U.S. patent application number 09/917292 was filed with the patent office on 2002-08-29 for compositions and methods for improving cardiovascular function.
Invention is credited to Butler, Terri L., Cyr, John St., Johnson, Clarence A..
Application Number | 20020119933 09/917292 |
Document ID | / |
Family ID | 27396951 |
Filed Date | 2002-08-29 |
United States Patent
Application |
20020119933 |
Kind Code |
A1 |
Butler, Terri L. ; et
al. |
August 29, 2002 |
Compositions and methods for improving cardiovascular function
Abstract
The present invention relates to compositions for supplementing
the diet of subjects suffering from cardiovascular or peripheral
vascular disease or those at risk for such conditions. Ribose is
given alone or in combination with one or a combination of
vasodilators, nutrients and vitamins. Preferred vitamins include
Vitamins C, B6, B12 and folic acid. Preferred nutrients include
glutamine and glucose.
Inventors: |
Butler, Terri L.; (Kirkland,
WA) ; Cyr, John St.; (Coon Rapids, MN) ;
Johnson, Clarence A.; (Wyoming, MN) |
Correspondence
Address: |
SCHWEGMAN, LUNDBERG, WOESSNER & KLUTH, P.A.
P.O. BOX 2938
MINNEAPOLIS
MN
55402
US
|
Family ID: |
27396951 |
Appl. No.: |
09/917292 |
Filed: |
July 27, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60221526 |
Jul 28, 2000 |
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60302200 |
Jun 29, 2001 |
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Current U.S.
Class: |
514/23 ; 424/608;
424/94.1; 514/251; 514/262.1; 514/263.31; 514/269; 514/307; 514/46;
514/509; 514/52; 514/565 |
Current CPC
Class: |
A61K 31/506 20130101;
A23V 2250/708 20130101; A61K 31/70 20130101; A23V 2002/00 20130101;
A61K 31/506 20130101; A61K 31/525 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A23V 2250/7052 20130101; A23V 2250/062
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A23V
2250/626 20130101; A61K 2300/00 20130101; A23V 2250/61 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A23V 2250/0606
20130101; A23V 2250/706 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/7004 20130101; A23V 2002/00 20130101;
A61K 45/06 20130101; A61K 31/195 20130101; A61K 31/21 20130101;
A61K 31/525 20130101; A61K 31/7004 20130101; A61K 31/519 20130101;
A61K 31/522 20130101; A23L 33/10 20160801; A61K 31/522 20130101;
A61K 33/06 20130101; A61K 31/195 20130101; A61K 31/70 20130101;
A61K 31/519 20130101; A61K 33/06 20130101; A61K 31/21 20130101 |
Class at
Publication: |
514/23 ; 514/46;
514/307; 514/263.31; 514/262.1; 514/565; 514/509; 514/52; 514/251;
424/94.1; 514/269; 424/608 |
International
Class: |
A61K 031/70; A61K
031/525; A61K 038/43; A61K 031/519; A61K 031/522 |
Claims
We claim:
1. A method for improving cardiovascular function of a subject
comprising the administration of two to ten grams of D-ribose one
to four times daily to the subject.
2. The method of claim 1 wherein three to five grams of D-ribose is
administered one to four times daily to the subject.
3. The method of claims 1 or 2 wherein D-ribose is administered one
to four times daily for at least one week.
4. A composition for improving cardiovascular function of a subject
comprising administering an effective amount of D-ribose in
combination with a vasodilator to the subject.
5. The composition of claim 4 wherein the effective amount of
D-ribose is one to 30 grams and the vasodilator is L-arginine,
nitroglycerine, a nitrate, a nitrite, papaverine, isoproterenol,
nylidrin, isoxsuprine, nitroprusside, adenosine, xanthine, ethyl
alcohol, dipyramide, hydrazaline, minoxidil or diazoxide.
6. The composition of claim 4 wherein the effective amount of
D-ribose is two to 10 grams.
7. The composition of claim 4 wherein the effective amount of
D-ribose is three to eight grams.
8. The composition of claim 4 further comprising at least one of
glucose, glutamine, Vitamin C, Vitamin B6, Vitamin B12, folic
acid.
9. The composition of claims 4 or 8 further comprising at least one
of L-carnitine, taurine, creatine, Coenzyme Q10 or pyruvate.
10. A method for improving cardiac function in a subject comprising
the administration of any one of the compositions of claims 4, 5,6,
7, 8 or 9 to the subject one to four times per day.
11. A composition for improving cardiac function in a subject
comprising: one to 20 grams of D-ribose; 0 to 20 grams of glucose;
one to eight grams of L-arginine; 100 to 1000 milligrams of Vitamin
C; 0.1 to one milligrams of folic acid; 0.1 to one milligrams of
Vitamin; and one to 50 milligrams of Vitamin B6.
12. A composition for improving cardiac function in a subject
comprising: five grams of D-ribose; five grams of glucose; two
grams of L-arginine; 500 milligrams of Vitamin C; 0.2 milligrams of
folic acid; 0.25 milligrams of Vitamin B 12; and six milligrams of
Vitamin B6.
13. A method for improving cardiac function in a subject comprising
the administering any one of the compositions of claims 11 and 12
to the subject one to four times per day.
