or about 0-15 g medium chain
triglycerides. The proportions disclosed herein are scalable and
alterable so long as it improves cardiovascular health.
[0049] The compositions may also optionally comprise vitamins. The
vitamins may be fat-soluble or water soluble vitamins. Suitable
vitamins include vitamin C, vitamin A, vitamin E, vitamin B12,
vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid,
pyridoxine, thiamine, pantothenic acid, and biotin. The form of the
vitamin may include salts of the vitamin, derivatives of the
vitamin, compounds having the same or similar activity of a
vitamin, and metabolites of a vitamin.
[0050] The compositions may also comprise at least one excipient.
Non-limiting examples of suitable excipients include a buffering
agent, a preservative, a stabilizer, a binder, a compaction agent,
a lubricant, a dispersion enhancer, a disintegration agent, a
flavoring agent, a sweetener, a coloring agent, and combinations of
any of these agents.
[0051] In one embodiment, the excipient is a buffering agent.
Non-limiting examples of suitable buffering agents include sodium
citrate, magnesium carbonate, magnesium bicarbonate, calcium
carbonate, and calcium bicarbonate.
[0052] The excipient may comprise a preservative. Suitable examples
of preservatives include antioxidants, such as alpha-tocopherol or
ascorbate, and antimicrobials, such as parabens, chlorobutanol, or
phenol.
[0053] In another embodiment, the excipient may be a binder.
Suitable binders include starches, pregelatinized starches,
gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium
carboxymethylcellulose, ethylcellulose, polyacrylamides,
polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid
alcohol, polyethylene glycol, polyols, saccharides,
oligosaccharides, polypeptides, oligopeptides, and combinations
thereof.
[0054] In another embodiment, the excipient may be a lubricant.
Suitable non-limiting examples of lubricants include magnesium
stearate, calcium stearate, zinc stearate, hydrogenated vegetable
oils, sterotex, polyoxyethylene monostearate, talc,
polyethyleneglycol, sodium benzoate, sodium lauryl sulfate,
magnesium lauryl sulfate, and light mineral oil.
[0055] The excipient may be a dispersion enhancer. Suitable
dispersants may include starch, alginic acid,
polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood
cellulose, sodium starch glycolate, isoamorphous silicate, and
microcrystalline cellulose as high HLB emulsifier surfactants.
[0056] In yet another embodiment, the excipient may be a
disintegrant. The disintegrant may be a non-effervescent
disintegrant. Suitable examples of non-effervescent disintegrants
include starches such as corn starch, potato starch, and
pregelatinized and modified starches thereof; sweeteners, clays
such as bentonite, micro-crystalline cellulose, alginates, sodium
starch glycolate, gums such as agar, guar, locust bean, karaya,
pecitin, and tragacanth. The disintegrant may be an effervescent
disintegrant. Suitable effervescent disintegrants include sodium
bicarbonate in combination with citric acid, and sodium bicarbonate
in combination with tartaric acid.
[0057] The excipient may include a flavoring agent. Flavoring
agents incorporated into the outer layer may be chosen from
synthetic flavor oils and flavoring aromatics and/or natural oils,
extracts from plants, leaves, flowers, fruits, and combinations
thereof. By way of example, these may include cinnamon oils, oil of
wintergreen, peppermint oils, clover oil, hay oil, anise oil,
eucalyptus, vanilla, citrus oil, such as lemon oil, orange oil,
grape and grapefruit oil, fruit essences including apple, peach,
pear, strawberry, raspberry, cherry, plum, pineapple, and
apricot.
[0058] In another embodiment, the excipient may include a
sweetener. By way of non-limiting example, the sweetener may be
selected from glucose (corn syrup), dextrose, invert sugar,
fructose, and mixtures thereof (when not used as a carrier);
saccharin and its various salts such as the sodium salt; dipeptide
sweeteners such as aspartame; dihydrochalcone compounds,
glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of
sucrose such as sucralose; sugar alcohols such as sorbitol,
mannitol, sylitol, and the like. Also contemplated are hydrogenated
starch hydrolysates and the synthetic sweetener
3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide,
particularly the potassium salt (acesulfame-K), and sodium and
calcium salts thereof. The choice of sweetener may be directed by
the insulin resistance of the patient.
[0059] Depending upon the embodiment, it may be desirable to
provide a coloring agent in the composition's outer layer. Suitable
color additives include food, drug and cosmetic colors (FD&C),
drug and cosmetic colors (D&C), or external drug and cosmetic
colors (Ext. D&C). These colors or dyes, along with their
corresponding lakes, and certain natural and derived colorants may
be suitable for use in the present invention depending on the
embodiment.
