U.S. patent application number 10/838128 was filed with the patent office on 2005-11-03 for pharmaceutical compositions for metabolic insufficiencies.
Invention is credited to Blass, John P..
Application Number | 20050245612 10/838128 |
Document ID | / |
Family ID | 35187939 |
Filed Date | 2005-11-03 |
United States Patent
Application |
20050245612 |
Kind Code |
A1 |
Blass, John P. |
November 3, 2005 |
Pharmaceutical compositions for metabolic insufficiencies
Abstract
Disclosed in certain embodiments is a pharmaceutical composition
comprising a sugar; a Krebs cycle intermediate, precursor of a
Krebs cycle intermediate, salt thereof, or combination thereof; and
a component selected from the group consisting of an unsaturated
lipid, phenylethylamine, a soluble calcium compound, or a
combination thereof.
Inventors: |
Blass, John P.; (Bronxville,
NY) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
14th Floor
485 Seventh Avenue
New York
NY
10018
US
|
Family ID: |
35187939 |
Appl. No.: |
10/838128 |
Filed: |
May 3, 2004 |
Current U.S.
Class: |
514/560 ;
514/649 |
Current CPC
Class: |
A23G 1/36 20130101; A61K
35/02 20130101; A61K 33/06 20130101; A61K 31/05 20130101; A23G 1/42
20130101; A61K 31/7004 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/137 20130101; A61K 36/87 20130101;
A23G 1/32 20130101; A23L 2/02 20130101; A61K 35/02 20130101; A23L
33/10 20160801; A61K 31/137 20130101; A23L 2/52 20130101; A61K
36/82 20130101; A61K 33/06 20130101; A61K 31/7004 20130101; A61K
31/05 20130101 |
Class at
Publication: |
514/560 ;
514/649 |
International
Class: |
A61K 031/202; A61K
031/137 |
Claims
1. A pharmaceutical composition comprising: a sugar; a Krebs cycle
intermediate, precursor of a Krebs cycle intermediate, salt
thereof, or combination thereof; and a component selected from the
group consisting of an unsaturated lipid, phenylethylamine, a
soluble calcium compound, a combination thereof, or a combination
thereof.
2. The pharmaceutical composition of claim 1, wherein the component
is an unsaturated fatty acid.
3. The pharmaceutical composition of claim 1, wherein the component
is phenylethylamine.
4. The pharmaceutical composition of claim 1, wherein the component
is a soluble calcium compound.
5. The pharmaceutical composition of claim 1, wherein the component
is a combination of an unsaturated fatty acid and
phenylethylamine.
6. The pharmaceutical composition of claim 1, wherein the component
is a combination of an unsaturated fatty acid and a soluble calcium
compound.
7. The pharmaceutical composition of claim 1, wherein the component
is a combination of a phenylethylamine and a soluble calcium
compound.
8. The pharmaceutical composition of claim 1, wherein the
unsaturated lipid is selected from the group consisting of
unsaturated monoglycerides, unsaturated diglycerides, unsaturated
triglycerides, unsaturated fatty acids, unsaturated fatty alcohols,
unsaturated phosphatides, unsaturated sterols, unsaturated
fat-soluble vitamins, unsaturated terpenes, and mixtures
thereof.
9. The pharmaceutical composition of claim 1, wherein the
unsaturated lipid is selected from the group consisting of high
oleic sunflower oil, sunflower oil, rapeseed oil, soybean oil,
peanut oil, canola oil, cottonseed oil, coconut oil, palm oil, palm
kernel oil, corn oil, flax seed oil, olive oil, safflower oil, fish
oil, and mixtures thereof.
10. The pharmaceutical composition of claim 1, wherein the
unsaturated lipid is selected from the group consisting of flax
seed oil, fish oil, and mixtures thereof.
11. The pharmaceutical composition of claim 1, wherein the
phenylethylamine is phenylethyl-2-amine.
12. The pharmaceutical composition of claim 1, wherein the soluble
calcium compound is selected from the group consisting of calcium
lactate, calcium sulfate, calcium citrate, calcium malate, calcium
gluconate and combinations thereof.
13. The pharmaceutical composition of claim 1, wherein the soluble
calcium compound is calcium malate.
14. The pharmaceutical composition of to claim 1, wherein the Krebs
cycle intermediate is selected from a group consisting of citric
acid, aconitic acid, isocitric acid, a-ketoglutaric, succinic acid,
fumaric acid, malic acid, oxaloacetic acid, and combinations
thereof.
15. The pharmaceutical composition of claim 1, wherein the
precursor is selected from a group consisting of
2-keto-4-hydroxypropanol, 2,4-dihydroxybutanol,
2-keto-4-hydroxybutanol, 2,4-dihydroxybutyric acid,
2-keto-4-hydroxybutyric acid, aspartate, mono-alkyl esters of
oxaloacetate, di-alkyl esters of oxaloacetate, and mixtures
thereof.
16. The pharmaceutical composition of claim 1, wherein the sugar is
selected from the group consisting of a monosaccharide,
disaccharide, polysaccharide, and mixtures thereof.
17. The pharmaceutical composition of claim 16, wherein the
monosaccharide is selected from a group consisting of glucose,
fructose, mannose, galactose, and mixtures thereof.
18. The pharmaceutical composition of claim 16, wherein the
disaccharide is selected from a group consisting of sucrose,
maltose, lactose, and mixtures thereof.
19. The pharmaceutical composition of claim 16, wherein the
polysaccharide is a starch.
20. The pharmaceutical composition of claim 1, further comprising a
mitochondrial function enhancing compound.
21. The pharmaceutical composition of claim 20, wherein the
mitochondrial function enhancing compound is selected from the
group consisting of a vitamin, a mineral, an antioxidant, a
metabolism-enhancing compound, and mixtures thereof.
22. The pharmaceutical composition of claim 21, wherein the
metabolism-enhancing compound is selected from the group consisting
of creatine, L-carnitine, L-carnitine derivatives, and mixtures
thereof.
23. The pharmaceutical composition of to claim 21, wherein the
vitamin is selected from the group consisting of thiamin,
riboflavin, niacin, pyridoxine derivatives, pantothenic acid, and
mixtures thereof.
24. The pharmaceutical composition of claim 21, wherein the mineral
is selected from the group consisting of calcium, magnesium,
sodium, potassium, zinc, and mixtures thereof.
25. The pharmaceutical composition of claim 21, wherein the
antioxidant is selected from the group consisting of ascorbic acid,
alpha-tocopherol, resveritrol, quercetin, and mixtures thereof.
26. The pharmaceutical composition of claim 1, further comprising
at least one pharmaceutically acceptable excipient.
27. The pharmaceutical composition of claim 1, in the form of an
oral solid dosage form, a parenteral product, an intramucosal
product or a suppository.
28. The pharmaceutical composition of claim 1, in the form of an
edible solid or liquid.
29. The pharmaceutical composition of claim 1, wherein the edible
solid is in the form of a confectionary product.
30. The pharmaceutical composition of claim 1, wherein the edible
liquid comprises a fruit juice.
31. A method of treating a disease associated with impaired
mitochondrial function comprising administering a pharmaceutical
composition of any of claims 1-30 to a patient in need thereof.
32. The method of claim 31, wherein the disease is a nervous system
disorder, a cardiovascular disorder or a musculoskeletal
disorder.
33. The method of claim 32, wherein the nervous system disorder is
Alzheimer's Disease, Huntington's Disease, Parkinson's Disease,
spinocerebellar ataxia, or a psychosis.