14. A method for relieving the symptoms of peripheral vascular
disease in a subject comprising administering any one of the
compositions of claims 5, 6, 7, 8, 9,11 or 12 to the subject one to
four times per day.
15. The method of claims 4, 10 or 13 wherein the vasodilator is
nitroglycerine, a nitrate, a nitrite, or nitroprusside, and the
D-ribose is ingested orally fifteen minutes before the vasodilator
is administered sublingually, buccally or transdermally.
16. A method of reducing blood pressure of a subject comprising
administering D-ribose to the subject.
17. The method of claim 16 wherein D-ribose or any one of the
compositions of claims 5,6,7,8,9,10,11 or 12 is administered to the
subject one to four times per day.
Description
RELATED APPLICATIONS
[0001] The following commonly assigned U.S. patent applications are
relied upon and hereby incorporated by reference in this
application:
[0002] This application is related to U.S. Provisional Patent
Application Ser. No.: 60/221,526, filed Jul. 28, 2000, entitled
"COMPOSITIONS FOR ENHANCING PHYSICAL REHABILITATION IN HUMANS AND
METHOD OF USING THE SAME", which is related to U.S. Provisional
Patent Application Serial No.:______ , filed Jun. 29, 2001,
entitled "COMPOSITIONS FOR ENHANCING PHYSICAL REHABILITATION IN
HUMANS AND METHOD OF USING THE SAME" which is related to U.S.
patent application Ser. No.: 09/677,639, filed Oct. 3, 2000,
entitled "COMPOSITIONS FOR IMPROVING ATHLETIC PERFORMANCE" which is
a continuation-in-part U.S. Pat. No.: 6,159,942, issued Dec. 12,
2000, entitled"COMPOSITIONS FOR INCREASING ENERGY IN VIVO".
BACKGROUND OF THE INVENTION
[0003] Nutritional therapies are commonly applied in ill people in
order to enhance physical capacity and recovery from stresses due
to medical conditions. Many times the recommendations simply
include dietary advice regarding the distribution of carbohydrates,
proteins, and fats in the overall diet. A more advanced approach is
to recommend supplementation of key nutrients that will aid healing
and enhance the physical state of the individual. Such nutritional
formulations may be termed "dietary supplements," "functional
foods" or "medical foods." In order to formulate an effective
dietary supplement or functional or medical food, an understanding
of the scientific basis behind the key ingredients is essential.
Once a well-grounded recommendation toward dietary modification is
made it can have a powerful influence on the rate of recovery in
the individual who is in poor health.
[0004] Often, persons who consider themselves to be in good health
with a good nutritional status are actually somewhat suboptimal in
both parameters, rendering them at risk for developing such medical
conditions. Dietary supplements, functional or medical foods
developed for improving cardiovascular function may also benefit
such persons as cardioprotectors.
[0005] In the area of medically recommended supplementation
artificial diets have played a key role for many years.
Post-surgery, the gastro-intestinal tract of a patient is typically
unable to properly digest food for several days. In such cases
parenteral nutrition is essential, wherein the patient is given
glucose or a carefully formulated mixture of salts, carbohydrates,
amino acids, fatty acids, and vitamins. Even after the patient is
weaned from parenteral nutrition, enteral nutrition with a similar
composition may be established orally or via a feeding tube, or a
medical food enteral supplement may be added to his or her diet in
order to optimize the types and amounts of nutrients the patient
requires and receives.
[0006] The most pressing need for improved prevention,
rehabilitation and maintenance regimens is in the area of
cardiovascular disease, which is the leading cause of death
worldwide. It has been projected that one of five persons in the
United States has cardiovascular disease. Within this arena,
myocardial infarction accounts for more than half a million deaths
per year. Furthermore, survivors face a level of morbidity and
subsequent disability that affects their medical, social, and of
equal importance, economic status. Therefore, surviving the initial
acute event of a myocardial infarction leaves patients with a
variety of challenges. Such patients may be left in a state of
compromised cardiovascular function such as chronic ischemic
disease, congestive heart failure or reduced peripheral blood
flow.
[0007] Congestive heart failure may have a more insidious onset
than that following myocardial infarction. Atherosclerosis may
gradually lessen circulation to the heart or uncontrolled
hypertension may weaken the heart muscle. Another condition,
cardiomyopathy, may occur from a variety of causes including
ischemia, hypertension or chronic infection. Whatever the cause,
these types of cardiovascular disease may present a similar
clinical picture and pose the same problems of treatment and
maintenance as does myocardial infarction.
[0008] Peripheral vascular disease is closely related to
cardiovascular disease, in that the same underlying cause,
atherosclerosis, may impair circulation to the skeletal muscles,
brain or kidneys, interfering with their function. A nutritional
supplement that benefits subjects with cardiovascular disease will
also benefit these subjects.
[0009] Over the past twenty years, cardiac rehabilitation has
provided survivors with an increased quality of life. Cardiac
rehabilitation programs have continued to change to meet the needs
and expectations of these afflicted individuals. An important
aspect of successful rehabilitation is a gradual programmed
increase in exercise training with an attention to modifying
existing cardiac risk factors. The ultimate goal in any cardiac
rehabilitation program is the improvement of functional capacity,
the lessening of awareness of activity-produced symptoms, the
reduction of disability and the modification of known coronary risk
factors for the prevention of subsequent cardiovascular events,
that is, to provide cardioprotection. Many patients feel strongly
that a good quality of life includes the ability to resume their
pre-disease activity, if at all possible.
