U.S. patent application number 09/854831 was filed with the patent office on 2001-11-15 for composition for improvement of cellular nutrition and mitochondrial energetics.
Invention is credited to Jeejeebhoy, Khursheed N., Sole, Michael J..
Application Number | 20010041741 09/854831 |
Document ID | / |
Family ID | 27357233 |
Filed Date | 2001-11-15 |
United States Patent
Application |
20010041741 |
Kind Code |
A1 |
Sole, Michael J. ; et
al. |
November 15, 2001 |
Composition for improvement of cellular nutrition and mitochondrial
energetics
Abstract
This invention provides a dietary supplement comprising
L-Carnitine (or its functional analogues such as Acetyl-Carnitine
or Proprionyl-1-Carnitine), Coenzyme Q10 and Taurine for the
correction of the abnormality in mitochondrial energetics in
cardiac failure and certain other diseases. A high protein
nutritional feeding supplementation with Cysteine, Creatine,
Vitamin E (RRR-d-alpha-tocopherol), Vitamin C (ascorbic acid),
Selenium, and Thiamin in may be added.
Inventors: |
Sole, Michael J.; (Toronto,
CA) ; Jeejeebhoy, Khursheed N.; (Toronto,
CA) |
Correspondence
Address: |
Kevin S. Lemack
Nields & Lemack
Suite 8
176 E. Main Street
Westboro
MA
01581
US
|
Family ID: |
27357233 |
Appl. No.: |
09/854831 |
Filed: |
May 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09854831 |
May 14, 2001 |
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09414689 |
Oct 7, 1999 |
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6232346 |
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09414689 |
Oct 7, 1999 |
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09002765 |
Jan 6, 1998 |
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6080788 |
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09002765 |
Jan 6, 1998 |
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08826234 |
Mar 27, 1997 |
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Current U.S.
Class: |
514/561 ;
514/553 |
Current CPC
Class: |
A23V 2002/00 20130101;
A23V 2250/0616 20130101; A23V 2250/306 20130101; A23V 2250/0612
20130101; A61K 31/12 20130101; A23V 2250/314 20130101; A23V
2250/54252 20130101; A23V 2250/54246 20130101; A23V 2250/70
20130101; A61K 2300/00 20130101; A61K 31/185 20130101; A23V 2002/00
20130101; A23V 2250/0644 20130101; A61K 31/205 20130101; A61K
31/205 20130101; A23L 33/40 20160801; A61K 31/205 20130101; A23L
33/00 20160801 |
Class at
Publication: |
514/561 ;
514/553 |
International
Class: |
A61K 031/205; A61K
031/185 |
Claims
We claim:
1. A method of medical treatment of a disease, disorder or abnormal
physical state in a mammal selected from the group consisting of
heart disease and functional deterioration associated with ageing,
the method comprising administering to a mammal an effective amount
of a carrier and a nutritional supplement comprising L-Carnitine or
its functional analogue, Coenzyme Q10 (Ubiquinone) or its
functional analogue and Taurine or a Taurine precursor in a single
or divided daily dose.
2. The method of claim 1, wherein the method comprises
administering to a mammal an effective amount of a carrier and a
nutritional supplement comprising L-Carnitine, Coenzyme Q10
(Ubiquinone) and Taurine or a Taurine precursor in a single or
divided daily dose.
3. The method of claim 1, wherein the mammal is selected from the
group consisting of humans, dogs, cats.
4. The method of claim 1, wherein the disease, disorder or abnormal
physical state comprises a disease, disorder or abnormal physical
state that is due in whole or in part to aging.
5. A method of increasing neuromuscular or athletic performance in
a mammal, the method comprising administering to the mammal an
effective amount of a carrier and a nutritional supplement
comprising L-Carnitine or its functional analogue, Coenzyme Q10
(Ubiquinone) or its functional analogue and Taurine or a Taurine
precursor in a single or divided daily dose.
6. The method of claim 5, wherein the method comprises
administering to the mammal an effective amount of a carrier and a
nutritional supplement comprising L-Carnitine, Coenzyme Q10
(Ubiquinone) and Taurine or a Taurine precursor in a single or
divided daily dose.
7. The method of claim 5, wherein the mammal is selected from the
group consisting of humans, dogs and cats.
8. The method of claim 7, wherein the mammal is a human.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/002,765, filed Jan. 6, 1998, which is a
continuation-in-part of U.S. application Ser. No. 08/826,234 filed
Mar. 27, 1997.
BACKGROUND
Organ Failure and Nutrition
[0002] There are four critical organ systems that are especially
likely to fail in aging and critical illness. They are the
cardiovascular, central nervous, musculoskeletal and immune
systems.
Relationship of Malnutrition to Mitochondrial Function
[0003] Protein-calorie malnutrition contributes to both skeletal
and cardiac.sup.1 muscle dysfunction in patients with cardiac
failure. Muscle is composed of water, minerals, nitrogen and
glycogen.sup.2,3. Feeding wasted individuals results in a gain of
the multiple elements in lean tissue.sup.4 including potassium.
Body potassium, has been used as an index of body cell mass.sup.5,
the metabolically active component of the lean tissue. In contrast
to body nitrogen, body potassium responds rapidly to feeding by
both oral and intravenous routes.sup.6,7,8,9,10. It has been shown
that in malnutrition there is a change in muscle membrane potential
resulting in reduced intracellular ionic potassium. The reduced
cellular potassium cannot be simply corrected by giving potassium
but requires restitution of nutrition. The above mentioned
observations suggest that cell ion uptake, an energy dependent
process, occurs earlier than protein synthesis during nutritional
support. This concept has received experimental support by two
studies using .sup.31P-NMR which showed that malnutrition was
associated with a reduced rate of oxidative phosphorylation,
suggesting a mitochondrial abnormality.sup.11,12.
[0004] Cell energetics are also important for muscle activity and
it has been shown.sup.13,14,15,16,17,18,19,20,21,22 that skeletal
muscle function, including that of the diaphragm, can be rapidly
altered by nutrient deprivation and restored by refeeding. Also the
changes in muscle function are specific to alterations in the
nutritional status and are not influenced by sepsis, trauma, renal
failure and steroid administration.sup.15,17. Christie and Hill
indicated that nutritional support improves muscle, t, including
diaphragmatic function before any increase in body protein or body
mass.sup.20. Windsor and Hill.sup.21 demonstrated that the
functional effects of nutrition are more important than subnormal
body protein as an index of surgical risk. Hanning and her
colleagues.sup.22 demonstrated the ability of stimulated muscle
function as demonstrated by a slow relaxation rate and an altered
force-frequency curve to predict the ability of patients with
cystic fibrosis to grow as an outcome measure. In contrast, body
composition, protein biochemistry, muscle power on an ergometer or
use of supplements did not predict growth potential. Among the
macronutrients, Castenada et al.sup.23 have shown that protein
deficiency can profoundly alter muscle function even when energy
intake is sufficient to meet requirements.
[0005] The data given above indicate that it is critical to correct
protein-calorie malnutrition, with an emphasis on protein
repletion, in order to obtain the maximum functional benefits of
administering skeletal muscle specific micronutrients. Current diet
supplementing strategies for correcting protein-calorie
malnutrition focus on giving supplements of protein and energy
(carbohydrates and fats). No supplement to date has addressed the
cascading series of metabolic abnormalities that can lead to
mitochondrial dysfunction.
SUMMARY OF THE INVENTION
[0006] We have found that nutrition can be used to prevent or delay
the onset of cardiac failure and thereby, promote recovery in
disease states affecting the heart. Similar considerations apply to
diseases of the other organ systems indicated above.