34. The method of claim 32, wherein the cardiovascular disorder is
selected from the group consisting of atherosclerotic
cardiovascular disease, cardiomyopathies, cardiac valvular
disorders, and disorders causing cardiac failure.
35. The method according to claim 31, wherein said administering is
oral, rectal, parenteral, or by application to mucous
membranes.
36. A method of improving cerebral function comprising
administering a pharmaceutical composition of claim 1 to a patient
in need thereof.
37. The method of claim 30, wherein the pharmaceutical composition
is in the form of an edible solid or liquid.
38. The method of claim 30, wherein the edible solid is in the form
of a confectionary product.
39. The method of claim 30, wherein the edible liquid comprises a
fruit juice.
40. The method of claim 30, wherein the pharmaceutical formulation
is in the form of chewable or edible bars, confectionary products,
cookies, baked or simulated baked goods, biscuits, lozenges, juice
drinks or chewing gum.
41. A chocolate food product comprising cocoa, edible filler and
added 2-phenylethylamine, wherein the ratio of the amount of
2-phenylethylamine in the product as compared to the
2-phenylethylamine provided by the cocoa and edible filler is at
least 2:1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions
for individuals suffering from metabolic insufficiencies, e.g.,
cerebral and cardiac insufficiencies, and methods of treatment
thereof.
BACKGROUND OF THE INVENTION
[0002] During normal operation of the catabolic process, energy is
harvested and subsequently stored in a readily available form,
namely, the phosphate bonds of adenosine triphosphate ("ATP"). When
energy is required for anabolic processes, a phosphate bond of ATP
is broken to yield energy for driving anabolic reactions and
adenosine diphosphate ("ADP") is regenerated. The process of
catabolism involves the breakdown of proteins, polysaccharides, and
lipids. Proteins are broken into smaller peptides and constituent
amino acids, polysaccharides and disaccharides are broken down into
their monosaccharide constituents, and lipids are broken down into
glycerol and the fatty acid constituents. These compounds are
further broken down into even smaller compounds, principally,
two-carbon acetyl groups.
[0003] The two-carbon acetyl group, an essential component in the
catabolic process, is introduced into the Krebs tricarboxylic acid
cycle ("Krebs cycle") via acetyl coenzyme A. The acetyl group
serves as a carbon source for the final stages of catabolism. The
Krebs cycle and an accompanying electron transport system involve a
series of enzymatically controlled reactions that enable complete
oxidation of the two-carbon acetyl group to form carbon dioxide and
water. As shown in FIG. 1, acetyl groups are introduced into the
Krebs cycle by bonding to oxaloacetic acid to form citric acid.
During subsequent steps of the Krebs cycle, citric acid is
converted into aconitic acid and then into isocitric acid. As
isocitric acid is converted into ketoglutaric acid, one carbon atom
is completely oxidized to carbon dioxide. As ketoglutaric acid is
converted into succinic acid, a second carbon atom is completely
oxidized to carbon dioxide. During the remaining steps, succinic
acid is converted into fumaric acid, fumaric acid is converted into
malic acid, and malic acid is converted into oxaloacetic acid. Each
complete turn of the Krebs cycle harvests the energy of the acetyl
group to yield one molecule of ATP, three molecules of nicotinamide
adenine dinucleotide ("NADH"), and one molecule of flavin adenine
dinucleotide FADH.sub.2. The NADH and FADH.sub.2 are subsequently
used as electron donors in the electron transport system to yield
additional molecules of ATP.
[0004] The Krebs cycle and the accompanying electron transport
system occur in the mitochondria, which are present in different
types of cells in varying numbers depending upon the cellular
energy requirements. For example, neuronal and cardiac muscle cells
have high numbers of mitochondria because they have extremely high
energy requirements. Because of their high energy requirements,
these types of cells are particularly vulnerable to disorders or
conditions associated with a breakdown of the catabolic pathways or
otherwise defective intracellular energy metabolism. Exemplary
disorders or conditions include Alzheimer's Disease, Parkinson's
Disease, Huntington's Disease and other neurodegenerative disorders
(Beal et al., "Do Defects in Mitochondrial Energy Metabolism
Underlie the Pathology of Neurodegenerative Diseases?," Trends
Neurosci. 16(4):125-131 (1993); Jenkins et al., "Evidence for
Impairment of Energy Metabolism in vivo in Huntington's Disease
Using Localized .sup.1H NMR Spectroscopy," Neurol. 43:2689-2695
(1993)).
[0005] Alzheimer's Disease is one of the most common causes of
disabling dementia in humans. Because Alzheimer's Disease is a
progressive, degenerative illness, it affects not only the
patients, but also their families and caregivers. In early stages
of Alzheimer's Disease, activities of daily living are only
minimally affected by cognitive or functional impairment, which may
often be a first clinical sign of the disease (Small et al.,
"Diagnosis and Treatment of Alzheimer Disease and Related
Disorders," Consensus Statement of the American Association for
Geriatric Psychiatry, the Alzheimer's Association, and the American
Geriatrics Society, JAMA 278:1363-1371 (1997)). As Alzheimer's
Disease progresses, the patients' ability to perform activities of
daily living diminishes and the patients become increasingly more
dependent upon caregivers and other family members (see Galasko et
al., "An Inventory to Assess Activities of Daily Living for
Clinical Trials in Alzheimer's Disease," Alzheimer Dis. Assoc.
Disord. 11 (Suppl. 2):S33-S39 (1997)).
[0006] Parkinson's Disease is widely considered to be the result of
degradation of the pre-synaptic dopaminergic neurons in the brain,
with a subsequent decrease in the amount of the neurotransmitter
dopamine that is being released. Inadequate dopamine release,
therefore, leads to the onset of voluntary muscle control
disturbances symptomatic of Parkinson's Disease. The motor
dysfunction symptoms of Parkinson's Disease have been treated in
the past using dopamine receptor agonists (including L-Dopa),
monoamine oxidase binding inhibitors, tricyclic antidepressants,
anticholinergics, and histamine H1-antagonists. Some investigators
state that MAO inhibitors treat the primary disease process. The
disease continues to progress and, frequently after a certain
length of time, dopamine replacement treatment will lose its
effectiveness. In addition to motor dysfunction, however,
Parkinson's Disease is also characterized by neuropsychiatric
disorders or symptoms. These include apathy-amotivation,
depression, and dementia. Parkinson's Disease patients with
dementia have been reported to respond less well to standard L-dopa
therapy. Moreover, these treatments have little or no benefit with
respect to the neuropsychiatric symptoms.
[0007] Huntington's Disease is a familial neurodegenerative
disorder that afflicts about 1 in 10,000 individuals (Martin et
al., "Huntington's Disease: Pathogenesis and Management," N. Engl.
J. Med. 315:1267-1276 (1986); Gusella, "Huntington's Disease," Adv.
Hum. Genet. 20:125-151 (1991)). Huntington's Disease is inherited
in an autosomal dominant manner and is characterized by choreiform
movements, dementia, and cognitive decline. The disorder usually
has a mid-life onset, between the ages of 30 to 50 years, but may
in some cases begin very early or much later in life. The symptoms
are progressive and death typically ensues 10 to 20 years after
onset, most often as the result of secondary complications of the
movement disorder. The major site of pathology in Huntington's
Disease is the striatum, where up to 90% of the neurons may be
depleted. The impaired cognitive functions and eventual dementia
may be due either to the loss of cortical neurons or to the
disruption of normal activity in the cognitive portions of the
basal ganglia. The characteristic chorea is believed to be caused
by the neuronal loss in the striatum, although a reduction in
subthalamic nucleus activity may also contribute.