[0060] The weight fraction of the excipient or combination of
excipients in the formulation may be about 30% or less, about 25%
or less, about 20% or less, about 15% or less, about 10% or less,
about 5% or less, about 2%, or about 1% or less of the total weight
of the amino acid composition.
[0061] Also disclosed herein are methods of delivering a
composition or means for improving cardiovascular health, including
but not limited to dosage. The compositions disclosed or made
obvious herein may be formulated into a variety of forms and
administered by a number of different means. The compositions may
be administered orally, rectally, or parenterally, in formulations
containing conventionally acceptable carriers, adjuvants, and
vehicles as desired. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, or intrastemal injection,
or infusion techniques. In an exemplary embodiment, the disclosed
compounds are administered orally.
[0062] Solid dosage forms for oral administration may include
capsules, tablets, caplets, pills, troches, lozenges, powders, and
granules. A capsule typically comprises a core material comprising
a disclosed composition and a shell wall that encapsulates the core
material. The core material may be solid, liquid, or an emulsion.
The shell wall material may comprise soft gelatin, hard gelatin, or
a polymer. Suitable polymers include, but are not limited to:
cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose,
ethyl cellulose, cellulose acetate, cellulose acetate phthalate,
cellulose acetate trimellitate, hydroxypropylmethyl cellulose
phthalate, hydroxypropylmethyl cellulose succinate and
carboxymethylcellulose sodium; acrylic acid polymers and
copolymers, preferably formed from acrylic acid, methacrylic acid,
methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl
methacrylate and/or ethyl methacrylate (e.g., those copolymers sold
under the trade name "Eudragit"); vinyl polymers and copolymers
such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate
phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl
acetate copolymers; and shellac (purified lac). Some such polymers
may also function as taste-masking agents.
[0063] Tablets, pills, and the like may be compressed, multiply
compressed, multiply layered, and/or coated. The coating may be
single or multiple. In one embodiment, the coating material may
comprise a polysaccharide or a mixture of saccharides and
glycoproteins extracted from a plant, fungus, or microbe.
Non-limiting examples include corn starch, wheat starch, potato
starch, tapioca starch, cellulose, hemicellulose, dextrans,
maltodextrin, cyclodextrins, inulins, pectin, mannans, gum arabic,
locust bean gum, mesquite gum, guar gum, gum karaya, gum ghatti,
tragacanth gum, funori, carrageenans, agar, alginates, chitosans,
or gellan gum. In another embodiment, the coating material may
comprise a protein. Suitable proteins include, but are not limited
to, gelatin, casein, collagen, whey proteins, soy proteins, rice
protein, and corn proteins. In an alternate embodiment, the coating
material may comprise a fat or oil, and in particular, a high
temperature melting fat or oil. The fat or oil may be hydrogenated
or partially hydrogenated, and preferably is derived from a plant.
The fat or oil may comprise glycerides, free fatty acids, fatty
acid esters, or a mixture thereof. In still another embodiment, the
coating material may comprise an edible wax. Edible waxes may be
derived from animals, insects, or plants. Non-limiting examples
include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran
wax. Tablets and pills may additionally be prepared with enteric
coatings.
[0064] Alternatively, powders or granules embodying the
compositions disclosed and made obvious herein may be incorporated
into a food product. The food product may be a drink. Non-limiting
examples of a suitable drink include fruit juice, a fruit drink, an
artificially flavored drink, an artificially sweetened drink, a
carbonated beverage, a sports drink, a liquid diary product, a
shake, and so forth. The food product may also be a solid
foodstuff. Suitable examples of a solid foodstuff include a food
bar, a snack bar, a cookie, a brownie, a muffin, a cracker, an ice
cream bar, a frozen yogurt bar, and the like.
[0065] The compositions may also be in liquid dosage forms for oral
administration. Liquid dosage forms include aqueous and nonaqueous
solutions, emulsions, suspensions and solutions and/or suspensions
reconstituted from non-effervescent granules, containing suitable
solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, coloring agents, and flavoring agents.
[0066] The disclosed compositions may be utilized in methods to
improve cardiovascular health. In an embodiment, the method
comprises administering the composition as described above twice
per day between meals. The amount per dose may be about 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
or 30 g. Alternatively, the composition may be administered one day
per day, three times per day, or four times per day.
[0067] In an alternative or further embodiment of a method of
delivery, the composition may also be used in conjunction with
exercise. For example, the composition may given before or
immediately after exercise.
[0068] The following example provides embodiments of compositions,
methods, their use, and the effects of such use.