[0007] We have found that the central effect of nutrition in all
these systems can be unified into its influence on mitochondrial
energetics. That is: inadequate nutitional substrate is a cause of
impaired cell energetics. This has led us to invent a composition
for the improvement of mitochondrial energetics.
[0008] We have shown that in the skeletal muscle protein-calorie
malnutrition profoundly reduces mitochondrial oxidative
phosphorylation and reduces calcium cycling in cardiac
muscle.sup.1. We have found that there is profound reduction of
respiratory chain complex I, II and IV activity in animals given a
protein-calorie deficient diet. In addition, complex I activity is
similarly reduced in lymphocyte mitochondria showing that these
effects are not cardiac specific but apply to mitochondria in other
tissues, and protein feeding rapidly restored the abnormality when
it was simply due to protein-energy malnutrition (unpublished
data).
[0009] In addition, certain micronutrients and amino acids also
influence mitochondrial function in general. For example, carnitine
improves mitochondrial DNA transcription and translation in aged
animals.sup.24. A specific acyl derivative of carnitine,
acetyl-carnitine has been used for mitochondrial DNA synthesis
based on findings observed in patients treated with anti-retroviral
agents.sup.25. Coenzyme Q can alter immune function.sup.26 and may
protect the central nervous system from injury and
neurodegeneration.sup.27. On the basis of the above considerations,
a nutritional supplement that could maintain or restore
mitochondrial function will prevent cardiac failure or aid recovery
from cardiac disease. In addition it could also aid in the
management of neurodegenerative, musculoskeletal including the
muscular abnormality in chronic obstructive lung disease
(COPD).sup.16 and immune disorders.
Heart Failure
[0010] Congestive heart failure has emerged as a major health
problem during the past two decades. Its morbidity and mortality
have shown a steady increase since 1970.sup.28; heart failure now
affects approximately 1% of the population of the United States and
Canada. These data reflect both the aging of our population and the
success of modern cardiovascular medicine in converting acute,
often previously fatal, cardiac disease into a more chronic
process.
[0011] The underlying abnormality in congestive heart disease is
myocardial dysfunction leading to inadequate blood flow to
peripheral tissues. Although there have been considerable advances
in our understanding of the pathogenesis of heart failure in recent
years, critical questions remain about the evolution of cardiac
dysfunction to terminal failure. The importance of elucidating the
mechanisms responsible for the evolution of maladaptive hypertrophy
to cardiac failure is emphasized by the fact that in spite of our
advances, no presently available therapeutic intervention has been
shown to substantially improve the long-term survival of patients
with dilated cardiomyopathy and congestive heart failure. The
underlying heart disease is relentlessly progressive in almost all
patients who develop symptoms of overt failure and mortality
continues to be unacceptably high; for example, in a recent heart
failure trial, SOLVD, 40% of patients in the symptomatic treated
group were dead within 4 years.sup.29. Heart transplantation
appears to be the only prospect to improve long term survival for
many patients.
[0012] The reason for this dismal outcome despite modern advances
lies in the fact that several metabolic abnormalities have been
found in the failing myocardium which together as indicated below
result in progressive loss of cardiac myocytes (muscle).
[0013] There is a progressive accumulation of calcium in the
muscle, which in turn results in increased calcium in the
mitochondria. The progressive increase in mitochondrial calcium as
well as the basic cardiac disease (ischemic, viral, toxic, genetic)
decrease myocyte energy production and increase oxidative stress
resulting in free radical damage. The combined result of these
three processes promotes myocyte dysfunction and death. In addition
these processes also influence skeletal muscle and contribute to
fatigue and disability.
[0014] The modern pharmacological therapy of heart failure has
focused on the amelioration of fluid overload and hemodynamic
abnormalities and has not addressed the fundamental fact that if
there is progressive loss of cardiac muscle then the patient will
inevitably succumb. That is: the inexorable myocyte loss by
apoptosis that occurs in heart failure is the key factor
responsible for myocardial decompensation and the demise of the
patient.sup.30. Oxidative stress, calcium overload and cellular
energy deficiency are well known as principal stimuli for the
development of apoptosis.
[0015] Among the factors that aggravate myocyte dysfunction there
is increasing evidence for the role of nutritional deficiencies
both due to reduced intake and to insufficient intake in relation
to augmented requirements caused by the underlying disease state, a
phenomenon which we will refer to as "conditioned deficiency". In
this situation the recommended daily allowances (RDA) do not apply,
as requirements may exceed the standard RDA.
[0016] The presence of protein-energy malnutrition has been
recognized by surveys of hospitalized patients using
anthropometric, biochemical and immunologic measures of nutritional
status.
[0017] These surveys have indicated that 50-68% of patients with
congestive heart failure were significantly malnourished.sup.31.
The proportion of malnourished heart failure patients has been
found to be higher than that of patients with cancer, alcoholism or
those with acute infection. The cause of protein-energy
malnutrition is due to both reduced intake and increased energy
demands. Cardiac failure results in a cascade of metabolic effects
such as tissue hypoxia, anorexia, hypermetabolism, weakness,
dyspnea and hypomotility of the gastrointestinal tract all leading
to poor nutrient intake. Anorexia can be aggravated by unpalatable
restrictive diets or by converting enzyme inhibitors or by an
excess of diuretics, opiates and digitalis. Characteristics of the
disease process such as fatigue and early satiety have all been
reported in congestive heart failure patients consuming
self-selected diets.sup.32,33. These factors lead to compromised
food and nutrient intake and subsequently contribute to the poor
nutritional status of these cardiac patients. In addition, patients
with heart failure have been shown to have significantly increased
resting metabolic rates.sup.34,35,36,37 possibly due to the
increased work of breathing, fever, cytokines or elevated
sympathetic nervous system outflow.
[0018] The RDA for the vitamins and related micronutrients
recommended by federal nutrition authorities in Canada, the United
States and Western Europe (e.g. The Canada Food Guide) are obtained
through the analysis of deficiency data in otherwise healthy humans
and animals. We have found that with the advent of disease, or due
to genetic predisposition, specific metabolic pathways in
individual organs and the function of some of these systems alter
the nutritional requirements causing conditioned deficiency of both
macro- (protein including amino acids, carbohydrates and fats) and
micronutrients (electrolytes, trace elements, vitamins and special
nutrient substances). Certain pharmaceutical agents or treatment
strategies also influence these requirements.
[0019] The above considerations indicate that for heart failure and
in other conditions detailed below the nutrient intake is
instrumental in determining the evolution of tissue damage--its
amelioration or acceleration. RDA data, although suitable for a
healthy population, are not necessarily appropriate for patients
suffering from certain forms of illness or predisposed to sickness
through genetic constitution. There is a need for a nutritional
supplement that can be taken by persons suffering from illness or
with a genetic predisposition to illness.
Musculoskeletal System
[0020] Data given above have clearly demonstrated the relationship
of protein deficiency and mitochondrial dysfunction in skeletal
muscle. In addition several nutrient agents have been shown to
improve skeletal muscle performance. These include creatine,
carnitine and taurine.
Central Nervous System
[0021] Mitochondrial dysfunction has been noted as an important
factor in several neurodegnerative diseases.sup.38. A central role
for defective mitochondrial energy production, and the resulting
increased levels of free radicals, in the pathogenesis of various
neurodegenerative diseases is gaining increasing
acceptance.sup.39.
Immune System
[0022] Immune dysfunction occurs with aging and there is growing
evidence that reduced immunity is related to reduced mitochondrial
dysfunction.sup.40.