[0008] Glutamate-induced neuronal cell death is believed to
contribute to Huntington's Disease. Glutamate is the principal
excitatory transmitter in the brain. It excites virtually all
central neurons and is present in the nerve terminals in extremely
high concentrations (over 10.sup.-3 M). Glutamate receptors are
divided into four types (named after their model agonists): kainate
receptors, N-methyl-D-aspartate ("NMDA") receptors,
.alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionate ("AMPA")
receptors, and metabolotrophic receptors. Many normal synaptic
transmission events involve glutamate release. However, glutamate
can also induce neurotoxicity and neuronal death at high levels
(Choi, "Glutamate Neurotoxicity and Diseases of the Nervous
System," Neuron, 1:623-634 (1988)). The mechanism of cell death
occurs primarily by the persistent action of glutamate on the NMDA
receptors. These toxic changes produced by glutamate, called
glutamate excitotoxicity, are believed to be a major cause of cell
damage and death after acute brain injury such as stroke or
excessive convulsions. It has been suggested that excitotoxicity
may be involved in brain ischemia, Alzheimer's Disease and
Huntington's Disease (Greenamyre et al., "Alterations in
L-glutamate Binding in Alzheimer's and Huntington's Diseases,"
Science, 227:1496-1499 (1985); Choi, "Glutamate Neurotoxicity and
Diseases of the Nervous System," Neuron, 1:623-634 (1988)).
[0009] The administration of agents that improve energy metabolism,
and possibly prevent cell death, has been suggested for the
treatment of disorders characterized by energy-deficient cells
(Beal et al., "Do Defects in Mitochondrial Energy Metabolism
Underlie the Pathology of Neurodegenerative Diseases?," Trends
Neurosci. 16(4):125-131 (1993)). One approach to augmenting the
energy level of energy-deficient cells (i.e., as a result of
hypoxia or hypoglycemia) involves the administration of pyruvate,
which is later converted to acetate during normal metabolism.
According to U.S. Pat. No. 5,395,822 to Izumi et al. ("Izumi"), the
administration of pyruvate to a patient before or after an ischemic
event (i.e., which produces a state of hypoxia or hypoglycemia) is
sufficient to prevent neuronal degradation that normally is
associated with the ischemic event. Izumi also identified the
administration of glucose prior to an ischemic event as
undesirable, because its administration resulted in lactic acid
accumulation, which is a factor contributing to brain damage.
[0010] An approach for the treatment of Alzheimer's Disease
includes the administration of NADH or nicotinamide adenine
dinucleotide phosphate ("NADPH"), or the salts thereof. The
administration of NADH or NADPH is described in U.S. Pat. No.
5,444,053 to Birkmayer, which discloses the use of salts formed
with various acids including, among others, malic acid, succinic
acid, and acetic acid. Similar approaches to treating Parkinson's
Disease using NADH and NADPH are described in U.S. Pat. Nos.
5,019,561 and 4,970,200, both to Birkmayer.
[0011] U.S. Pat. No. 6,537,969 by the present inventor is directed
toward overcoming these above-noted deficiencies in treating
conditions associated with a breakdown of the catabolic pathways or
otherwise defective intracellular energy metabolism.
[0012] Another metabolic problem is obesity. Obesity has reached
epidemic proportions in the United States (Hill J O, Wyatt H r,
Reed G W, Peters J C, Obesity and the environment: where do we go
from here? Science 2003; 301:598; Bray G A, Evaluation of obesity:
Who are the obese?. Postgrad Med 2003; 114:19-27; Wyatt H R, The
prevalence of obesity, Prim Care 2003; 30: 267-279) and in the rest
of the world (Zimmerman-Belsing T, Feldt-Rasmussen U, Obesity: the
new worldwide epidemic threat to general health and our complete
lack of effective treatment, Endocrinology 2004; 145:1501-1502).
The best available data indicate that, in 2004, over 60% of the
total U.S. population is overweight or obese. The epidemic of
obesity involves children and adolescents as well as adults and the
elderly. All indications are that obesity is becoming more severe,
not less. Obesity is recognized to be the major nutritional problem
in the U.S. today and may be, or is fast becoming, the most
important current public health problem in this country.
[0013] Studies of the causes of obesity and specifically of feeding
behavior, including hunger and satiety, are extensive. The
mechanisms involved are complex at the levels of brain anatomy,
physiology, pharmacology, endocrinology, biochemistry and molecular
biology. Certain relatively simple generalizations can, however, be
validly made. Obesity is the result of ingesting more energy in the
form of calories in food than is expended in the normal activities
of the body, including exercise. (In other words, the first law of
Thermodynamics holds.) If the amount of food is not limited, people
eat until they are satisfied. The relationship among amount and
type of food ingested, nutritional needs defined in terms of
physiology, and satisfaction with eating (satiation) is very
complex. It involves emotional as well as "rational" factors. For
instance, change in the amount of food ingested can be a sign of
depression or mania or other disorders affecting mood/affect. At a
milder level, "binge eating" is a well-known response to emotional,
professional and other stresses.
[0014] Amphetamine is a "weight loss" medication that has been
useful in controlling excessive appetite and the resulting obesity,
but that is not now used for this purpose because of its side
effects (Makris A P, Rush C R, Frederich R C, Kelly T H,
Wake-promoting agents with different mechanisms of action:
comparison of effects of madafinil and amphetamine on food intake
and cardiovascular activity, Appetite 2004; 42: 185-195; Kuo D Y,
Further evidence for the mediation of both subtypes of dopamine
D1/D2 receptors and cerebral neuropeptide Y (NPY) in
amphetamine-induced appetite suppression, Behav Brain Res 2003;
147: 149-155). It can cause dangerous changes in the heart
including cardiac death, and it can easily over-stimulate the
brain. Chronic amphetamine use can cause a syndrome that resembles
schizophrenia. Therefore, there is a need for an alternative
approach that utilizes the effects of amphetamine in combating
overweight/obesity without incurring the unacceptable side effects
of amphetamine itself
[0015] 2-Phenylethylamine (.beta.-phenylethylamine) is a normal
constituent of the diet that has "amphetamine-like" affects, but is
much less potent than amphetamine itself and is not dangerous (Kato
M, Ishida K, Chuma T, Abe K, Shigenaga T, Taguchi K, Miyatake T,
.beta.-Phenylethylamine modulates acetylcholine release in the rat
striatum: involvement of a dopamine D(2) receptor mechanism, Eur J
Pharmacol 2001; 418: 65-71; Gianutsos G, Chute S, Pharmacological
changes induced by repeated exposure to phenylethylamine,
Pharmnacol Biochem Behav 1986; 25: 129-134; Kuroki T, Tsutsumi T,
Hirano M, Matsumoto T, Tatebayashi Y, Nishiyama K, Uchimura H,
Shiraishi A, Nakahara T, Nakamura K, Behavioral sensitization to
.beta.-phenylethylamine (PEA): enduring modifications of specific
dopaminergic neuron systems in the rat, Psychopharmacology 1990;
102: 5-10; Barroso N, Rodriguez M, Action of
.beta.-phenylethylamine and related amines on nigrostriatal
dopamine neurotransmission, Eur J Pharmacol 1996; 297: 195-203).