Example 1
[0069] The aim of the study was to investigate the effect of
supplementation of the diet with EAA+arginine on plasma, liver and
muscle lipids in elderly individuals. Twelve elderly volunteers
participated in a 16 week study period. They ingested 11 g of
EAA+arginine two times a day, between meals. Diet and activity were
not otherwise modified, Every 4th week body composition was
measured by a full-body dual-energy x-ray absorptiometry (DEXA)
scan. In addition, a plasma lipid panel was determined. Muscle and
liver lipids were measured by magnetic resonance spectroscopy (MRS)
every 8th week. At weeks 0 and 16, a muscle biopsy was also
collected from m. vastus lateralis for measurement of activities of
oxidative enzymes.
[0070] Twelve elderly individuals (7 females, 5 males, 67.0.+-.5.6
(SD) years, 74.3.+-.19.7 kg at baseline) participated in the study.
They were fully informed about the purpose and procedures of the
study before written consent was obtained. Each subject had a
complete medical screening prior to participation in the
experiments (51.+-.9 days before start of supplementation),
including vital signs, blood tests, urine tests, and a 12-lead
electrocardiogram. Exclusion criteria included evidence for heart
disease, hyperlipidemia, kidney or liver disease, or any other
disease that might influence the results of the study. The subjects
also underwent a standard oral glucose tolerance test (OGTT) using
75 g of dextrose. Only subjects with impaired glucose tolerance
defined as a plasma glucose concentration >180 mg/dl at 1 hr or
>140 mg/dl at 2 hr after oral intake of 75 g glucose, were
included. Diabetic subjects (plasma glucose concentration >200
mg/dl at 1 hr or 2 hr after glucose intake) with a reduced insulin
production, and subjects taking any medication to treat abnormal
blood lipid levels, were not included in the study.
[0071] Each dose of the nutritional supplement consisted of 11 g of
amino acids with the following composition: 0.36 g histidine, 0.94
g isoleucine, 3.95 g leucine, 1.88 g lysine, 0.39 g methionine,
0.51 g phenylalanine, 1.05 g threonine, 0.82 g valine, 1.10 g
arginine. This was taken in two daily doses in the form of
capsules, and recorded in a diary. The first dose was taken between
breakfast and lunch, and the second dose was ingested between lunch
and dinner. The subjects visited the hospital every two weeks to
pick up a new supply of supplements. In the weeks with no hospital
visits, the subjects were given follow-up calls to check on the
intake of the supplements, as well as on diet, activity and
anything else (sickness, etc.) that might influence the results of
the study.
[0072] Before the start of the study the subjects were counseled to
maintain their typical dietary intake and physical activity
pattern. During their visits to the hospital and in telephone calls
between visits, they were asked about this and reminded to not make
any changes. The Physical Activity Scale for Elderly (PASE) was
used to measure their physical activity during the study period.
Further, at the start of the study the subjects were instructed by
the dietician at the GCRC on how to complete a diet diary. In the
week before the first overnight stay and every 4th week thereafter
(week 3, 7, 11, and 15), the participants recorded their diet for 3
days (two week-days and one weekend-day).
[0073] Every 8th week, the intramuscular lipid concentration of m.
soleus was measured with a .sup.1H knee coil on a GE Advantage 1.5
Tesla whole-body imager (General Electric, Milwaukee, Wis.). The
widest part of the calf was located during the first study, and
measured from the floor and marked. A marker was placed at the
location during the scan, and this slice of leg was always used for
scans. Four areas were selected from the coronal slice localizer
and were traced onto a transparency along with multiple anatomic
landmarks. These four areas were then rescanned during each
subsequent MRS analysis. A tube of 20% INTRALIPID.RTM. (i.e,
high-fat total parenteral feeding solution; Baxter Healthcare,
Deerfield Park, Ill.) was placed inside the knee coil to obtain a
standard external reference. After a preliminary localization
image, three to seven voxels (7 mm.times.7 mm.times.10 mm each)
were chosen in m. soleus free from fascia, gross fat marbling, and
vessels. The exact voxel volumes were recorded. A voxel was also
chosen from the INTRALIPID.RTM. external reference. An optimized
PRESS (Point RESolved Spectroscopy) sequence with a repetition time
of 2000 ms and an echo time of 35 ms was run. Peak positions and
areas of interest [extramuscular (CH).sub.2, intramuscular
(CH).sub.2, extramuscular CH.sub.3, intramuscular CH.sub.3, total
creatine, and trimethylamines] were determined by time domain
fitting using jMRUi. In brief, all water-suppressed free induction
decay (FID) (metabolite FID) were deconvoluted with the
water-unsuppressed FID (water FID) acquired from the same voxel to
correct for zero-order phasing and removal of eddy current-induced
artifacts. The resulting metabolite FIDs were analyzed with AMARES
(Method of Accurate, Robust and Efficient Spectral fitting), a
nonlinear least-square-fitting algorithm operating in the time
domain. Spectra from voxels, which did not have optimal shimming or
clear intracellular and extracellular lipid peak resolution, were
not used in the AMARES fitting analysis. This process was repeated
for the INTRALIPID.RTM. phantom. The TG levels were computed as a
ratio relative to the Intralipid standard using the following
formula: TG=[(PM/VM)/(PI/VI)], where PM is the methylene peak area,
VM is the total measured tissue voxel volume, PI is the
INTRALIPID.RTM. peak area, and VI is the INTRALIPID.RTM. voxel
volume. This measurement is a TG concentration normalized to
INTRALIPID.RTM. concentration, and thus it is unitless.