THE INTERACTING PATHWAYS RESPONSIBLE FOR MITOCHONDRIAL FUNCTION
[0023] We have found that the critical path in these interactions
is the flow of energy substrates into the mitochondria through
carnitine, the transfer of electrons through the complexes via
CoQ10, and the modulation of the calcium pump by taurine. We
consider the constituents of this path, namely Carnitine, CoQ10 and
Taurine, to be the core constituents required to promote
mitochondrial function. We have found that these compounds act
together on this critical path to provide a synergistic effect.
[0024] The other constituents of the cascade given in FIG. 1 aid
the action of this core by modulating oxidative stress which
results from external factors and mitochondrial dysfunction and in
turn promotes further dysfunction.
[0025] Adequate energy production is essential not only for
cellular function but also for long term cell survival. Cellular
energy production from nutrients, especially fatty acids need the
coordinated action of a number of co-factors. Three factors namely,
carnitine (critical for the transport of long chain fatty acid
substrate), coenzyme Q10 (a key transducer for mitochondrial
oxidative phosphorylation), and taurine (a key modulator of calcium
accumulation) are important in promoting normal cell
energetics.
DETAILS OF ALTERED MITOCHONDRIAL ENERGETICS IN HEART FAILURE
[0026] The data for mitochondrial energetic dysfunction has been
clearly documented in heart failure and therefore the following
details will focus on heart failure as a paradigm.
[0027] In heart failure deficiency of carnitine promotes
accumulation of toxic long-chain fatty acids; deficiency of CoQ10
alters electron transport and mitochondrial calcium accumulation
also occurs, which can be corrected by the action of taurine. From
FIG. 1 it can be seen that normalization of any one of the above
three constituents alone will not be sufficient to significantly
benefit myocardial energy production in the presence of
abnormalities the other factors in the myocardial bioenergetic
pathway. In addition, from FIG. 1, it can also be seen that the
added action of creatine, known to be deficient in cardiac failure
and antioxidants to reduce oxidative stress, known to be elevated
in cardiac failure, will enhance the action of the three core
constituents carnitine, CoQ10 and taurine. For these constituents
to be effective in remodelling the heart, the addition of protein
is essential in any supplement. These substances can be given as
oral replacements to benefit both myocyte function and long-term
survival. Details of the deficiencies and altered metabolism of
these constituents in cardiac failure and other diseases are given
below. However, it has become apparent that this paradigm applies
to a number of other diseases; these will be briefly discussed in
each section where appropriate.
REGULATING INTRACELLULAR CALCIUM
[0028] The failing myocardium exhibits an increase in calcium
content and impaired movement of intracellular calcium. Impaired
uptake of calcium adversely affects diastolic relaxation whereas
the kinetics of transsarcolemmal calcium flux and calcium release
by the sarcoplasmic reticulum is a principal determinant of
systolic function. Chronic intracellular calcium overload
ultimately leads to cell death.
Taurine
Metabolism and Physiological Role of Myocardial Taurine
[0029] Taurine (2-aminoethanesulfonic acid) is a unique amino acid,
which lacks a carboxyl group, and as such it does not enter into
protein synthesis. Taurine appears to be an important amino acid
for the modulation of cellular calcium levels, exhibiting a
remarkable biphasic action by increasing or decreasing calcium
levels appropriate to the maintenance of cellular calcium
homeostasis.sup.41,42,43. In the heart, taurine appears to do this
by affecting several myocardial membrane Systems.sup.41,42,43. It
is reported to enhance Ca.sup.++-induced Ca++ release from the
sarcoplasmic reticulum both directly and through inhibition of the
enzyme phospholipid methyl transferase, influencing the
phospholipid environment of the ryanodine-sensitive calcium
channel. It also modulates cardiac Ca.sup.++ and Na.sup.+ through
the cardiac sarcolemmal Na.sup.+-Ca.sup.++ exchanger and a
taurine/sodium exchanger. Taurine also has antioxidant properties
and reacts with a variety of potentially toxic intracellular
aldehydes including acetaldehyde and
malonlyldialdehyde.sup.44,45.
[0030] Taurine is found in particularly high concentrations in the
heart (15-25mmole/g protein) representing approximately 60% of the
free amino acid pool.sup.41,46. Plasma levels are approximately
50-80mmol/L. Taurine is not an essential amino acid in humans as it
can be synthesized from cysteine or methionine.sup.46; however,
most taurine in humans is obtained directly through dietary
sources, particularly from fish and milk. Biosynthetic capacity is
maturation dependent, being almost non-existent in the human fetus
and newborn and progressively increasing until adulthood.sup.47,48.
Taurine uptake by the myocyte is an active process and b-amino
acids such as beta-alanine share the transport site; it is
saturable at taurine concentrations of 200 mmole.sup.46,48. In the
heart the transport of taurine, like that of carnitine, can be
stimulated by beta-adrenergic agonists or dibutyryl-c-AMP; however,
in other tissues the c-GMP pathways seem to be important.sup.46.
The taurine transporter of all tissues is regulated by the
activation of two calcium sensitive enzymes: protein kinase C
(which inhibits the transporter) or calmodulin (which stimulates
transport).sup.48. This reciprocal regulation of intracellular
taurine levels by these two enzymes is consistent with a
physiologic role for taurine in the maintenance of intracellular
calcium homeostasis.
[0031] The observation that TNF-.alpha. levels.sup.49 and soluble
TNF receptors.sup.50,51 are raised in heart failure suggest
increased cytokine activity in this condition. Grimble.sup.52 has
shown that the requirement for sulfur containing amino acids is
increased when TNF-.alpha. is infused. Of greater significance is
the fact that transsulfuration of dietary methionine to cysteine is
reduced and in consequence levels of taurine and lung glutathione
fall unless the animals are supplemented with cysteine. These
findings suggest that with increased cytokine activity as observed
by us.sup.51 in severe heart failure, the need for cysteine and
taurine will increase. Since cysteine will replenish not only
taurine but also glutathione (an important endogenous antioxidant
-see `Oxidative Stress` section, below), it may be an important
supplement for replenishing both.
Taurine Levels and Taurine Supplementation in Heart Failure
[0032] Cardiac taurine concentrations are altered in heart disease.
Cats have very little taurine biosynthetic capacity and may exhibit
a taurine deficient cardiomyopathy.sup.53. Prolonged taurine
depletion of the myocardium has been shown to decrease contractile
force through reduction of myofibrils.sup.54. This finding is of
interest because increased calcium levels in the myocyte can
activate calcium dependant proteinases that in turn can lead to the
breakdown and loss of myofibils.sup.54. Taurine depletion also
renders the heart more susceptible to ischemic injury.sup.55. In
this context it should be noted that myocardial taurine depletion
has been reported following acute ischemic injury.sup.56 and
cardiovascular bypass surgery.sup.57.
[0033] In species other than the cat, myocardial hypertrophy and
failure is associated with an increase in cardiac taurine
concentration.sup.41,58- . In spite of this increase, orally
administered taurine has been shown to have a cAMP-independent
positive inotropic effect in animal models of left ventricular
dysfunction.sup.41. Taurine administration has been shown
significantly reduce calcium overload and myocardial damage in a
variety of heart failure models including that induced by the
calcium paradox, doxorubicin or isoproterenol or in hamster
cardiomyopathy.sup.41,59,60,61,62; it also has been reported to
increase the survival of rabbits with aortic regurgitation.sup.63.