2-Phenylethylamine ("2PE") is a normal constituent of chocolate and
of many cheeses, among other foodstuffs. 2PE is present in
chocolate itself at about 60 .mu.g/gm chocolate or more, and
significantly higher in unprocessed cocoa and a number of cheeses
(Baker G B, Wong J T, Coutts R T, Pasutto F. Simultaneous
extraction and quantitation of several bioactive amines in cheese
and chocolate, J Chromatogr 1987; 392: 317-31). A "chocolate binge"
could lead to the ingestion of about 3 mg of 2PE. Experimental
animals have ingested amounts of 2PE over 10,000 times higher than
this for months (Kuroki T, Tsutsumi T, Hirano M, Matsumoto T,
Tatebayashi Y, Nishiyama K, Uchimura H, Shiraishi A, Nakahara T,
Nakamura K, Behavioral sensitization to .beta.-phenylethylamine
(PEA): enduring modifications of specific dopaminergic neuron
systems in the rat, Psychopharmacology 1990; 102: 5-10). 2PE
stimulates, albeit more weakly, the same dopamine (D1 and D2)
receptors that amphetamine stimulates. Some of the medicinal
effects of chocolate and other preparations of the cocoa bean have
been attributed to 2PE, notably the satisfying and calming aspects.
2PE appears to have a mild anti-depressant affect (Paetsch P R,
Greenshaw A J, 2-Phenylethylamine-induced changes in catecholamine
receptor density: implications for antidepressant drug action,
Neurochem Res 1993; 18: 1015-1022). 2PE levels are not consistently
altered in patients with psychosis (Szymanski H V, Naylor E W,
Karoum F, Plasma phenylethylamine and phenylalanine in chronic
schizophrenic patients, Biol Pyschiat 1987; 22: 194-198).
[0016] One of the major problems in treating obesity is the
tendency for people to regain the weight they have lost. Animal
studies indicate that this effect is due at least in part to
inadequate stimulation of dopamine receptors in the brain after
weight loss. Pothos et al. concluded that "Low extracellular DA
[dopamine] may also underlie the increase in food and drug intake
typically observed in underweight animals and humans when they
attempt to restore extracellular DA levels by natural or artificial
means." (Pothos E N, Creese I, Hoebel B G, Restricted eating with
weight loss selectively decreases extracellular dopamine in the
nucleus accumbens and alters dopamine response to amphetamine,
morphine, and food intake, J Neurosci 1995; 15: 5540-6650.) These
observations are in accord with extensive data on humans who regain
weight after weight loss, even though available techniques do not
allow direct measurement of these parameters in the brains of
living humans. The drive to eat too much reflects the chemistry of
the brain, not the nutritional needs of the whole body. The
alteration in brain chemistry drives the harmful excess intake of
calories. The obvious treatment is to feed a material that restores
the physiological action in the brain that was diminished by weight
loss, and does so without inducing unacceptable side effects. The
action of the low extracellular DA can presumably be restored by
feeding either precursors of dopamine (notably L-DOPA) or mimics of
dopamine actions such as amphetamine. Though L-DOPA has been used
(usually with carbidopa) to treat Parkinson's Disease, it has well
known and severe side effects that limit its use even for that
disease. The unacceptable side effects of amphetamine as a weight
loss medication have been discussed above. Ingestion of 2PE in low
mg amounts allows the mimicking of the action of extracellular DA
without significant side effects.
[0017] Chocolate is now accepted to have additional beneficial
health effects due to its contents of antioxidants. (The sweet
science: dark chocolate may be good for you, Harv Health Lett.
2004; 29:7; Lee K W, Kim Y J, Lee H J, Lee C Y, Cocoa has more
phenolic phytochemicals and a higher antioxidant capacity than teas
and red wine, J Agric Food Chem. 2003; 51: 7292-5.) These health
effects are apart from its effects on mood and satiety, which are
more reasonably attributed to its content of 2PE. Polyphenols are
antioxidants that are found in both chocolate and red wine and have
beneficial effects (Lee K W, Kim Y J, Lee H J, Lee C Y, Cocoa has
more phenolic phytochemicals and a higher antioxidant capacity than
teas and red wine, J Agric Food Chem. 2003; 51: 7292-5; Constant J,
Alcohol, ischemic heart disease, and the French paradox, Clin
Cardiol. 1997; 20: 420-4).
[0018] The addition of a Krebs tricarboxylic acid cycle substrate
(such as malate) and of a source of substrate (pyruvate derived
from glucose) can be expected to enhance the antioxidant activity
of the antioxidant compounds found in chocolate, since the
combination of glucose and a Krebs cycle substrate can be expected
to enhance the ability of the brain cells to generate the reducing
equivalents needed to carry out antioxidant activities.
Calculations of free radical production in normal humans indicate
that it is impossible to ingest enough "antioxidant" to
significantly reduce the burden of free radicals produced during
normal human metabolism. The "priming" of the parts of the cells
that produce the reducing equivalents necessary to regenerate
antioxidants is therefore critical. Glucose and malate are
particularly appropriate for producing the desired effect, since
both cross easily into the brain across the "blood-brain barrier."
Use of glucose rather than another sugar has the advantage that it
promptly elevates blood glucose and thereby brain glucose,
increasing satisfaction and satiation and providing an "energy
boost."
[0019] In preparing a form of chocolate that contains added 2PE, as
well as glucose, calcium malate, and added antioxidant as disclosed
herein, it is advisable to use a vegetable oil to allow the mixing
together of the ingredients. A particularly healthy form of
vegetable oil is that from flax seed, due to its contents of
.omega.-3 fatty acids (Bloedon L T, Szapary P O, Flaxseed and
cardiovascular risk, Nutr Rev 2004; 62: 18-27; Prasad K, Dietary
flax seed in prevention of hypercholesterolemic atherosclerosis,
Atherosclerosis 1997; 132: 69-76).
[0020] Phenylethylamine (PEA), is also found in some red wines,
promotes energy and elevates mood. A deficiency in PEA renders the
person weak, tired, sluggish and depressed. Taking PEA rapidly
restores well-being. PEA is a natural, physiological treatment of
depression. Approximately 60% of depressed patients have a
reduction in PEA metabolism, and PEA is effective in 60% of
depressed patients. PEA relieves depression rapidly, in a matter of
hours or days, and produces no toxic effects, tolerance or abuse.
PEA controls depression in 60% of depressed persons--the same
percentage as major antidepressants such as Prozac--but is less
toxic. See Sabelli, H. (2002). Phenylethylamine deficit and
replacement in depressive Illness. In D. Mishooulon and J. F.
Rosenbaum. (Eds.), Natural medications for psychiatric disorders.
(pp 83-110), Baltimore: Lippencott Williams and Wilkins; also see
Sabelli, H. (2000). Aminoacid precusors for depression. Psychiatric
Times, 17. 42-49.
[0021] Lipids are concentrated sources of energy as well as
structural components of cell membranes. Everybody needs a certain
amount of dietary fat for normal body functions. When fats are
digested, emulsified and absorbed, they facilitate the intestinal
absorption and transport of fat soluble vitamins A, D, E and K.
They are also used to cushion and protect the heart, kidneys and
liver. In certain climates, subcutaneous body fat helps to insulate
the body from the cold and prevent heat loss through the skin.
These functions can be met by a daily intake of 15 to 25 grams of
fat. Lipids provide the body with maximum energy (9 kcal per gram),
approximately twice that for an equal amount of protein or
carbohydrates.
[0022] Lipids enter the body through the mouth and pass to the
stomach, but are little affected by its acidic environment. They
are absorbed primarily in the small intestines, where they are
emulsified by salts of the bile acids and are hydrolyzed to fatty
acids and glycerol by various water-soluble enzymes (lipases). From
the intestines, the hydrolyzed lipids enter the bloodstream and are
transported to other organs, mainly the liver, for further
metabolism. Ultimately the fatty acids may be degraded to carbon
dioxide and water to furnish energy.