[0074] Liver lipid concentration was measured with a .sup.1H
whole-body coil on the same system. Hepatic measurements were
performed in the middle right lobe. The scans were localized to the
same area of the liver via anatomic landmarking of the hepatic
blood flow and the ribs, so that approximately the same area of
liver was scanned with each study. A tube of INTRALIPID.RTM. was
again used for reference. After a preliminary localization scan, a
voxel (-30 mm.times.30 mm.times.20 mm) was chosen at a location
free from large vessels. An optimized PRESS sequence was run 256
times without respiratory gating. These spectra represent an
average lipid concentration measurement over the mid-right lobe
because respiratory gating was not conducted. By placing the
subjects prone, using light restraints, and coaching shallow
breathing, the movement induced by respiration was reduced. Spectra
were manually phased, and final analysis was then performed with
jMRUI.
[0075] The subjects underwent a full-body DEXA scan every 4.sup.th
week to determine body composition. All DEXA scans were performed
on a Hologic QDR 4500 A system (Hologic, Inc., Bedford, Mass.).
[0076] Plasma glucose concentration was determined enzymatically
(YSI 1500, Yellowspring Instruments, Yellowspring, Ohio, USA).
Plasma insulin concentration was determined by a radioimmunoassay
method (Diagnostic Products Corporation, Los Angeles, Calif., USA).
Plasma amino acid concentrations were analyzed by high-performance
liquid chromatography (Waters Alliance HPLC System 2690, Milford,
Mass.). Enzymatic methods were used to determine plasma FFA
(NEFA-C, Wako Chemicals GmbH, Neuss, Germany) and glycerol
(Sigma-Aldrich, St. Louis, Mo.) concentrations. The lipid panel was
comprised of triglycerides (TG), total cholesterol, and
HDL-cholesterol concentrations. They were all measured on a Vitros
950 system (Ortho-Clinical Diagnostics, Raritan, N.J.). The
HDL-cholesterol was measured by precipitation of the LDL and VLDL,
and the cholesterol left in the supernatant (HDL) was then
determined. The LDL-cholesterol (mgdl) was calculated using the
Friedewald equation (LDL-cholesterol=Total
cholesterol-HDL-cholesterol-Triglyceride/5). Thus, the quotient
([TG]/5) is used as an estimate of VLDL-cholesterol
concentration.
[0077] Overall significance of differences in response of diet
intake, ISI, tissue lipids, and fasting plasma lipids, insulin, and
glucose concentrations with time was tested by one-way repeated
measures analysis of variance (ANOVA) followed by Dunnett's test
with week 0 as control (SigmaStat 2.03, SPSS Inc., Chicago, Ill.).
The correlation between plasma TG concentrations at week 0 and
changes in plasma TG concentration during the supplementation
period was measured by Spearman rank correlation coefficient,
whereas the corresponding correlation for liver lipid content was
determined by linear regression analysis. Changes in amino acid
concentration or muscle oxidative enzymes from week 0 to 16 were
tested by paired t-tests. Comparisons of plasma lipid
concentrations and ISI at screening (week 7) and week 0 were also
done by paired t-tests. Results were considered significant if
P<0.05. The results are presented as means.+-.SE unless
otherwise noted.
[0078] The amino acid supplementation was well tolerated by the
subjects, and there were no overall changes in physical activity or
diet during the study period. The dietary intake was 1733.+-.226
kcal/day when no supplement was taken vs. an average of 1735.+-.176
kcal/day during the supplementation period (n=9). Corresponding
values for protein intake were 72.5.+-.10.6 vs. 68.9.+-.8.5 g/day
(with vs. without supplement); fat intake was 64.3.+-.12.2 vs.