Taurine may have a beneficial effect on cardiac arrhythmias.sup.64
including those associated with digitalis or catecholamine
excess.sup.65. Studies of taurine administration in humans have
been limited. However, in patients suffering from congestive heart
failure taurine, given in an oral dose of 1 gram three times per
day, has been reported to be extremely well tolerated and to
improve both hemodynamic state and functional
capacity.sup.41,56,67.
[0034] Taurine also appears to function as an osmoregulator and
neuromodulator in the brain.sup.68. In addition there is evidence
that taurine modulates calcium influx and efflux in the brain,
increases resistance to hypoxia and reduces seizure activity when
administered intraperitoneally. In streptozotocin-induced diabetic
rats taurine also appears to protect against the development of
renal dysfunction.sup.45; cardiac studies have not been performed
in this model. On the same lines taurine also protects the kidney
and liver against doxorubicin (adriamycin) toxicity.sup.69.
MYOCARDIAL ENERGETICS
L--Carnitine
Carnitine in Health and Disease
[0035] L-carnitine, an amino acid derivative
(3-hydroxy-4-N-trimethylamino- butyric acid), plays a critical role
in this bioenergetic pathway as it is essential for the transport
of long-chain fatty acids from the cytoplasm into the sites of
beta-oxidation within the mitochondrial matrix..sup.70 The
importance of carnitine has been recognized by the observation that
carnitine deficiency occurs in several genetically determined
metabolic abnormalities.sup.71,72 where it is associated with the
development of cardiomyopathy and skeletal muscle dysfunction.
L-carnitine administration to these patients restored to a great
extent cardiac and skeletal muscle function.
[0036] Evaluation of carnitine metabolism in several cardiac
pathologies has led to the realization that carnitine deficiency
may also be acquired and organ selective, a finding of great
significance because fatty acid oxidation is a major source of
energy for the myocardium. The impaired heart, regardless of the
etiology of the dysfunction (including ischemic or non-ischemic
dilated cardiomyopathy, coronary, hypertensive, diabetic and
valvular heart disease), exhibits a marked depletion (up to 50%) of
myocardial carnitine levels (particularly free carnitine) in both
animal models and man.sup.73,74,75, with evolution of the heart
disease. On the other hand, despite low cardiac levels, plasma
carnitine levels increased.sup.76. This finding makes plasma levels
unrepresentative of the levels in the heart.
[0037] In addition to promoting the entry of fat into the
mitochondria, carnitine binds acyl groups and releases free CoA.
These processes benefit the myocyte in two ways, first it removes
toxic short chain acyl groups and second maintains sufficient
amounts of free CoA for mitochondrial function.
[0038] An example of the detoxifying action of carnitine is seen in
the ischemic myocardium.sup.77,78. In ischemic myocardium or
skeletal muscle there is an accumulation of long chain acyl-CoA;
these compounds are potentially toxic as they exhibit both
detergent-like properties and can impair mitochondrial energy
production through the inhibition of a mitochondrial membrane
enzyme, adenine nucleotide translocase, which transfers newly
synthesized ATP from the inner mitochondria space into the
cytoplasm. Carnitine protects the heart (or skeletal muscle) from
the accumulation of these metabolic poisons by forming
acylcarnitines, which can freely diffuse out of the cell and be
eliminated through the urine.
[0039] Carnitine deficiency has also been observed in patients with
chronic renal failure; an improvement in cardiac function following
carnitine therapy has been reported for those on
hemodialysis.sup.79.
Carnitine Supplementation and Treatment
[0040] Body stores of 1-carnitine are supplied by both diet and via
endogenous biosynthesis from trimethyllysine. The concentration of
carnitine in normal adult cardiac and skeletal muscle is
approximately 8-15 nmol/mg non-collagen protein; plasma levels are
approximately 35-50 mmol/L. Thus plasma levels are generally not
good measures of tissue concentrations. Under normal conditions
approximately 80% of carnitine is free and the remainder complexed
as fatty acylcarnitine. A 20-50:1 intracellular to extracellular
carnitine gradient is maintained by a sodium-dependent plasma
membrane transport system. Carnitine transport can be stimulated by
beta-adrenergic agonists or dibutyryl-cAMP.
[0041] Following oral administration, peak plasma concentration
occurs at 3 hours and decays with a T.sub.1/2 of 3-4 hours; the
turnover of endogenous cardiac or skeletal muscle carnitine is
likely on the order of several days. The bioavailability of
1-carnitine is limited to approximately 5-20% probably due to
clearance by the liver. L- carnitine is well tolerated and no
adverse effects have been described.
[0042] Acetyl-1-carnitine and proprionyl-1-carnitine are naturally
occurring derivatives of 1-carnitine.sup.80. Acetyl-1-carnitine has
been shown to influence mitochondrial DNA synthesis, is depleted by
antiretroviral drugs and is non-toxic when infused
intravenously.sup.81. The administration of acetyl-1-carnitine has
been shown to effectively replace decreased carnitine stores in the
brain and heart associated with aging in rats.sup.82.
Acetyl-1-carnitine has excellent penetration of the CSF and is
likely to be of benefit in neurodegenerative conditions such as
Alzheimer's disease.sup.81,83. Acetyl-1-carnitine has also been
shown to be of benefit to peripheral nerve function in experimental
diabetes.sup.84.
[0043] Proprionyl-1-carnitine has also been used for cardiac
therapy.sup.85,86,87,88. Proprionyl-1-carnitine directly penetrates
the cell membrane and has a high affinity for the protein carriers;
within the mitochondria the enzyme carnitine acetyl transferase
releases 1-carnitine and proprionyl-CoA and the latter is
transformed into succinyl CoA which can prime the citric acid cycle
and the production of ATP.sup.89,90. The proprionyl group appears
to stimulate fatty acid oxidation (whereas the acetyl group
inhibits this).sup.87.
[0044] L-carnitine (3-5 grams) or proprionyl-1-carnitine (1.5-3.0
grams) administration has been shown to result in significant
hemodynamic improvement and an overall benefit in the functional
capacity of animals and patients with heart failure or myocardial
ischemia.sup.72,73,79,85,86- ,,91,92,93,94,95,96,97,98,. Clinical
studies report a reduction in cardiac damage, when 1-carnitine is
taken from 4-12 weeks following myocardial infarction.sup.78,92. It
also appears to benefit patients who suffer from skeletal muscle
ischemia manifested as intermittent claudication. Circulating
levels of tumour necrosis factor, a cytokine that leads to muscle
wasting and cardiac dysfunction, correlates with functional class
and prognosis of patients with heart failure.sup.51; in this
context it is of interest that proprionyl-1-carnitine
administration tends to normalize the circulating levels of this
cytokine in patients with heart failure.sup.98.
Ubiquinone or Coenzyme Q10
Coenzyme Q10 in Health and Disease.sup.reviewed in 99
[0045] Coenzyme Q10 or ubiquinone (2,3 dimethoxy-5
methyl-6-decaprenyl benzoquinone) plays a vital role as a
rate-limiting carrier for the flow of electrons through complexes
I, II and III of the mitochondrial respiratory chain. It is also a
major endogenous lipophilic antioxidant and, like vitamin C, can
regenerate a-tocopherol, the active form of vitamin E by reducing
the a-tocopherol radical. A deficiency of ubiquinone caused by
actual loss or through oxidation of the molecule can result in an
impairment of energy production. The molecule is sited within the
inner mitochondrial membrane but is also associated with the
membranes of other intracellular organelles. It is also an
important component of circulating LDL particles, protecting LDL
from oxidation.