[0023] There are many types of fatty acids, but they can be divided
into three groups--saturated fats, monounsaturated fats and
polyunsaturated fats. Polyunsaturated fats include .omega.-3 and
.omega.-6 fatty acids, among others. Intake of .omega.-3 and
.omega.-6 fatty acids is known to protect against atherosclerosis,
which contributes to metabolic insufficiency in the brain, heart
and other tissue by impairing their blood supply. A major
polyunsaturated fatty acid is arachidonic acid, which is neither
.omega.-3 nor .omega.-6.
[0024] There exists a need in the art for pharmaceutical
compositions that provide the combined benefits of the
pharmaceutical formulations of U.S. Pat. No. 6,537,969 with the
benefits of phenylethylamine, antioxidants and/or unsaturated
lipids (e.g., .omega.-3 and .omega.-6 fatty acids). There exists a
further need in the art to improve palatability of the
pharmaceutical formulations of U.S. Pat. No. 6,537,969.
[0025] All documents referred to herein are incorporated by
reference in their entireties for all purposes.
SUMMARY OF THE INVENTION
[0026] The present invention in certain embodiments is directed to
a pharmaceutical composition which includes a sugar, a Krebs cycle
intermediate or salt thereof, or a precursor of a Krebs cycle
intermediate; and a component selected from the group consisting of
an unsaturated lipid, phenylethylamine, a soluble calcium compound,
or a combination thereof. The present invention in certain
embodiments is directed to chocolate products (e.g., a chocolate
bar or a chocolate drink) fortified with added 2-phenylethylamine
in order to make a small amount of the satisfying product at the
cost of little intake of calories amounts. In certain embodiments,
the ratio of the amount of 2-phenylethylamine present in the
fortified product as compared to the amount in a comparable
non-fortified product can be at least 2:1; at least 10:1; at least
50:1; at least 100:1; at least 500:1; or at least 1000:1.
[0027] The present invention in certain embodiments is also
directed to a method of treating impaired mitochondrial function
while simultaneously providing the additional benefits (e.g.,
improvement in cerebral and/or cardiac function) of unsaturated
lipids and phenylethylamine as discussed herein. The method
includes administering certain pharmaceutical compositions of the
present invention to a subject in need thereof.
[0028] The present invention in certain embodiments is also
directed to a method of treating impaired mitochondrial, cerebral
and/or cardiac function with a pharmaceutical formulation which is
palatable to a patient in need thereof.
[0029] The present invention further relates to a method of
improving cerebral function in an individual having impaired
cerebral metabolism. This method includes administering a
pharmaceutical composition of the present invention to a subject in
need thereof.
[0030] The pharmaceutical compositions of the present invention are
particularly desirable for the prophylaxis or treatment of
disorders associated with impaired mitochondrial function while
simultaneously providing weight loss, increased energy and mood,
and/or a desirable lipid profile. Disorders that can be treated
include conditions or diseases characterized by a decreased level
of oxidative metabolism, such as conditions or diseases of the
nervous system, conditions or diseases of other parts of the body
(e.g., cardiovascular disorders, musculoskeletal disorders, etc.),
and conditions or diseases of the body as a whole. The
pharmaceutical composition is particularly desirable for use in
treating nervous system disorders that are indicated by symptoms of
dementia. Upon administration of the pharmaceutical compositions of
the present invention, it is possible to reduce the severity of
dementia through enhancing cerebral cellular metabolism (i.e.,
improving mitochondrial function in cerebellar tissues). Thus, the
pharmaceutical compositions are particularly useful as a
prophylactic for delaying the onset of dementia or as a treatment
for delaying the progression of dementia associated with various
nervous system disorders. The pharmaceutical compositions are also
useful for ameliorating the clinical manifestations of dementing
illnesses by improving the function of the remaining, but often
metabolically compromised, cells.
[0031] The pharmaceutical compositions of the present invention are
also particularly desirable for treating diseases of the heart or
other organs, where metabolic insufficiency of those organs occurs
due to compromised blood supply or other causes.
[0032] Disease states that can be treated with selected
compositions of the present invention include degenerative diseases
of the nervous system (including but not limited to Alzheimer's
Disease, Parkinson's Disease, Diffuse Lewy body disease) as well as
part of the regimen for the treatment of stroke, ischemic heart
disease, and other forms of vascular disease. Other selected
compositions can treat depression or malignancies.
[0033] The above benefits of the present invention can be provided
in a palatable formulation which provides the benefits of a sugar;
a Krebs cycle intermediate, precursor of a Krebs cycle
intermediate, salt thereof, or combination thereof; as well as
phenylethylamine, antioxidants and/or unsaturated lipids.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 illustrates the Krebs cycle and the relationship
between each of its intermediates. Oxaloacetic acid and an acetyl
group (from acetyl-CoA) combine to form citric acid. In the course
of the cycle, two of the carbon atoms of citric acid are oxidized
completely to carbon dioxide, and oxaloacetic acid is regenerated.
This process generates one molecule of ATP, three molecules of
NADH, and one molecule of FADH.sub.2. Ultimately, the reduced
cofactors NADH and FADH.sub.2 are introduced into an electron
transport mechanism that results in their oxidation, which yields
additional molecules of ATP.
DETAILED DESCRIPTION OF THE INVENTION
[0035] The present invention relates to a pharmaceutical
composition which includes a sugar in combination with a Krebs
cycle intermediate or a precursor of a Krebs cycle intermediate;
and a component selected from the group consisting of an
unsaturated lipid (e.g., .omega.-3 and .omega.-6 fatty acids),
phenylethylamine, a soluble calcium compound, a combination
thereof, or a combination thereof. The composition can also contain
a further ingredient to enhance mitchochondrial function (e.g., an
anti-oxidant).
[0036] Krebs cycle intermediates are the acids or salts of
compounds that are utilized during the Krebs tricarboxylic acid
cycle. Thus, Krebs cycle intermediates include citric acid,
aconitic acid, isocitric acid, .alpha.-ketoglutaric acid, succinic
acid, fumaric acid, malic acid, oxaloacetic acid and mixtures
thereof. Referring to FIG. 1, depending upon which Krebs cycle
intermediate the pharmaceutical composition of the present
invention contains, the pharmaceutical composition will be
predicted ultimately to yield differing amounts of ATP. It is
believed that a number of disorders involving altered oxidative
metabolism include a disruption of the Krebs cycle at or prior to
conversion of .alpha.-ketoglutaric acid to succinic acid. For such
disorders, the pharmaceutical compositions of the present invention
preferably contain a Krebs cycle intermediate such as succinic
acid, fumaric acid, malic acid, oxaloacetic acid or mixtures
thereof.
[0037] Precursors of Krebs cycle intermediates are compounds that,
upon administration to a subject, are converted by the body (i.e.,
in vivo) into a Krebs cycle intermediate. Generally, mono- and
di-alkyl citrates, aconitates, isocitrates, .alpha.-ketoglutarates,
succinates, fumarates, malates and oxaloacetates are desirable
precursors because the ester-bonds are readily broken by the body
to yield the Krebs cycle intermediate. Other ester precursors may
be developed using known technology for enhancing entry of the
precursor molecule into affected cells. For example, U.S. Pat. No.
5,739,117 to Yokoyama, which is hereby incorporated by reference,
discloses a variety of glucose ester derivatives which more
effectively enter brain cells. One preferred class of precursors of
Krebs cycle intermediates are compounds that are converted by the
body into oxaloacetic acid or oxaloacetate. Exemplary precursors in
this class include 2-keto-4-hydroxypropanol, 2,4-dihydroxybutanol,
2-keto-4-hydroxybutanol, 2,4-dihydroxybutyric acid,
2-keto-4-hydroxybutyric acid, aspartates, as well as the previously
identified mono- and di-alkyl oxaloacetates. The amino acid
aspartate is converted into oxaloacetic acid by the transamination
reaction.