[0010] While general nutritional supplementation is the standard
mode of therapy as part of a disease management program, a more
focused nutritional program can have more specific and powerful
benefits. For example glutamine is useful in the treatment of
diseases of the liver due to its ability to increase blood flow to
the liver (U.S. Pat. No. 6,001,878). Glutamine is also effective at
maintaining the immune system. This was shown in a study where
there was a lower level of infection in patients following bone
marrow transplantation when their parenteral nutritional program
was supplemented with glutamine (Calder and Yapoob 1999). Another
example is taurine which has a positive inotropic effect on the
heart and can be used as a treatment in congestive heart failure.
In a clinical trial 4 weeks of taurine supplementation led to a
highly significant improvement in dyspnea, palpitation, crackles,
edema, and New York Heart Association functional class (Azuma et al
1983).
[0011] Several of the vitamins are known to be beneficial in
repairing tissue damage and enhancing rehabilitation. Individual
patients vary in diet and physiologic needs and thus in the
requirement of supplementation. Ideally, each patient could be
evaluated for those supplements that are most suboptimal in the
diet or for which there is a higher than expected requirement.
However, it is impractical to fine-tune supplementation to each
patient, and therefore a useful supplement will contain sufficient
vitamins to provide adequate daily intake for the majority of
prospective patients.
[0012] The best therapy for cardiovascular disease is prevention.
Hypertension is a prevalent cause of cardiovascular disease.
Persistent hypertension is accompanied by left-ventricular
hypertrophy and myocardial stiffness. These factors result in left
ventricular diastolic dysfunction. Many drugs are marketed to
reduce blood pressure, and the current philosophy suggests that
combination therapy is preferred to single drug therapy. A
nutritional supplement that caused a reduction in blood pressure is
desirable.
[0013] Thus the need remains to select the best choice of nutrients
and the balance of such nutrients as will benefit the majority of
subjects both for recovery from cardiovascular disease and for
cardioprotection for the prevention of onset or recurrence of
cardiovascular disease.
SUMMARY OF THE INVENTION
[0014] The present invention relates to compositions and methods
for supplementing the diet of subjects who are either recovering
from or living with disease or medical injury, or subjects at risk
for such disease who are in need of cardioprotection. Examples of
such subjects include those with atherosclerosis resulting in
cardiovascular disease or peripheral vascular disease, those who
suffer from hypertension, myocardial infarction, those who are
recovering from surgery, chemotherapy, or other medical trauma or
those who are at risk for these conditions.
[0015] According to the methods of this invention, D-Ribose (which
may be subsequently referred to as "ribose") is administered to a
patient at least once a day in unit dosages of from two to ten
grams. A preferred method is the administration of a unit dosage of
two to eight grams of ribose two or three times a day. The most
preferred method is the administration of a unit dosage of five
grams of ribose given three times per day. The unit dosage may be
dissolved in a suitable amount of water or may be ingested as a
powder.
[0016] Compositions comprising a vasodilator and ribose are
provided. Ribose in a unit dosage of one to 20 grams is
administered with an effective amount of a vasodilator. A more
preferred dosage of ribose is two to ten grams. A most preferred
dosage of ribose is five grams. The vasodilator may be L-arginine,
nitroglycerine, nitrates, nitrites, papaverine, isoproterenol,
nylidrin, isoxsuprine, nitroprusside, adenosine, xanthine, ethyl
alcohol, dipyramide, hydrazaline, minoxidil, diazoxide or analogs
of the foregoing. A most preferred vasodilator is L-arginine. The
components may be mixed together in a powder for simultaneous
administration. When the vasodilator is nitroglycerine, a nitrate
or a nitrite, ribose is preferably administered orally about
fifteen minutes before the vasodilator is given buccally,
sublingually or transdermally. This composition is administered
from one to four times daily.
[0017] Compositions comprising ribose and vitamins are provided.
Ribose in a unit dosage of one to 20 grams is administered along
with one or more of vitamins C, B6, B12 and/or folic acid. It is
most convenient to prepare ribose and vitamins as a triturated
powder. A more preferred unit dosage of ribose to be administered
with vitamins is two to 10 grams of ribose. A most preferred unit
dosage of ribose to be administered with vitamins is five grams of
ribose.
[0018] Compositions comprising ribose, a vasodilator and vitamins
are provided. Ribose in a unit dosage of one to 20 grams is
administered along with a vasodilator and one or more of vitamins
C, B6, B 12 and/or folic acid. It is most convenient to prepare
ribose, a vasodilator and vitamins as a triturated powder. A more
preferred unit dosage of ribose to be administered with a
vasodilator and vitamins is two to 10 grams of ribose. A most
preferred unit dosage of ribose to be administered with vitamins is
five grams of ribose. A most preferred composition comprises
ribose, L-arginine, and/or folic acid.
[0019] Glutamine may be added to each of the above compositions.