[0046] Ubiquinone is actively biosynthesized with the cells. The
quinone ring is synthesized from the amino acid tyrosine and the
polyisoprenoid side chain is formed through the acetyl
CoA-mevalonate pathway. The latter pathway is under the control of
the enzyme hydroxy-methylglutaryl coenzyme A reductase (HMGCoA
reductase) and is also used for cholesterol synthesis; inhibition
of this pathway using HMGCoA reductase inhibitors, drugs which
decrease plasma cholesterol, also results in a parallel decrease in
plasma ubiquinone.sup.100 and may also reduce tissue ubiquinone
levels.sup.101.
[0047] Significantly reduced levels of myocardial ubiquinone are
found in heart failure in both animal models and
man.sup.102,103,104. Since the heart depends upon aerobic oxidation
for its energy needs, ubiquinone, which is critically necessary for
oxidative energy production is very important for cardiac function.
The antioxidant properties of ubiquinone would add to this
benefit.
Ubiquinone Supplementation and Treatment.sup.99,105,106,107
[0048] Ubiquinone is widespread throughout all food groups and thus
body stores may also be partially supplied by diet. The
concentration of ubiquinone in normal cardiac muscle is
approximately 0.4-0.5 mg/mg dry weight, slightly less in skeletal
muscle and 0.6-1.3mg/ml in plasma. Oral absorption is slow and
markedly enhanced in the presence of lipid; plasma levels peak at
5-10 hours and decay with a T.sub.1/2 of 34 hours. There is a large
hepatic first pass effect so that only about 2-5 % of an oral dose
is taken up by the myocardium. The mean steady state level in
plasma increases 4-7 fold after 4 days of dosing at 100 mg 3 times
daily. Side effects are virtually absent; however, asymptomatic
elevations in liver enzymes (LDH, SGOT) have been described with
doses of 300 mg/day.
[0049] Oral ubiquinone therapy has been shown to result to
beneficially affect cardiac dysfunction in a variety of animal
paradigms.sup.108,109,1- 10. Oral ubiquinone also has been reported
to reduce the age-associated decline in mitochondrial respiratory
function in rat skeletal muscle.sup.111. The controlled trials in
patients with heart failure show clinical benefit, reducing
symptoms, lessening hospitalization and improving myocardial
performance.sup.99,,102,103,105,,112,113,114,115.
Creatine
Role of Creatine in Health and Disease
[0050] Creatine phosphate (PCr) is the primary high-energy
phosphate reservoir of the heart and skeletal muscle. High-energy
phosphate is transferred from PCr to ADP to form ATP through
catalysis by creatine kinase.sup.116:
PCr+ADP+H.sup.+<-->ATP+Cr
[0051] Muscle creatine stores are maintained through biosynthesis
from endogenous precursors arginine, glycine, and methionine in the
liver, pancreas and kidneys, and through the ingestion of meat and
fish. The concentration of total creatine in normal adult human
myocardium or skeletal muscle is approximately 140 mmol/g protein;
creatine phosphate constitutes about 65-80% of the total creatine
under aerobic conditions.sup.116. Creatine is accumulated by muscle
against a large concentration gradient from the blood; the
transporter is probably driven by the extracellular/intracellular
Na.sup.+ electrochemical potential.sup.116,117. There is evidence
that increased adrenergic drive (a characteristic of heart failure)
can decrease myocardial creatine and creatine kinase
stores.sup.123,124.
[0052] Experimental creatine depletion in animals results in
structural, metabolic and functional abnormalities in
muscle.sup.117. Myocardial creatine content and myocardial
energetics is reduced in a wide variety of animal paradigms of
heart failure.sup.116,118,119,123,120. No data is available
regarding creatine replacement in these models. However creatine
has been shown to attenuate myocardial metabolic stress in rats
caused by inhibition of nitric oxide synthesis.sup.121.
[0053] Hearts from patients with coronary artery disease, aortic
stenosis or heart failure all show a marked reduction in total
creatine (up to 50%) with an expected concomitant reduction in
creatine phosphate.sup.122,123; creatine kinase is also
reduced.sup.116,117. These reductions interact synergistically
decreasing myocardial capacity for ATP synthesis by up to
80%.sup.116,117,124. Such an energy deficit has a significantly
adverse impact on myocardial function and survival. Similar
abnormalities of energy stores and production are seen in the
skeletal muscles of patients of heart failure; these play an
important role in compromising the functional capacity of these
patients.sup.125. Recently, it has been reported that the
myocardial PCr/ATP ratio may be a better predictor of patient
mortality in dilated cardiomyopathy than left ventricular ejection
fraction or the patient's functional class.sup.126.
Creatine Supplementation and Treatment
[0054] The role of creatine supplementation may not be observed in
normal cardiac or skeletal muscle under normal levels of
performance. However, supplementation has been shown to increase
performance in situations where the availability of creatine
phosphate is important.sup.127,128. Ingestion of 3 g of creatine
per day for one month (or 20 g per day for one week) increases
muscle creatine content and can improve performance.sup.99. Daily
turnover of creatine to creatinine for a 70 kg male has been
estimated to be approximately 2 g.sup.129. Creatine supplements
will increase skeletal muscle creatine and increase muscle
resistance to fatigue during short-term intense exercise where it
reduces lactate accumulation.sup.130,131,132. It also appears to be
of benefit when given in adequate doses to patients with heart
failure where myocardial and perhaps skeletal muscle creatine and
creatine phosphate levels are depressed. The administration of a
creatine supplement to patients with heart failure did not increase
cardiac ejection fraction but significantly increased not only
skeletal muscle creatine phosphate but also muscle strength and
endurance.sup.133 and thus would benefit patient symptom-limited
performance.
Thiamine
[0055] Thiamine or vitamin B.sub.1 status may be compromised in
heart failure due to a variety of causes. Thiamine is a
water-soluble vitamin which functions as a coenzyme in a variety of
enzyme systems especially those related to energy metabolism.
Thiamine is stored in very small quantities (approximately 30 mg)
with approximately half of the body stores being found in skeletal
muscle with the remainder being found in the heart, kidney and
nervous tissue including the brain. Since little is stored,
thiamine requirements must be met daily. Thiamine requirements are
related to daily energy expenditure.sup.134 and metabolizable
energy intake, especially carbohydrate intake and therefore
patients with increased metabolic rates or poor intakes, such as
those with heart failure, may be at increased risk for deficiency
during acute illness.sup.134,135. The Food and Nutrition Board, USA
recommends that for adults with energy intakes below 2000 kcal/day
that a basal requirement of 1.0 mg thiamine per day be
maintained.sup.136. The Canadian recommendations support an intake
of 0.4 mg/1000 kcal or no less than 0.8 mg/day for adults.sup.137.
Thiamine intake in patients with heart disease has been examined in
only one study using a semi-quantitative food frequency
questionnaire focusing on foods high in thiamine.sup.138. Nutrient
analysis indicated a low overall intake of thiamine of 0.966 mg/day
with 33% of patients not meeting the Recommended Dietary Allowance
(RDA) for thiamine.sup.65. This study also indicated that
thiamine-deficient diets were more common among patients treated as
out-patients rather than in-patients.
[0056] Necropsy studies indicate that thiamine deficiency is
underdiagnosed in life.sup.135. Classical deficiency signs are
often absent or they are not recognized.sup.139. Thiamine
deficiency results in beri beri, which can have neurological or
cardiac effects. The symptoms that are most common are mental
confusion, anorexia, muscle weakness ataxia, edema, muscle wasting,
tachycardia and an enlarged heart.sup.140. Thiamine deficiency
leads to several major derangements of the cardiovascular system
including peripheral dilatation leading to a high output state,
biventricular myocardial failure, retention of sodium and water
leading to edema as well as a relative depression of left
ventricular function with low ejection fraction.sup.140,141. This
picture will be masked in preexisting low-output heart failure.