[0038] Krebs cycle intermediates or precursors of Krebs cycle
intermediates which are acidic tend to be unpalatable to the
patient, especially when included in a pharmaceutical formulation
that is intended to be chewed or taken as an oral solution. By
virtue of certain embodiments of the present invention, a calcium
compound is included in order to neutralize and mask the unpleasant
taste of the Krebs cycle intermediates or precursor thereof.
[0039] Suitable calcium compounds include, but are not limited to,
soluble calcium salts such as calcium lactate, calcium sulfate,
calcium citrate, calcium malate, calcium gluconate and combinations
thereof.
[0040] The calcium compound is preferably soluble so as not to
provide a chalky texture to the pharmaceutical formulation, which
can be as unpleasant to the patient as an obnoxious taste.
[0041] The presence of calcium is also beneficial to the patient as
it can aid in the prophylaxis of osteoporosis in the patient being
administered the pharmaceutical. Further, the calcium will not have
a deleterious effect on a patient with cardiovascular issues, as
compared to a sodium- or potassium-containing compound.
[0042] Sugars which are suitable for use with the present invention
include monosaccharides, such as glucose, fructose, mannose and
galactose; disaccharides such as sucrose, maltose and lactose; and
polysaccharides (i.e., starches such as amylose) that are digested
by the body to form monosaccharides.
[0043] The unsaturated lipid of the present invention can be
selected from, e.g., the group consisting of unsaturated
monoglycerides, unsaturated diglycerides, unsaturated
triglycerides, unsaturated fatty acids, unsaturated fatty alcohols,
unsaturated phosphatides, unsaturated sterols, unsaturated
fat-soluble vitamins, unsaturated terpenes and mixtures
thereof.
[0044] Particular unsaturated lipids include high oleic acid
content sunflower oil, sunflower oil, rapeseed oil, soybean oil,
peanut oil, canola oil, cottonseed oil, coconut oil, palm oil, palm
kernel oil, corn oil, flax seed oil, olive oil, safflower oil, fish
oil and mixtures thereof.
[0045] Unsaturated fatty acids which include .omega.-3 and/or
.omega.-6 fatty acids, such as fish oils and flax seed oil, are
particularly preferred.
[0046] The phenylethylamine included in the pharmaceutical
formulation of the present invention is preferably
2-phenylethylamine.
[0047] The pharmaceutical composition of the present invention can
also include an adjuvant for enhancing mitochondrial function
(i.e., oxidative metabolism). Suitable adjuvants include vitamins,
minerals, antioxidants and other metabolism-enhancing compounds.
B-complex vitamins are preferred for administration as adjuvants
because of their involvement with metabolism. Exemplary vitamins
that are useful as an adjuvant include thiamin (vitamin B.sub.1),
riboflavin (vitamin B.sub.2), niacin (Vitamin B.sub.3), pyridoxine
derivatives (vitamin B.sub.6) and pantothenic acid. Exemplary
minerals that are useful as an adjuvant include calcium, magnesium,
sodium, potassium and zinc. Exemplary antioxidants include ascorbic
acid, .alpha.-tocopherol, resveratrol, quercetin and other
flavonoids. Exemplary metabolism-enhancing compounds include
L-carnitine and its derivatives, and creatine. Creatine
supplementation is described in U.S. Pat. No. 5,767,159 to Hultman,
which is hereby incorporated by reference. L-carnitine has been
found to ameliorate abnormalities associated with AD in a model
system (Malow et al., "Cultured Cells as a Screen for Novel
Treatments of Alzheimer's Disease," Arch. Neurol. 46:1201-1203
(1989), which is hereby incorporated by reference).
[0048] Preferred antioxidants are those found in catechins and
(-)-epicatechins (such as those that occur in green tea and
chocolate) and curcumin (which occurs in curry spices such as
turmeric).
[0049] The pharmaceutical composition of the present invention can
be administered orally, by anal suppository, parenterally (for
example, subcutaneously, intravenously, intramuscularly,
intraperitoneally or intrathecally), by interstitial infusion, by
intranasal instillation or by application to mucous membranes, such
as those of the nose, throat and bronchial tubes. They may be
administered alone or with suitable pharmaceutically acceptable
vehicles, and can be in solid or liquid form such as tablets,
capsules, powders, solutions, suspensions or emulsions.
[0050] The solid unit dosage forms can be of the conventional type,
such as an ordinary gelatin capsule containing the active
ingredients and a pharmaceutically acceptable vehicle. Suitable
vehicles include lubricants and inert fillers. The above described
sugars can also serve as fillers.
[0051] In another embodiment, these compounds are tableted with
conventional tablet bases (i.e., sugars as described above) in
combination with binders like acacia, gum tragacanth, cornstarch or
gelatin; disintegrating agents such as cornstarch, potato starch or
alginic acid; a lubricant such as stearic acid or magnesium
stearate; and sweetening agents such as the above described sugars,
saccharine or aspartame; and flavoring agents such as peppermint
oil, oil of wintergreen or artificial flavorings.
[0052] The pharmaceutical compositions of the present invention may
also be administered in injectable dosages by solution or
suspension of these materials in a physiologically acceptable
diluent with a pharmaceutical vehicle. Such vehicles include
sterile liquids such as water and oils, with or without the
addition of a surfactant and other pharmaceutically acceptable
adjuvants such as those described above. Illustrative oils are
those of petroleum, animal, vegetable or synthetic origin, for
example, peanut oil, soybean oil or mineral oil. In general, water,
saline, aqueous sugar solutions formed with the above-described
sugars, and glycols such as polypropylene glycol or polyethylene
glycol, are preferred liquid vehicles, particularly for injectable
solutions. In order to maintain sterility and prevent action of
microorganisms, antibacterial and antifungal agents, such as
parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the
like, may be added to the vehicle.
[0053] In certain embodiments, the pharmaceutical formulations are
in the form of edible or drinkable compositions, e.g., foodstuffs
such as chewable or edible bars, confectionary products (e.g.,
chocolate bars), cookies, juice drinks, baked or simulated baked
goods (e.g., brownies), biscuits, lozenges or chewing gum.
Preferred chewable or edible bars include chocolate bars and
brownies. Such embodiments are beneficial as they provide the
benefits as disclosed above and also provide the benefit of
relieving hunger or fatigue. Such formulations can be particularly
useful to people participating in sports or other forms of
exercise.
[0054] In certain embodiments, a sugar (e.g., glucose) can be
utilized to improve flavor and satisfaction. A preferred embodiment
includes calcium malate, resveritrol, and flax seed oil to fortify
the healthy effects of the edible or drinkable product.
[0055] In certain embodiments (e.g., chocolate products), various
flavors can be included in the product such as orange, lemon,
cherry, bourbon, Irish whiskey, brandy and the like.
[0056] In certain embodiments, the invention is directed to a
chocolate food product comprising cocoa, edible filler and added
2-phenylethylamine, wherein the ratio of the amount of
2-phenylethylamine in the product as compared to the
2-phenylethylamine provided by the cocoa and edible filler is at
least 2:1; at least 10:1; at least 50:1; at least 100:1; at least
500:1; or at least 1000:1.
[0057] In certain embodiments, the foodstuff can be in the form of
icing on a food product (e.g., cookie) or a spread between two food
products (e.g., cookies), wherein the beneficial ingredients of the
present invention can be in the icing/spread, the other food
product, or both. Such an embodiment is useful for those who do not
tolerate chocolate.