Dextrose may be added to each of the above compositions in the same
amount as ribose, if it is desired to eliminate potential
hypoglycemia. L-Carnitine may be added to each of the above
compositions. Taurine may be added to each of the above
compositions. Creatine may be added to each of the above
compositions. Pyruvate may be added to each of the above
compositions. Coenzyme Q10 may be added to each of the above
compositions.
[0020] A most preferred composition is provided comprising ribose,
L-arginine, glutamine, folic acid, glucose, vitamins B12, B6 and C.
Ornithine, citrulline or other orally administered vasodilators may
be added in place of or in addition to L-arginine. Any one or a
combination of L-carnitine, taurine, creatine, pyruvate may be
added to the above compositions
[0021] Any of the compositions of this invention are preferably
dissolved in about eight ounces of water and ingested as a
solution. Flavorings and other additives may be added to make the
solution more palatable. In each of the compositions of this
invention, D-ribose in a unit dosage of one to 20 grams is
administered two to four times per day. The other ingredients may
vary in accordance with recommended daily allowance.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The invention comprises compositions that include D-ribose,
alone and in combination with a vasodilator. Nutrients that improve
cardiovascular function, healing, or have other healthful
characteristics are also provided. Those nutrients selected will
have effects on metabolic pathways or physiological functions
different from those of ribose and thus will have incremental
benefit over the basic benefit of ribose alone. Improvement of
cardiovascular function results inherently in improvement of a
subject's physical capability and hence enhances the subject's
quality of life. Therefore, in the present invention, when the term
"cardiovascular function" is used, it is understood to include
improvement of physical capability and enhancement of quality of
life. Nutrients to be used in this invention in combination with
D-ribose include, but are not limited to those that may enhance
endothelium-dependent vasodilation by acting on nitric oxide
release including ascorbic acid, L-arginine, ornithine, citrulline,
glutamine, folic acid, vitamin B6 and vitamin B12. Also included
are other energy enhancing compounds such as L-carnitine, pyruvate,
taurine, and coenzyme Q10.
[0023] D-ribose (otherwise referred to as ribose) is a natural
5-carbon sugar found in every cell of the body. It forms part of
the backbone of the genetic materials ribonucleic acid and
deoxyribonucleic acid as well as part of the basic structure of the
body's main energy carrying molecule, adenosine triphosphate
(ATP).
[0024] During disease or stress, the body's energy resources become
depleted. In particular, intracellular levels of ATP can be lowered
significantly. Since cells and organs need adequate energy in order
to maintain integrity and function, it is essential that the supply
of ATP be replenished soon after it is consumed. This is possible
over the short term in the presence of oxygen via the respiratory
metabolic pathways. However, when the oxygen supply is inadequate
because of decreased circulation, even temporarily, energy
metabolism is impaired and ATP molecules are not regenerated
quickly enough to meet the body's energy demands.
[0025] For example, when the myocardium becomes oxygen depleted due
to ischemia (restricted blood flow to the heart) resulting from
stenotic and/or occluded arteries, heart attack, heart surgery,
heart transplantation or other surgery requiring general
anesthesia, myocardial levels of ATP will fall dramatically and can
take up to 10 days to recover (Ward et al 1984). Under conditions
of such energetic depletion myocardial function is compromised and
there is an increased risk of permanent loss of myocardial
tissue.
[0026] Because of its ability to enhance ATP recovery and synthesis
ribose can increase exercise capacity in both ill and healthy
people. One study found that orally administered high doses of
ribose increased the treadmill performance of angina patients
(Pliml et al 1992). Another study found that in athletes on
exercise bikes, power output was greater in the group that was
taking supplemental ribose (U.S. Pat. No. 6,159,942).
[0027] Ribose is the key ingredient in the compositions described
in this invention. Other energy enhancers might be included that
increase the effect of ribose. Nutrients that act by other
mechanisms can be energy enhancers that would optimize the
nutritional composition. For example, increasing a vessel's
diameter would enable blood to reach outlying muscle tissue and
thus transport ribose and nutrients to that tissue. Enhancement of
other physiological functions in addition to energy would compound
the effect of the nutritional composition.
[0028] Nitric oxide (NO) is one of the primary inducers of
vasodilation and is generated in many of the tissues of the body.
It can diffuse across membranes rapidly, thus acting on elements
that are some distance from the site of production. NO is
synthesized from L-arginine (also referred to as arginine) by the
action of NO synthase (NOS), leading to the production of
L-citrulline. L-citrulline is then recycled to L-arginine by
argininosuccinate synthase and argininosuccinase. Ornithine can
serve as a precursor to L-arginine. Many physiological processes
are regulated by NO including endothelial vasodilator tone which is
essential for the regulation of blood pressure, formation or memory
by acting as a neurotransmitter, regulation of various
gastrointestinal, respiratory, and genitourinary tract functions by
mediating some forms of neurogenic vasodilation, and contribution
to and the regulation of cardiac contractility.
[0029] In addition, the number of physiological processes in which
NO has been implicated is growing rapidly. Beyond what is mentioned
above, NO may also be involved in the regulation of muscle function
by modulating glucose uptake, mitochondrial oxygen metabolism,
blood supply to muscle and contractility. In most cases, muscle NO
can be viewed as a positive regulator of muscle function, in that
it has been experimentally shown to promote glucose transport and
presumably to increase blood supply to muscle through its
vasodilatory capabilities. Tidball et al. (1998) found that
mechanical activity of muscle can influence NO production by the
muscle in the short term, by regulating NO activity and in the long
term by regulating NO expression. It was concluded from this study
that NO plays a significant role in increasing glucose transport
and contributing to vasodilation of vessels that supply the
muscle.