Since thiamine deficiency will exacerbate co-existing heart
failure, correction of this deficiency through supplementation has
the potential to improve cardiac status in patients with congestive
heart failure.
[0057] In addition to poor dietary intake and increased metabolic
utilization, referred to above, patients with heart failure also
may be at risk for thiamine deficiency because of their need for
diuretics. There is evidence from both animal and human studies
that diuretics, especially those which affect the Loop of Henle
such as furosemide, cause increased urinary losses of thiamine even
in the presence of thiamine deficiency.sup.142,143. It appears that
furosemide treatment may block the kidneys' ability to adapt
thiamine excretion in order to prevent thiamine deficiency. These
data demonstrate that patients with heart failure are at increased
risk of thiamine deficiency due to a combination of 1) poor intake
resulting from anorexia and unpalatable diets, 2) hypermetabolism,
and 3) enhanced excretion caused by the concurrent use of
diuretics.
[0058] There have been a handful of studies which support a high
prevalence of thiamine deficiency in both in- and outpatients with
congestive heart failure--from 13% to 91% depending on the
population studied.sup.138,143,144,145. A very high (91%)
prevalence of thiamine deficiency has been reported in a group of
congestive heart patients on long-term furosemide
treatments.sup.143. The average dose of furosemide ranged from
80-240 mg/day. Biochemically, the furosemide-treated group had
severe thiamine deficiency indicating that doses of this magnitude
have significant effects on thiamine status. These investigators
undertook a randomized double-blind trial of thiamine
supplementation in 30 in-patients with heart failure and on
long-term furosemide therapy.sup.146. Patients were randomized to
receive 200 mg intravenous thiamine or a placebo for seven days
after which all subjects were placed on an oral supplement of 200
mg/day of thiamine and followed for an additional six weeks. They
saw a significant diuresis with increased excretion of sodium and
water within two days of thiamine supplementation in comparison
with the placebo group whose excretion remained constant. The mean
left ventricular ejection fraction increased significantly after
one week of thiamine supplementation but not with the placebo.
After six weeks of oral thiamine supplementation left ventricular
ejection fraction was increased by 22%. This study demonstrates a
significant improvement in left ventricular function as a result of
thiamine supplementation in patients with CHF. In addition,
improvement in left ventricular function was accompanied by
diuresis and increased sodium excretion, which is hypothesized to
be one of the major effects of thiamine supplementation.
[0059] Finally, it should also be noted that thiamine deficiency is
also commonly present in patients on hemodialysis.sup.147, in
patients in intensive care units.sup.148 and perhaps cognitive
impairment in the aged.sup.149.
REDUCING OXIDATIVE STRESS
[0060] Cells are constantly subjected to interplay between free
radical injury and protective mechanisms to prevent or minimize
free radical injury. Oxidative stress has been defined as a
disturbance in the equilibrium between pro- and anti-oxidative
systems. A number of different challenges increase oxidative stress
resulting in damage to lipids, proteins, DNA and carbohydrates.
[0061] Dietary Antioxidants--Vitamin E, Vitamin C, Cysteine and
Selenium--counteract the effect of free radicals generated by
external factors and by mitochondrial dysfunction. Cysteine is the
precursor of glutathione, one of the most potent antioxidants
present in the cell.
Role of Oxidative Stress in Cardiac Disease
[0062] Until recently there has been a reluctance to accept that
oxidative stress can be important in the pathogenesis of cardiac
disease however, recent investigation suggests that oxidative
stress may be a very important contributor to the deterioration of
the hypertrophied or failing myocardium.
[0063] For example, reactive oxygen species have been shown to be
critical components of the apoptosis pathway.sup.150; myocyte loss
by apoptosis is now thought to be a significant contributor to the
inexorable deterioration of the failing myocardium.sup.151. The
importance of oxidative stress in heart failure is not surprising
because a number of factors associated with heart failure, such as
increased plasma catecholamines,.sup.152 and cardiac sympathetic
tone.sup.153, microvascular reperfusion injury.sup.154,155 cytokine
stimulation.sup.49,50 and mitochondrial DNA mutations (particularly
complex I).sup.156 are known stimuli for free radical production
and oxidative stress.sup.157,158,159,160. Coenzyme Q10 and taurine
(and its precursor cysteine), discussed above are important
endogenous antioxidants or antioxidant precursors.
[0064] Peroxidative damage has been demonstrated in the hearts of
dogs, guinea pigs and rats with heart failure due to pressure or
volume overload.sup.161,162,163 . Vitamin E administration
benefited.sup.164 both myocardial structure and function. We have
observed decreases in the levels of glutathione peroxidase and
a-tocopherol and a concomitant increase in protein oxidation in the
myocardium of cardiomyopathic hamsters during the late stages of
hamster cardiomyopathy.sup.165; an elevation of myocardial free
radicals and lipid peroxides have also been demonstrated in this
model.sup.166. The administration of vitamin E appears to
completely normalize these findings.sup.163.
[0065] Recently, we have also demonstrated a significant increase
in the plasma level of lipid peroxides and malonyldialdehyde,
markers of oxidative stress, in patients suffering from congestive
heart failure.sup.51. The increase in oxidative stress was related
to the clinical severity of heart failure with the highest levels
of lipid peroxidation and malonyldialdehyde being observed in class
3 and class 4 patients. Increased free radical activity is also
seen in patients on life support or in intensive care unit
settings.sup.167. These observations suggest that antioxidant
supplements should be important additions to the therapy of heart
failure and severely ill patients.
[0066] The ability to withstand peroxidative injury is partially
dependent on diet. A good dietary intake of the antioxidant
vitamins C and E, and trace nutrient minerals such as selenium
together with adequate cysteine as a precursor for glutathionc
synthesis arc important for protection against free radical injury.
Fat intake and composition is also important, the need for vitamin
E may be increased by an increased intake of polyunsaturated fatty
acids.sup.168. It has been suggested that the vitamin E
requirement=5.96+0.25(% PUFA kcal+g PUFAs). With the North American
diet increasing in PUFA, Diplock has suggested that the current RDA
(recommended daily allowances) be increased fourfold.sup.169.
Dietary antioxidants may reduce the risk of ischemic heart disease
and the extent of myocardial infarction.sup.170,171,172. Recent
reports suggest an increased need for vitamin C in patients with
diabetes mellitus.sup.173. Finally oxidative stress is also felt to
be a major contributor to chronic neurodegenerative disease and the
tissue deterioration and immune dysfunction associated with
aging.sup.174,175,176,177,178,179,180,181,182- ,183,184.
[0067] Correction of Mitochondrial Abnormalities
[0068] Other investigators have used certain of these nutrients
alone. We have found that a preferred nutritional supplement would
replace the constituents given above and influence several
metabolic pathways interacting to subserve mitochondrial function.
We have found that replacing only one of the core constituents will
not correct the connected abnormalities in multiple parts of the
myocardial bioenergetic pathway which is deranged in cardiac
failure. Rather, our supplement helps to correct the cascading
series of metabolic abnormalities in patients with myocardial
dysfunction and other diseases mentioned above, rather than merely
a problem at a single point in a pathway.