[0058] The pharmaceutical composition of the present invention is
useful for augmenting cellular metabolism in subjects (e.g.,
patients) who suffer from a disorder characterized by abnormally
decreased levels of oxidative metabolism. It is believed that
administration of the pharmaceutical composition of the present
invention enhances the ability of cells to regulate themselves in a
healthy state, i.e., to maintain homeostasis. It does this, in
part, by enhancing mitochondrial function by augmenting operation
of the Krebs cycle. Administering sugar to a subject provides a
carbon source for producing acetyl groups and administering the
Krebs cycle intermediate or the precursor of a Krebs cycle
intermediate to a subject increases the concentration of the
particular Krebs cycle intermediate at the mitochondrial level. It
is believed that this has a priming effect, because a four carbon
intermediate is needed in order for the two-carbon derivatives of
glucose and other substrates to enter the Krebs cycle.
Specifically, the two-carbon acetyl group must combine with the
four-carbon oxaloacetate to form citrate in order for the Krebs
cycle to continue. Malate is in equilibrium with oxaloacetate, and
other Krebs cycle intermediates are readily converted to malate and
oxaloacetate. The conversion of succinate and fumarate to malate
and oxaloacetate is particularly rapid. Metabolically compromised
cells tend to utilize Krebs cycle intermediates for the direct
generation of energy. More specifically, they utilize the
intermediates to generate electrons that then generate ATP through
electron transport. While utilizing the intermediates provides an
immediate source of energy, doing so compromises the subsequent
activity of the Krebs cycle. Administration of the pharmaceutical
compositions of the present invention is believed, therefore, to
prime the Krebs cycle so that it again operates efficiently.
[0059] Thus, another aspect of the present invention relates to a
method of treating a subject having a disorder involving impaired
mitochondrial function. Generally, the method includes
administering the pharmaceutical composition of the present
invention to a subject under conditions effective to improve
mitochondrial function.
[0060] This method of the present invention is particularly useful
for the treatment or prophylaxis of disorders associated with
impaired mitochondrial function. Disorders that can be treated
according to this method generally include conditions or diseases
characterized by a decreased level of oxidative metabolism. The
disorders may be caused by genetic factors, environmental factors
or both. More specifically, such disorders include conditions or
diseases of the nervous system (e.g., neurodegenerative, psychoses,
etc.), conditions or diseases of other parts of the body, and
conditions or diseases of the body as a whole. Exemplary conditions
or diseases of the nervous system include Alzheimer's Disease,
Parkinson's Disease, Huntington's Disease, spinocerebellar ataxias,
and psychoses (including depression or schizophrenia) associated
with oxidative metabolic abnormalities. Exemplary conditions or
disorders of other parts of the body include cardiovascular
disorders (e.g., atherosclerotic and cardiovascular diseases
including myocardial infarctions, angina, cardiomyopathies, cardiac
valvular disorders, and other conditions or disorders causing
cardiac failure), musculoskeletal disorders in which oxidative
metabolism is abnormal (De Coo et al., A Mitochondrial tRNA(Val)
Gene Mutation (G1642A) in a Patient With Mitochondrial Myopathy,
Lactic Acidosis, and Stroke-like Episodes," Neurol. 50:293-295
(1998), which is hereby incorporated by reference), and other
conditions or disorders of non-neural tissues in which oxidative
metabolism is abnormal, such as frailty, which is a recognized
geriatric syndrome often associated with metabolic alterations
(Fayette et al., Eur. J. Clin. Nutrition 52:45-53 (1998), which is
hereby incorporated by reference).
[0061] Many conditions or diseases of the nervous system (e.g.,
Alzheimer's Disease and those described above) are characterized by
cerebral metabolic insufficiencies, which are manifested as
impaired cerebral function such as dementia. Therefore, another
aspect of the present invention relates to a method of improving
cerebral function in a subject having cerebral metabolic
insufficiencies. Generally, a pharmaceutical composition of the
present invention is administered to a subject having impaired
cerebral metabolism under conditions effective to improve the
cerebral cellular metabolism. By improving cerebral cellular
metabolism, the subject's cerebral function is improved
significantly.
[0062] Treatment for nervous system disorders typically involves
administration of the pharmaceutical composition of the present
invention so that the Krebs cycle intermediate or the precursor of
a Krebs cycle intermediate is introduced into brain tissue. To
exert its desired therapeutic or prophylactic effects, the sugar
and the Krebs cycle intermediate or the precursor of a Krebs cycle
intermediate must be transported into the brain cells, and
subsequently the Krebs cycle intermediate and derivatives of the
sugar (e.g., pyruvate, acetate) must be incorporated into the brain
cell mitochondria (i.e., where they may be incorporated into the
Krebs cycle).
[0063] Depending upon how the pharmaceutical composition of the
present invention is administered (e.g., oral preparation,
intravenous injection, etc.) and the conditions of the patient to
be treated, effective administration may require overcoming the
cerebrovascular endothelium, also called the blood-brain barrier
("BBB"). The BBB is formed by cerebral endothelial cells under the
influence of astroglial cells of the brain (Johansson,
"Experimental Models of Altering the Blood Brain Barrier," Progress
in Brain Research, 91:171-175 (1992); Ermisch, "Peptide Receptors
of the Blood-Brain Barrier and Substrate Transport into the Brain,"
Progress in Brain Research, 91:155-161 (1992), which are hereby
incorporated by reference). The BBB contains a monolayer of tightly
connected microvascular endothelial cells with anionic charges,
which layer separates two fluid-containing compartments: the blood
plasma and extracellular fluid of the brain parenchyma. One of the
main functions of the BBB is to regulate the transfer of components
between blood plasma and extracellular fluid. The BBB limits free
passage of molecules from the blood to the brain cells. This
limited penetration into the CNS is noticeable with large molecules
of high polarity such as protein conjugates, enzymes, etc. (Bobo et
al., "Convection-enhanced Delivery of Macromolecules in the Brain,"
Proc. Natl. Acad. Sci. USA, 91:2076-2080 (1994), which is hereby
incorporated by reference).
[0064] According to one approach, the BBB is circumvented according
to any of a variety of known strategies, for example, intrathecal
injections (Ommaya, "Implantable Devices for Chronic Access and
Drug Delivery to the Central Nervous System," Cancer Drug Delivery,
1(2): 169-179 (1984), which is hereby incorporated by reference),
surgical implants (U.S. Pat. No. 5,222,982 to Ommaya, which is
hereby incorporated by reference), and interstitial infusion (Bobo
et al., "Convection-enhanced Delivery of Macromolecules in the
Brain," Proc. Natl. Acad. Sci. USA, 91:2076-2080 (1994), which is
hereby incorporated by reference). Each of these strategies
involves delivery of the Krebs cycle intermediate or the precursor
of a Krebs cycle intermediate to the central nervous system by
direct administration into the cerebrospinal fluid or into the
brain parenchyma.
[0065] According to another approach, the Krebs cycle intermediate
or the precursor of a Krebs cycle intermediate is linked to a
molecule that enhances crossing of the BBB. Various BBB crossing
enhancers have been identified (e.g., permeabilizer peptides), and
others are continually being identified.
[0066] As described above, the pharmaceutical composition of the
present invention is useful for treating a subject having a nervous
system disorder that involves impaired mitochondrial function.