[0030] Several nutrients have a positive influence on NO
production. Those that are described here are relevant to the
invented composition and include ascorbic acid, L-arginine,
ornithine, glutamine, and folic acid.
[0031] Ascorbic acid, otherwise known as vitamin C, is a
water-soluble vitamin that is an essential nutrient. It plays a
role in the detoxification of potentially damaging free radicals
and may be the most important antioxidant in the watery
extra-cellular environment of the body (Kanter, et. al., 1995).
Increases in oxygen consumption, body temperature, and
catecholamine levels along with exercise and the acute-phase
inflammatory response can lead to the promotion of free radicals.
Vitamin C is able to alleviate this oxidative stress by its ability
to quench singlet oxygen and the superoxide anion as well as to
stabilize the hydroxyl radical.
[0032] Due to its effect as an antioxidant vitamin, C may inhibit
atherogenesis and improve vascular function by two mechanisms: 1)
inhibition of LDL oxidation through an LDL-specific antioxidant
action, and 2) antioxidants present in cells of vascular walls
decrease cellular production and release endothelial-derived nitric
oxide. The most likely mechanism of ascorbic acid is either its
enhancement of the availability of tetrahydrobiopterin (a co-factor
for nitric oxide synthase reactions) or its increased affinity of
tetrahydrobiopterin for endothelial-derived nitric oxide
synthase.
[0033] Ascorbic acid has been shown to enhance impaired
endothelial-derived vasodilation in patients with atherosclerosis.
Nitric oxide has several vasoprotective activities, such as smooth
muscle relaxation, inhibition of platelet activity, and regulation
of endothelial cell permeability and adhesivity. A lack of nitric
oxide may actually promote the development of atherosclerosis. The
saturation of tissue with ascorbic acid provides the optimal
conditions for adequate nitric oxide synthesis in endothelial
cells. Decreases in cellular ascorbic acid may lead to or
exacerbate the development of endothelial dysfunction. A clinical
trial showed that dietary supplements of ascorbic acid prevented
the development of nitrate tolerance, thus maintaining the ability
of the endothelium to vasodilate (Watanabe et al 1998).
[0034] Plasma ascorbic acid levels are thought to be inversely
related to the mortality from coronary artery disease. The acute
application of ascorbic acid enhanced endothelial dependent
vasodilation in patients with diabetes coronary artery disease,
hypertension hypercholesterolemia, hyperhomocysteinemia, or chronic
heat failure, and in smokers (Frei, 1999; Heller 1999).
[0035] While the Recommended Daily Allowance (RDA) for vitamin C is
just 60 mg per day many of the above studies have shown that
significantly higher daily doses of vitamin C can be beneficial.
The current evidence suggests that heart patients would benefit
from 500 to 1000 mg per day. L-arginine (arginine) is a complex
amino acid often found at the active (or catalytic) site in
proteins and enzymes due to its amine-containing side chain. It is
incorporated in proteins at about 4.7% on a per-mole basis when
compared to the other amino acids. It is a non-essential amino acid
in adults, but essential in children. Natural sources of arginine
include brown rice, nuts, popcorn, raisins, and whole-wheat
products.
[0036] As a precursor of nitric oxide production arginine is
important for many critical physiological processes including
endothelial vasodilation. In a clinical trial 5.6 to 12.6 g/day of
supplemental arginine had benefits for patients with heart failure
including increased blood flow, increased distances in a 6-minute
walk test, and improved arterial compliance (Rector et al 1996).
Others have used arginine as a treatment for high vascular
resistance disorders such as hypertension, angina, cerebral
ischemia and asthma (U.S. Pat. No. 5,217,997). For example, one
study found that treatment with oral arginine, 6 g/day for 3 days,
improved exercise capacity in patients with angina (Ceremuzynski et
al 1997).
[0037] Glutamine can be a precursor to arginine and thus enhance
arginine effects. In addition glutamine acts to enhance immune
system after exercise and in clinical settings, while taurine has
also been shown to have a benefit.
[0038] L-carnitine has been shown to increase exercise capacity in
both athletes and patients with angina, presumably by increasing
the availability of fatty acids for oxidative metabolism. Pyruvate
and creatine are also commonly used supplements for athletic
enhancement.
[0039] Folic acid (or folate) is vital for cell division and
homeostasis due to the essential role of folate coenzymes in
nucleic acid synthesis, methionine regeneration (from the
remethylation of homocysteine), and in the shuttling, oxidation,
and reduction of one-carbon units required for normal metabolism
and regulation. Folate deficiency is thought to be one of the most
common avitaminoses. Decreased levels of plasma folate have been
linked to increased levels of plasma homocysteine, which has been
known to be a causative factor in vascular disease. Brouwer et al.
(1999) found significantly decreased levels of plasma homocysteine
and significantly increased levels of plasma and red blood cell
folate by supplementing the diet with either 500 pg/d or 250 pg/d.