[0069] In a preferred embodiment, the invention relates to a method
of medical treatment of a disease, disorder or abnormal physical
state in a mammal selected from the group consisting of heart
disease and functional deterioration associated with ageing, the
method comprising administering to a mammal an effective amount of
a carrier and a nutritional supplement comprising L-Carnitine or
its functional analogue, Coenzyme Q10 (Ubiquinone) or its
functional analogue and Taurine or its precursors in a single or
divided daily dose.
[0070] In one variation, the method includes administering to a
mammal an effective amount of a carrier and a nutritional
supplement comprising L-Carnitine, Coenzyme Q10 (Ubiquinone) and
Taurine or its precursors in a single or divided daily dose. The
mammal is preferably one of the group including humans, dogs, cats
and horses. The disease, disorder or abnormal physical state may
include a disease, disorder or abnormal physical state that is due
in whole or in part to aging.
[0071] Another variation of the invention includes a method of
increasing neuromuscular or muscular or athletic performance in a
mammal, the method including administering to the mammal an
effective amount of a carrier and a nutritional supplement
comprising L-Carnitine or its functional analogue, Coenzyme Q10
(Ubiquinone) or its functional analogue and Taurine or its
precursors in a single or divided daily dose. Another aspect of the
method includes administering to the mammal an effective amount of
a carrier and a nutritional supplement comprising L-Carnitine,
Coenzyme Q10 (Ubiquinone) and Taurine or its precursors in a single
or divided daily dose. The mammal is preferably one of the group
including humans, dogs, cats and horses. The method and composition
improves functional performance and muscular performance. In one
embodiment, for an 80 kg man, suitable amounts would include at
least about 2.7 g taurine, at least about 2.7 g L-carnitine and at
least about 135 mg of CoQ10.
BRIEF DESCRIPTION OF THE DRAWINGS
[0072] FIG. 1 is a schematic diagram of the interaction of the
nutrients included in this invention and their interaction in cell
energetics.
[0073] FIG. 2 shows electron micrographs of heart specimens from
hamsters in Experiment 1. (a) control non-treated heart (b)
cocktail treated heart (c) normal hamster heart.
[0074] FIG. 3 shows the mean pressure of contraction of hamster
hearts (Langendorff Model) in Experiment 1. (a) normal hamster
heart (b) control non-treated heart (c) control non treated heart
(d) control non-treated heart and cocktail treated heart (e)
cocktail treated heart (f) cocktail treated heart.
[0075] FIG. 4 shows plasma vitamin E levels as a measure of
compliance.
[0076] FIG. 5 shows that exercise capacity at 12 weeks with the
supplement increased by approximately 30%.
[0077] FIG. 6(a) shows a preferred embodiment of a supplement of
the invention. One packet includes about 125 mL of solution. About
250 mL is the recommended daily dose for a human (preferably for a
male of about 80 kg). Variations of this embodiment may be made.
For example, many of the compounds indicated in brackets on the
chart may be varied, such as to use forms of Vitamin C other than
the specific form indicated in brackets. Masses used in variations
are preferably at least about those masses listed in the chart. As
well, specific changes include using at least about 67.5 mg of
Coenzyme Q10, at least about 1.35 g of L-carnitine, at least about
875 mg of creatine and at least about 1.35 g of taurine per pack.
Each pack includes about 125 mL of solution (carrier). These
amounts are preferably given at 250 mL daily in a single or divided
daily dose. (b) shows a variation of the supplement. Amounts
greater or less than than the masses (including ranges, where
shown) shown in FIGS. 6(a) and (b) may be administered depending on
individual need. In another variation of the supplement of the
invention, carnitine, taurine, and coenzyme Q10 may be administered
alone.
DETAILED DESCRIPTION OF THE INVENTION
[0078] Researchers have not recognized that optimizing
mitochondrial function depends upon the synergistic correction of
cellular and mitochonidrial energy substrates (FIG. 1) which will
lead to improved energetics, reduced oxidative stress and better
calcium homeostasis, a synergistic response clinically beneficial
to the patient.
[0079] The conventional approach has been to try single nutrients.
This has led to conflicting results, at best.
[0080] The combination of nutrients of this invention addresses
what we have found to be an interrelated series of disruptions in
cellular metabolism, that are present in heart failure and
conditions such as aging, chronic neurodegenerative disease, immune
diseases such as AIDS, chronic multisystem disease, chronic lung or
renal disease, chronic fatigue syndrome, patients on
immunosuppressive drugs post-transplantation, cancer patients on
doxorubicin or related drugs, wasting or cachexia from cancer or
sepsis and in normal humans wishing better neuromuscular or
athletic performance, and thus provides more reliable, effective
treatment.
[0081] The combination is preferably delivered orally, but other
methods of administration such as intravenous administration may be
used.
[0082] The invention is a nutritional supplement that helps to
correct or prevent the cascading series of metabolic abnormalities
responsible principally for cardiac disease but will have a similar
effect on neuromuscular, central nervous and immune system
dysfunction in a wide variety of diseases. Rather than merely
addressing problems at particular points in metabolic pathways, the
nutritional supplement of the invention uses a holistic approach to
restoring and improving function at many points in cell metabolism,
for example at multiple points along the mitochondrial bioenergetic
pathway. The effectiveness of this nutritional supplement in
preventing and correcting myocardial dysfunction has been
demonstrated in vivo (Example 1).
[0083] This invention relates to a dietary supplement comprising
effective amounts of L-Carnitine (or its functional analogues such
as Acetyl-Carnitine or Proprionyl-1-Carnitine), Coenzyme Q10
(Ubiquinone or its functional analogues) and Taurine as the minimal
number of core constituents essential for the correction of the
abnormality in mitochondrial energetics in cardiac failure and the
different diseases referred to above. Additional supplementation
with Cysteine, Creatine, Vitamin E (RRR-d-alpha-tocopheryl),
Vitamin C (ascorbic acid), Selenium, and Thiamin in a high protein
nutritional feeding are preferred.
[0084] This invention relates to a dietary supplement taken in a
high protein formulation such as a dairy based drink, a dehydrated
dairy product, soya based drink or dehydrated product, or a
nutritional bar which may contain: L-Carnitine 0.5-5 g or its
functional analogues such as Acetyl- and Proprionyl-1-Carnitine 3
g, Coenzyme Q10 (Ubiquinone) 30-200 mg (preferably at least about
150 mg) or its functional analogues, Taurine 0.1-3 g. Addition of
Cysteine 0.5 gm-1.5 g, Creatine 2.5 g, Vitamin E
(RRR-d-alpha-tocopheryl) 600 IU, Vitamin C (ascorbic acid) 1000 mg,
Selenium 50 meg, Thiamine 25 mg will aid the action of the core
constituents. These doses may vary 25% to 300% for specialized
formulations. Coenzyme Q10 (Ubiquinone) preferably is at least
about 150 mg.
[0085] This formulation ensures a high quality protein to optimize
muscle function so as to allow the above nutrients in combination
to synergistically interact for the benefit of the patient--that is
the effect of all of the ingredients combined will be greater than
the sum of the individual parts as they address a cascading series
of metabolic abnormalities. There is a core of specific nutrients,
which must be combined to be effective, and a larger number for
optimal effectiveness. Conversely omission of the core will detract
from the overall efficacy of this supplement. In addition to
maintaining protein stores, the supplement corrects abnormalities
in: (a) myocardial energetics, (b) intracellular calcium and (c)
oxidative stress.