Several nervous system disorders are known to involve deficiencies
in neurotransmitter systems. For example, Alzheimer's Disease is
associated with degeneration of cholinergic neurons in the basal
forebrain that play a fundamental role in cognitive functions,
including memory (Becker et al., "Mechanisms of Cholinesterase
Inhibition in Senile Dementia of the Alzheimer Type: Clinical,
Pharmacological, and Therapeutic Aspects," Drug Dev. Res. 12:
163-195 (1988)). As a result of such degeneration, patients
suffering from the disease exhibit a marked reduction in
acetylcholine synthesis, choline acetyltransferase activity,
acetylcholinesterase activity and choline uptake. There have been
several approaches employed to treat Alzheimer's Disease. These
generally include the administration of acetylcholinesterase
inhibitors or acetylcholine synthesis, storage or release
modulators. Also, since activation of NMDA glutamate receptors has
also been implicated in the etiologies of Huntington's Disease,
amyotrophic lateral sclerosis, olivopontocerebellar atrophy and
Alzheimer's Disease, use of NMDA glutamate receptor antagonists may
be of clinical benefit for patients having these disorders
(Woodruff et al., "The Interaction Between MK-801 and Receptors for
N-methyl-D-aspartate: Functional Consequences," Neuropharm.
26:903-909 (1987); Greenamyre et al., "N-methyl-D-aspartate
Antagonists in the Treatment of Parkinson's Disease," Arch. Neurol.
48:977-981 (1991); Giuffra et al., "Glutamatergic Therapy of
Huntington's Chorea," Clin. Neuropharm. 15:148-151 (1992), which
are hereby incorporated by reference), as well as for patients
suffering from certain neurodegenerative effects of aging (Ferris,
S. H. "Therapeutic Strategies in Dementia Disorders" Acta Neurol.
Scand. 129(Suppl.):23-26 (1990), which is hereby incorporated by
reference). With respect to agents used in the treatment of PD,
L-dopa and its derivatives are primary therapeutic agents.
[0067] For treatment of certain nervous system disorders,
therefore, the pharmaceutical composition of the present invention
can be administered either alone or in combination with a
therapeutic agent for the treatment of a nervous system disorder.
Suitable therapeutic agents include conventional medications for
treating such nervous system disorders. By way of example, for
treatment of Alzheimer's Disease, the pharmaceutical composition
can be administered in combination with either an
acetylcholinesterase inhibitor, an acetylcholine synthesis, storage
or release modulator, an NDMA glutamate receptor antagonist, or
combinations thereof. A number of suitable acetylcholinesterase
inhibitors, acetylcholine synthesis, storage or release modulators,
and NDMA glutamate receptor antagonists are currently known and
others are continually being discovered and reported.
[0068] As described above, the pharmaceutical composition of the
present invention is useful for treating a subject having a
cardiovascular disorder that involves impaired mitochondrial
function. For treatment of certain cardiovascular disorders,
therefore, the pharmaceutical composition of the present invention
can be administered either alone or in combination with
conventional agents for the treatment of cardiovascular disorders.
By way of example, the pharmaceutical composition of the present
invention can be administered simultaneously with either
blood-thinners, cholesterol lowering agents, anti-platelet agents,
vasodilators, beta-blockers, angiotensin blockers, digitalis and
its derivatives, and combinations thereof. A number of suitable
blood-thinners, cholesterol lowering agents, anti-platelet agents,
vasodilators, beta-blockers, angiotensin blockers and digitalis
derivatives are currently known and others are continually being
discovered and reported.
[0069] As described above, the pharmaceutical composition of the
present invention is useful for treating a subject having a
musculoskeletal disorder that involves impaired mitochondrial
function. For treatment of certain musculoskeletal disorders,
therefore, the pharmaceutical composition of the present invention
can be administered either alone or in combination with
conventional agents for the treatment of musculoskeletal
disorders.
EXAMPLES
[0070] The following Examples are provided to illustrate
embodiments of the present invention but are by no means intended
to limit its scope.
Example 1
Fudge
[0071] Components:
[0072] unsweetened chocolate (30 gms)
[0073] flax seed oil (20 gm, i.e. 2 tablespoons)
[0074] glucose (50 gm)
[0075] calcium malate (13.4 gm)
[0076] green tea powder, from uncooked green tea leaves (4.7 gm; 1
teaspoon)
[0077] resveratrol (20 mg)
[0078] Formulation:
[0079] Melt chocolate and mix with flax seed oil. Stir in glucose,
then calcium malate, then reserveratrol, then green tea powder. The
mixture should be soft when formed. Then chill in the refrigerator
(4.degree. C.) until firm. This preparation retains the firm
consistency of a normal bar of chocolate at room temperature, but
it is routinely stored at refrigerator temperature.
[0080] The fudge of Example 1 can be used as an adjunct (i.e., part
of the regimen) for treatment of degenerative diseases of the
nervous system (including but not limited to Alzheimer's Disease,
Parkinson's Disease, Diffuse Lewy body disease) as well as part of
the regimen for the treatment of stroke, ischemic heart disease,
and other forms of vascular disease. The fudge of Example 1 can
also be used to help prevent the development of these diseases in
individuals at risk for them.
Example 2
Fudge
[0081] This preparation is identical to Example 1, except that 3 mg
of phenylethylamine is added to the flax oil before it is mixed
into the unsweetened chocolate.
[0082] The fudge of Example 2 can be used in the same uses as
Example 1, but in individuals who are apathetic or depressed and do
not develop headaches, excitement or other significant side effects
to the ingestion of phenylethylamine.
Example 3
Fudge
[0083] The fudge of Example 3 is identical to the fudge of Example
1, except that it also contains curcumin. The curcumin (100 .mu.g)
is added immediately before the resveratrol. Alternatively, the
fudge of Example 3 can be prepared in accordance with Example 2,
except for also containing curcumin (100 .mu.g) which can be added
immediately before the reserveratrol.
[0084] The fudge of Example 3 can be used as an adjuvant to
treatment of individuals with malignancies (i.e., cancers), or in
the attempted prevention of the development of recurrent or other
cancers.
Example 4
Juice Drink
[0085] Components:
[0086] unsweetened, organic (e.g., Knudsen brand) grape juice (16
fluid ounces)
[0087] phenylethylamine (1 microliter=1 .mu.l)
[0088] resveratrol (20 mg)
[0089] glucose (50 gm)
[0090] calcium malate (1.4 gm)
[0091] green tea powder, from uncooked green tea leaves (4.7 gm; 1
teaspoon)
[0092] Formulation:
[0093] The other components are added to the grape juice in the
order that are listed. The drink is kept at refrigerator
temperature.
[0094] The drink of Example 4 can be used as an energizing health
drink in adults or elderly, and further includes uses by the
military.
Example 5
Juice Drink
[0095] Components:
[0096] unsweetened, organic (e.g., Knudsen brand) grape juice (16
fluid ounces)
[0097] phenylethyl-2-amine (6 mg)
[0098] resveratrol (20 mg)
[0099] glucose (80 gm)
[0100] calcium malate (0.2 gm)
[0101] Formulation:
[0102] The other components are added to the grape juice in the
order that are listed. The drink is kept at refrigerator
temperature. Suggested amount: 4 ounces at a time.
Example 6
Chocolate
[0103] Components:
[0104] Chocolate, baker, high grade, dark, unsweetened (10 gm)
[0105] 2-Phenylethylamine (3 mg) and
[0106] resveratrol (15 mg), both dissolved in 7.5 ml of organic
flax seen oil
[0107] glucose (20 gm)
[0108] calcium malate (120 gm)
[0109] Suggested amount: 1 preparation after a light salad
lunch.
[0110] It is understood that one skilled in the art can make
obvious variations to the embodiments disclosed herein. These
obvious variations are meant to be encompassed by the appended
claims.
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