Plasma homocysteine levels were reduced by 22% with the 500 pg/d
dose and by 11% with the 250 pg/d dose. Supplementation with folic
acid in combination with vitamins B6 and B12 has been shown to be
more effective at lowering homocysteine levels than supplementing
with folic acid alone (Mansoor et al 1999). Mansoor showed that
supplementation of 300 pg/d in healthy individuals over 5 weeks
reduced plasma homocysteine levels 20% while 300 pg/d plus 120
mg/day of vitamin B6 reduced plasma homocysteine by 32%. Vitamin
B12 has likewise been shown to increase the folate effect.
[0040] Normally, a wholesome diet is considered to provide
sufficient amounts of these nutritive elements. Supplementation
with off-the-shelf multivitamins is common. However, patients
requiring improvement in cardiovascular function or peripheral
vascular function often are not able or willing to prepare or
choose a diet that will meet their enhanced requirements for these
nutritive elements, nor do the usual vitamin supplementations
provide sufficient levels for this group of patients. Therefore, it
is of increased benefit to add at least these vitamins to the
compositions of this invention.
[0041] The following examples are provided for illustrative
purposes only and do not limit the scope of the appended
claims.
EXAMPLE 1
[0042] Pliml (1992) has previously reported that 60 grams of
D-Ribose daily in four 15 gram doses taken for three days
benefitted patients with cardiovascular disease. This dosage of
ribose may bring on hypoglycemia with concomitant dizziness, nausea
and sweating. Subjects frequently experience abdominal distress and
diarrhea similar to that in individuals with lactose intolerance
who ingest milk. Because of these unpleasant side effects, patients
will be reluctant to continue ribose on a maintenance basis.
Therefore, a study was done to select a lower and safer dose of
ribose that is effective in increasing cardiovascular and
peripheral vascular function and can be taken long-term for
maintenance and cardioprotection.
[0043] A. Patient Selection and Protocol:
[0044] A double-blinded, randomized, crossover clinical study was
initiated to determine whether patients with cardiovascular disease
could find a ribose benefit at lower, safer doses. Patients with
known chronic coronary artery disease with stable angina pectoris
and chronic heart failure, class II and III (New York
Classification, NYHA) were selected for the study. All patients had
a history and ongoing occurrences of angina pectoris. All but two
patients had a previous history of myocardial infarction, with
one-third having two or more previous infarcts. Thirty-one percent
of the patients had a previous history of surgical intervention,
either coronary artery bypass graft (CABG) or angioplasty. All
patients were being treated with nitrates, molsidim and beta
blockers. Three patients were also on diltiazem and an additional
three on trapidil. Medications were not altered during the study.
Exclusion criteria included patients <18 years of age, those
with severe concurrent disease (renal failure, diabetes mellitus,
neoplasia), evidence of hyperthyroidism and inability to follow the
protocol.
[0045] The study consisted of two treatment periods, three weeks in
duration. Initially, either ribose or placebo (dextrose) was
administered three times a day with meals. Five grams of either
ribose of placebo was dissolved in approximately eight ounces of
fluid shortly before administration. Following the initial
treatment period, the patients were given no ribose or placebo
treatment for one week as a washout period. The patients were then
given the alternate treatment for three weeks for the crossover
phase of the study.
[0046] Measured objectives parameters of systolic and diastolic
function were assessed with transthoracic echocardiography.
Subjectively, quality of life using the SF36 form, and physical
function (exercise tolerance) were assessed. All of the above
parameters were assessed at pre- and post-treatment in both arms of
the study.
[0047] B. Echocardiographic Studies:
[0048] Each echocardiographic assessment was performed by the same
clinical individual and accumulated data were analyzed by two
cardiologists in a blinded manner, with a consensus establishing a
final result. All studies were conducted with commercially
available equipment (System V, GE, Norway). To allow off-line
quantitative analysis of the echocardiographic data, studies were
recorded on videotape with selected cine-loops and velocity spectra
digitally transferred to a Macintosh G4 computer (Apple Computers,
CA) for subsequent analysis. Software provided by the manufacturer
(Echopac.RTM., GE, Norway) was used for data evaluation.
[0049] Each echocardiographic assessment was performed
transthoracically and a 1.7/3.4 MHZ harmonic transducer was used
with the patient examined in the left lateral decubitus position. A
one-lead electrocardiogram was recorded continuously during
echocardiographic assessment. The M-Mode left atrial dimension was
measured at end-systole in the parasternal long-axis view and left
ventricular ejection fraction was determined according to the
recommendations of the North American Society of Echocardiography.
In addition, left atrial volume was determined using the Simpson's
rule in the 4 chamber view. Transmitral Doppler inflow velocities
were recorded from the apical four-chamber view with the sample
volume positioned between the tips of the mitral leaflets during
quiet respiration.
[0050] The parameters derived from the transmitral velocity spectra
were: peak velocity of the early (E) and atrial filling (A) waves,
the corresponding velocity time integrals (VTI.sub.E and VTI.sub.A)
and the percentage of atrial contribution to total left ventricular
filling. The deceleration slope of the E wave was also measured.
The percentage of atrial contribution to total left ventricular
filling was determined by dividing the VTI.sub.A by the total
diastolic velocity time integral. The results of five consecutive
heart cycles were averaged in each patient to obtain a justified
value.