[0086] This supplement also benefits patients, with or without
heart failure, with other conditions in which cellular nutrition,
mitochondrial energetics and function are impaired or less than
desired and oxidative stress is increased, including but not
exclusively for musculoskeletal, immune and disorders of the
central nervous system especially those related to aging. Such
disorders include neurodegenerative disease, immune diseases,
stroke, AIDS, chronic multisystem disease, respiratory muscle
fatigue such as chronic obstructive lung disease, lung or renal
disease, chronic fatigue syndrome, patients on immunosuppressive
drugs, cancer patients treated with drugs such as doxorubicin,
wasting, cachexia from cancer or sepsis
Effectiveness of Nutrient Cocktail In Vivo
[0087] In vivo data gained from cardiomyopathic hamsters showed the
synergistic effect of the nutritional supplement (Experiment 1). It
also showed the feasibility of providing a cocktail of nutrients to
cardiomyopathic hamsters and that the mixture positively affected
cardiac structure, function and markers of oxidative stress,
deterioration of mitochondrial and myofibrillar structures in
non-treated animals with improved preservation in treated animals.
The results show that there are increased areas of necrosis in
non-treated hearts in comparison with treated hearts. These results
show that this cocktail of nutrients is effective in preserving
myocyte function and structure.
Example 1
[0088] Cardiac Nutrient Cocktail Study
[0089] We performed a pilot study in order to determine the
feasibility of providing a "cocktail" of nutrients as well as their
effect on indices of oxidative stress as well as on myocardial
structure and function.
1 Composition of Cardiac Cocktail L-carnitine 300 mg/kg/day Vitamin
E 147 mg/kg/day Vitamin C 100 mg/kg/day Coenzyme Q.sub.10 15
mg/kg/day Thiamine (B.sub.1) 100 mg/kg Cysteine 12 mg/day Selenium
0.05 mg/day (5 mg/kg diet) Taurine 188 mg/day (18.8 g/L) Creatine
100 mg/day (1% diet)
Method of Delivery
[0090] The nutrients were delivered in 10 ml of raspberry Jell-O.
Water soluble nutrients were added directly to the cooled Jell-O
while lipid soluble components were mixed with 15 ml 20% intralipid
prior to their addition to the cocktail mixture.
Study Design
[0091] 180-day old cardiomyopathic hamsters were started on
supplementation after a two-week acclimation period. 18 animals
received Jell-O supplemented with nutrients while 18 received the
identical Jell-O but without nutrients. The animals received full
supplementation for eight weeks, at this time the animals were 278
days of age. At this time, 6 treated, 6 untreated and 6
non-diseased hamsters underwent the Langendorff procedure modified
for hamsters following which the hearts were preserved for electron
microscopy. The remaining animals were sacrificed and blood,
hearts, livers and muscle were collected for biochemistry.
Results
[0092] a) Mortality--In the treated group, 2 hamsters died. Of the
non-treated group, 4 hamsters died with an additional hamster being
moribund at the time of study.
[0093] b) Appearance--The treated hamsters remained active and
alert with no visible edema. In contrast, two of the non-treated
animals became grossly edematous with exceptionally large black
livers. The control non-treated animals were less active and
appeared less bright.
[0094] c) Biochemistry--The heart and plasma were analysed for
indices of oxidative stress.
2 Control - Non Cocktail Treated Treated Heart Glutathione
Peroxidase Activity 113.05 .+-. 8.20 134.34 .+-. 16.7 Units/min/mg
protein Heart Malondialydehyde ug/g wet 2.00 .+-. 0.25 1.67 .+-.
0.22 weight Plasma Malondialydehyde nmol/ml 0.17 .+-. 0.009 0.14
.+-. 0.04 plasma Plasma Glutathione Peroxidase Activity 5.24 .+-.
0.82 6.03 .+-. 0.51 Units/mm/mg protein Ratio Heart Weight: Body
Weight 0.008 .+-. 0.0007 0.007 .+-. 0.0006
[0095]
3 D. Function Non-Treated Treated Normal Hamster * MeanPressure-
20.84 .+-. 5.97 44.17 .+-. 4.55 92.50 .+-. 11.99 Langendorff mmHg
*See attached tracings (FIGS 3(a)-(f)
[0096] d) Microscopy
[0097] Electron micrographs (FIGS. 2(a)-c)) show deterioration of
mitochondrial and myofibrillar structures in non-treated animals
with markedly improved preservation in treated animals. In
addition, there are increased areas of necrosis in non-treated
hearts in comparison with treated hearts. The results achieved were
superior to those projected from individual studies of the
ingredients.
[0098] e) Recently we have completed another study with the
supplement and confirmed all the above results and in addition have
shown a complete restoration of systolic contractility as measured
by +dP/dT and diastolic relaxation as measured by -dP/dT.
Conclusions
[0099] Nutrients have been used, singly or in random combination to
treat several conditions including heart disease. We by contrast
have found that three defined key components, L-carnitine, coenzyme
Q10 and taurine, interact in a way which potentiates the action of
each on cell function and energetics. Creatine, thiamine and
antioxidants support the action of this core. In addition protein
enrichment also aids the maintenance of mitochondrial energetics.
We have demonstrated the validity of this claim by preventing the
development of heart failure in a genetic animal model normally
subject to the inexorable progression of heart failure culminating
in death. Other studies using nutrients have not shown comparable
benefit.
[0100] In another embodiment of the invention, the nutritional
supplement is adapted in an amount effective for administration to
humans for the purpose of enhancing muscular or athletic
performance.
[0101] A randomized placebo-controlled safety and efficacy study of
a liquid supplement, containing about: 2.7 grains of taurine, 2.7
grams of carnitine, 135 mg coenzyme Q10 plus antioxidant vitamins
(vitamin E--400 IU, Vitamin C--250 mg) and 1.75 grams of creatine
per 250 milliliters was performed in 33 healthy untrained human
volunteers. The supplement was given for 12 weeks at 125 ml twice
daily.
[0102] There were 2 dropouts in the placebo group between weeks 4
and 12. There were no dropouts in the active supplement group.
Exercise capacity, measured as time until exhaustion at 110% of
individual VO2 max, was assessed at baseline and at weeks 4 and 12.
FIG. 4 shows plasma vitamin E levels as a measure of compliance.
FIG. 5 shows the results where exercise capacity at 12 weeks with
the supplement increased remarkably by about 30%.
[0103] The nutritional supplement of may be adapted (appropriate to
body mass and metabolic rate) to be administered to humans and
other mammals, such as dogs, cats and horses, in amounts effective
for correcting diseases, conditions and infirmities described in
this application, including those due to aging. They may also be
adapted (appropriate to body mass and metabolic rate) to be
administered to humans and other mammals to enhance muscular
performance. Mammals tend to have a high and variable metabolic
rate. Their requirements per gram of tissue differs from humans. By
way of example, a rat has about four times the metabolic rate of a
human. The amounts to be administered will also vary with the age
of the mammal. The appropriate amount to be administered will be
apparent to one skilled in the art.
[0104] All publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as
if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety. U.S. application Ser. No. 09/002,765,
filed Jan. 6, 1998 ("Composition for Improvement of Cellular
Nutrition and Mitochondrial Energetics"), U.S. application Ser. No.
08/826,234 filed Mar. 27, 1997 and PCT application no.
PCV/CA98/00286 filed Mar. 25, 1998 ("Nutritional Composition for
Improvements in Cell Energetics") are incorporated by reference in
their entirety.
[0105] The present invention has been described in terms of
particular embodiments found or proposed by the present inventors
to comprise preferred modes for the practice of the invention. It
will be appreciated by those of skill in the art that, in light of
the present disclosure, numerous modifications and changes can be
made in the particular embodiments exemplified without departing
from the intended scope of the invention. All such modifications
are intended to be included within the scope of the appended
claims.
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