63.1.+-.6.5 g/day, and carbohydrate intake was 205.6.+-.30.2 vs.
212.6.+-.27.5 g/day.
[0079] The amino acid supplementation did not lead to changes in
overall body mass (week 0 vs. 16: 74.31.+-.5.67 vs. 74.60.+-.5.62
kg), total fat mass (24.19.+-.3.59 vs. 23.90.+-.3.70 kg), or trunk
fat mass (11.89.+-.1.76 vs. 11.67.+-.1.78). Plasma AA concentration
did not change during the study.
[0080] There were no changes in plasma lipid concentrations from
the screening time point until the start of the supplementation
period (51/9 days without supplementation; Table 1).
[0081] Table 1 follows, and shows plasma lipid concentrations in
IGT elderly (n=12) at baseline, and after 4, 8, 12, and 16 weeks of
amino acid supplementation. The data are mean.+-.SE. .dagger.ANOVA:
P<0.001; .dagger-dbl.ANOVA: P<0.05; *P<0.05 vs. week
0.
TABLE-US-00001 TABLE 1 Screening (~week -7) Week 0 Week 4 Week 8
Week 12 Week 16 Triglycerides 127 .+-. 14 128 .+-. 16 105 .+-. 11*
112 .+-. 15* 107 .+-. 13* 102 .+-. 14* (mg/dl).dagger. Total 199
.+-. 11 200 .+-. 11 199 .+-. 11 188 .+-. 11 190 .+-. 9 186 .+-. 12
cholesterol (mg/dl).dagger-dbl. HDL- 57 .+-. 6 58 .+-. 6 62 .+-. 7
55 .+-. 5 56 .+-. 6 60 .+-. 6 cholesterol (mg/dl) LDL- 116 .+-. 7
116 .+-. 8 117 .+-. 8 110 .+-. 8 113 .+-. 7 106 .+-. 8 cholesterol
(mg/dl) VLDL- 25 .+-. 3 26 .+-. 4 22 .+-. 3* 23 .+-. 3* 21 .+-. 2*
21 .+-. 3* cholesterol (mg/dl).dagger. FFA (mEq/l) -- 0.76 .+-.
0.06 0.60 .+-. 0.06 0.64 .+-. 0.05 0.62 .+-. 0.05 0.66 .+-.
0.04
[0082] Significant decreases were found in plasma TG (P<0.001),
total cholesterol (P=0.048) and VLDL-cholesterol (P<0.001)
concentrations during the study (Table 1). For TG and
VLDL-cholesterol the changes from baseline were significant at all
time points, whereas they did not reach significance at any
specific time point for total cholesterol concentration.
[0083] The changes in plasma TG concentrations during the study
were related to starting level, with the greatest decrease in the
subjects that initially had the highest plasma TG concentrations
(FIG. 5). As FIG. 5 shows, the average plasma triglyceride
concentration changes from baseline during 16 weeks of amino acid
supplementation in elderly that had baseline values between 50-99
mg/dl (left; n=4), between 100-149 mg/dl (middle; n=5); and >150
mg/dl (right; n=3). The normal reference range is 30-170 mg/dl.
Data are mean.+-.SE; *P=0.01 vs. zero; #P=0.004 vs. zero.
[0084] The correlation was not linear, therefore we calculated the
Spearman rank correlation coefficient, which was r=-0.828 between
the starting value and the average change from baseline at 4, 8, 12
and 16 weeks (P<0.001). Most of the concentration changes
occurred somewhere between 0-4 weeks (Table 1). Spearman rank
correlation coefficient between the start value and the change from
0-4 weeks was -0.872 (P<0.001).
[0085] No changes were found in plasma FFA, and LDL- and
HDL-cholesterol concentrations during the study (Table 1).
[0086] At the start of the study, there was a linear correlation
between liver fat content and plasma TG concentration (r=0.85;
P=0.007). Amino acid supplementation caused the liver fat content
(liver TG/INTRALIPID.RTM. standard) to drop about 50% from the
initial value of 0.34.+-.0.06 at week 0 (P=0.021; n=8 at week 0 and
16, n=6 at week 8; FIG. 2). FIG. 2 shows liver lipids (liver
TG/INTRALIPID.RTM. standard) at baseline, and after 8 and 16 weeks
of amino acid supplementation (mean.+-.SE; n=8 at week--and 16, n=6
at week 8); *P<0.05 vs. baseline. The change in liver fat
content was most dramatic for the subjects starting out with the
highest level (r=-0.86; P=0006). No significant changes were
observed in intramuscular fat content.
* * * * *