[0051] C. Quality Of Land and Physical Function Performance
[0052] Quality of life was assessed in each patient using the SF 36
form. These assessments were performed at baselines and at the
completion of supplement administration in each arm of the
study.
[0053] Semi-upright bicycle exercise tests were performed using an
Ergometer device (Blitz, Germany) in a standard manner on a with
incremental increase in the work load (25 watts every two minutes).
All tests involved symptom limited peak exercise performance with
at least an exercise induced 80-85% of age related maximal heart
rate, even though most patients are on b-blocker medication. Upper
extremity blood pressures were obtained by at every 2 minutes and
also at peak exercise. Rate pressure product (RPP) was calculated
using systolic blood pressure times heart rate and expressed in RPP
units.
[0054] D. Statistical Analysis
[0055] Analysis of variance for repeated measures (ANOVA) was used
for the analysis of serial changes of continuous parameters within
and between the randomized, assigned treatment arms, i.e. ribose vs
placebo. Further comparison were subject to Bonferroni correction.
In all cases, a p value .ltoreq.0.05 was considered statistically
significant.
[0056] E. Conclusions
[0057] Twelve adult CHF patients underwent subjective and objective
assessment, which included quality of life, physical functioning,
deceleration rate of the E wave, peak velocity of the E and A
waves, velocity time integral of both E and A, percentage of atrial
contribution to total left ventricular filling, left atrial volume,
(Table 1), left ventricular ejection fraction, left ventricular
volumes, and stroke volume. All patients were compliant throughout
the study and all completed both arms of the study. Patients
tolerated both supplements without any adverse effects, including
systemic and pulmonary-cardiovascular events.
1TABLE I THERAPY Edc* SVI* EF Ac # LVVs* Ribose 193.5 .+-. 45.9
2.63 .+-. .57 51.0 .+-. 7.3 45.3 .+-. 9.2 64.4 .+-. 24.8 Dextrose
250 .+-. 70.2 1.99 .+-. .71 40.9 .+-. .71 39.2 .+-. 9.7 78.4 .+-.
27.0 *(p .ltoreq. .005, #p < .01)
[0058] ECHO revealed a significant improvement in deceleration time
of the E wave (Edc in msec), stroke volume index (SVI, ml/body mass
index) ejection fraction (EF, %), atrial contribution (Ac, &),
and left ventricular systolic volume (LVVs, ml) in the ribose.
Analysis of parameters reflecting diastolic function revealed
significant findings. Ribose demonstrated a significant shorter
deceleration time of the E wave, with a significantly smaller left
atria volume and a higher atrial contribution to left ventricular
filling as compared to patients treated with placebo.
[0059] All patients completed exercise testing without any adverse
effects. The mean maximal attained exercise level was not changed
by either treatment, beginning vs at the end of the treatment
period.
[0060] On the other hand, a noted difference in quality of life and
physical functioning was observed between modalities. Patients
receiving oral ribose demonstrated a significant improvement in the
overall score of the quality of life index. This increase was
paralleled by a significant improvement in physical function..
[0061] Over a relatively short term, treatment with oral D-ribose
significantly improved diastolic cardiac function in patients with
severe coronary artery disease and congestive heart failure.
Administration of ribose resulted in an enhanced quality of life.
Longer term studies with ribose supplementation and studies on less
severely ill patients are expected to show greater improvement in
diastolic and systolic function. In the absence of adverse effects,
it is recommended that patients continue on a maintenance method of
at least one dose of ribose daily.
EXAMPLE 2.
Compositions Of Ribose With Other Components
[0062] It has been shown in other studies that the beneficial
effects of ribose are augmented in subjects with poor circulation
by the concomitant administration of vasodilators, which relax the
blood vessels, allowing better circulation and hence better
accessibility of ribose to the tissues. It can be noted in Example
1 that these severely ill patients are all taking at least one
vasodilator. Nitrates, especially nitroglycerine, are most commonly
used because of their rapid onset of action. Patients experiencing
angina self-administer nitrates buccally, sublingually or
transdermally, since nitrates administered orally are quickly
cleared on passage through the liver. Even when administered in
this manner, nitrates have a very short half-life in the body.
Nitrates are not a pleasant therapy, often causing severe
headaches. It is beneficial to administer a vasodilator with ribose
in order improve circulation, thereby making ribose more available
to the tissues. Ribose is most conveniently administered orally.
Therefore, in order to have the maximum benefits in subjects in
which the vasodilator cannot be administered orally, it is advised
to ingest ribose about fifteen minutes before administration of the
vasodilator. This minor inconvenience may be eliminated when the
vasodilator selected may be administered orally. Therefore, the
compositions below incorporate L-arginine or its equivalents as a
vasodilator. Other useful orally administered vasodilators include
L-arginine, nitroglycerine, nitrates, nitrites, papaverine,
isoproterenol, nylidrin, isoxsuprine, nitroprusside, adenosine,
xanthine, ethyl alcohol, dipyramide, hydrazaline, minoxidil,
diazoxide or analogs of the foregoing.
[0063] Subjects also may have suboptimal circulation or be in a
suboptimal nutritional state. Accordingly, the following
compositions have been made to provide additional benefit to the
cardiac patient, especially to the patient undergoing
rehabilitation, and to subjects needing cardioprotection.
[0064] The following compositions are to be taken one to four times
per day:
2 COMPOSITION A PREFERRED DOSE ACCEPTABLE RANGE D-ribose 5 g 1-20 g
L-arginine 2 g 0*-8 g *arginine can be replaced by citrulline or
ornithine or other orally administered vasodilators
[0065]
3 COMPOSITION B PREFERRED DOSE ACCEPTABLE RANGE D-ribose 5 g 1-20 g
Glucose 5 g 0-20 g (to equal ribose amount) L-arginine 2 g 0*-8 g
Glutamine 500 mg 40-1000 mg Vitamin C 500 mg 100-1000 mg Folic acid
0.2 mg 0.1-1.0 mg Vitamin B12 0.25 mg 0.1-1.0 mg Vitamin B6 6 mg
1-50 mg *arginine can be replaced by citrulline or ornithine or
other orally administered vasodilators
[0066] The ingredients are triturated as a dry powder. The powder
can be conveniently dissolved in any carrier, preferably one that
comprises a pleasant flavoring and color. Many patients will prefer
a sweeter composition. Sweeteners such as sucrose or corn syrup or
the like can easily be added to taste. It may be most convenient to
prepare a concentrated liquid solution to be diluted by the patient
with water or other liquid.
EXAMPLE 4
Additional Useful Ingredients
[0067] Any of the above compositions, or ribose alone, can be
supplemented with one or any combination of L-carnitine, taurine,
creatine, coenzyme Q10, and/or pyruvate. Supplementation with any
or all of these compounds will incrementally improve cardiovascular
or peripheral vascular function and provide cardioprotection
against onset or recurrence of cardiovascular or peripheral
vascular disease..
EXAMPLE 5
[0068] The following study was devised to check the benefits of
additions to the basic ribose treatment.
[0069] Patients recovering from recent myocardial infarction will
be selected according to these entrance criteria:
[0070] Adult (male/female) .gtoreq.21 years of age
[0071] Enrolled in a cardiac rehabilitation program .gtoreq.eight
weeks or under medical supervision
[0072] Patients with ejection fraction .ltoreq.30 % or Class IV
heart failure will be excluded
[0073] No symptomatic chronic obstructive pulmonary disease
[0074] No symptomatic peripheral vascular disease
[0075] No uncontrolled high blood pressure
[0076] No history of TIAs or CVAs
[0077] No condition that would prohibit treadmill or bicycling
exercise
[0078] Patients must fail two (2) baseline treadmill tests
[0079] Type II diabetic patients are eligible
[0080] One hundred patients (20 patients at each of five sites) who
have been enrolled in a cardiac rehabilitation program of
.gtoreq.eight weeks duration will be enrolled in a study. Once
informed consent has been obtained, patients will undergo two
baseline exercise (treadmill or cycling) assessments, as well as a
baseline quality of life questionnaire. Whichever exercise
assessment the patient begins, the patient must continue on this
type of exercise throughout the protocol period. Blind
randomizations will then occur.
[0081] After baseline assessment and randomization, as a pilot
study, four patients at each site will begin oral supplementation
with Composition B. Four patients at each site will be given a
placebo consisting of 5 g glucose. The supplementation will be
taken twice a day, around mealtime. All patients will discontinue
supplementation after eight weeks. During the supplementation
period, at week eight and each week for two weeks following
discontinuation of exercise assessment, patients will undergo an
evaluation consisting of exercise assessment and a quality of life
questionnaire. In addition, any non-insulin dependent diabetics
will have daily serum glucose levels drawn for the first weeks
after beginning oral supplementation.
[0082] The exercise assessment will include type of exercise test
(treadmill or bicycling) duration of exercise (time), grade or
level of exercise (resistance), and physical restraints or symptoms
while or shortly after each exercise bout. EKG tracings will be
taken to monitor cardiovascular or anginal changes. The same type
of exercise test will be used for each evaluation in a specific
patient for comparison purposes. Additionally, as assessment will
be made as to potential rate of increase in activity (exercise)
/time in cardiac rehabilitation for each designated tested time
point.
[0083] It is expected that the patients given the composition of
this invention will be able to exercise longer, at a higher level
and without restraint or cardiac symptoms than in those patients
receiving placebo. It is further expected that the reported quality
of life will be more favorable in the patients receiving the
composition of this invention than in those receiving placebo.
EXAMPLE 6
Treatment Of Hypertension
[0084] As shown in Example 1, treatment with ribose improves
diastolic cardiac function. Since hypertension is accompanied by
left ventricular dysfunction, it is expected that the
administration of ribose to patients experiencing hypertension with
result in a benefit. One subject has been tested. Her blood
pressure has been tested at borderline values of 130/90. Following
daily administration of ribose at 5-10 grams per day, her blood
pressure was lowered to as low as 108/78. Further studies with
ribose alone or with Composition A are expected to confirm the
pressure-lowering effects of ribose administration.
[0085] All references cited within are hereby incorporated by
reference. It will be understood by those skilled in the art that
variations and substitutions may be made in the invention without
departing from the spirit and scope of this invention.
* * * * *