U.S. patent application number 09/845741 was filed with the patent office on 2002-01-17 for use of medium chain triglycerides for the treatment and prevention of alzheimer's disease and other diseases resulting from reduced neuronal metabolism.
Invention is credited to Henderson, Samuel T..
Application Number | 20020006959 09/845741 |
Document ID | / |
Family ID | 22743976 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006959 |
Kind Code |
A1 |
Henderson, Samuel T. |
January 17, 2002 |
Use of medium chain triglycerides for the treatment and prevention
of Alzheimer's Disease and other diseases resulting from reduced
Neuronal Metabolism
Abstract
Methods and compositions for treating or preventing, the
occurrence of senile dementia of the Alzheimer's type, or other
conditions arising from reduced neuronal metabolism and leading to
lessened cognitive function are described. In a preferred
embodiment the administration of triglycerides or fatty acids with
chain lengths between 5 and 12, to said patient at a level to
produce an improvement in cognitive ability.
Inventors: |
Henderson, Samuel T.;
(Broomfield, CO) |
Correspondence
Address: |
SWANSON & BRATSCHUN L.L.C.
1745 SHEA CENTER DRIVE
SUITE 330
HIGHLANDS RANCH
CO
80129
US
|
Family ID: |
22743976 |
Appl. No.: |
09/845741 |
Filed: |
May 1, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60200980 |
May 1, 2000 |
|
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Current U.S.
Class: |
514/552 ;
514/561 |
Current CPC
Class: |
A61K 31/215 20130101;
A61K 31/22 20130101; A61K 31/25 20130101; A61K 45/06 20130101; A61P
3/10 20180101; A61P 25/16 20180101; A61K 31/205 20130101; A61P
25/28 20180101; A61K 31/12 20130101; A61K 31/20 20130101; A61P
25/00 20180101; A61P 25/14 20180101; A61K 31/23 20130101; A61K
31/221 20130101; A61P 43/00 20180101; A61K 31/205 20130101; A61K
2300/00 20130101; A61K 31/215 20130101; A61K 2300/00 20130101; A61K
31/22 20130101; A61K 2300/00 20130101; A61K 31/221 20130101; A61K
2300/00 20130101; A61K 31/23 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/552 ;
514/561 |
International
Class: |
A61K 031/23; A61K
031/195 |
Claims
What is claimed is:
1. A method of treating or preventing dementia of Alzheimer's type,
or other loss of cognitive function caused by reduced neuronal
metabolism, comprising administering an effective amount of medium
chain triglycerides to a patient in need thereof.
2. The method of claim 1, wherein said administration is oral.
3. The method of claim 1, wherein said administration is
intravenous.
4. The method claim 1, wherein said medium chain triglycerides are
administered medium chain triglycerides are administered at a dose
of about 0.5 g/kg/day to about 10 g/kg/day.
5. The method of claim 1, further comprising coadministering
L-camitine or a derivative of L-camitine.
6. The method claim 5, wherein said administration is oral, and
said medium chain triglycerides are administered at a dose of about
0.5 g/kg/day to about 10 g/kg/day and said L-camitine or said
derivative of L-camitine is administered at a dose of about 0.5
mg/kg/day to about 10 mg/kg/day.
7. The method of claim 1, wherein said medium chain triglycerides
are emulsified.
8. The method of claim 7, further comprising coadministering
L-camitine or a derivative of L-carnitine.
9. The method of claim 8, wherein said emulsified medium chain
triglycerides and L-camitine or a derivative of L-camitine are
administered in a formulation comprising 10-500 g emulsified medium
chain triglycerides and 10-2000 mg L-camitine or derivative of
L-camitine.
10. A method of treating or preventing dementia of Alzheimer's
type, or other loss of cognitive function caused by reduced
neuronal metabolism, comprising administering an effective amount
of free medium chain fatty acids.
11. A method of treating or preventing dementia of Alzheimer's
type, or other loss of cognitive function caused by reduced
neuronal metabolism, comprising administering an effective amount
of a medium chain triglyceride prodrug to a patient in need
thereof.
12. A method of treating or preventing dementia of Alzheimer's
type, or other loss of cognitive function caused by reduced
neuronal metabolism, comprising administering an effective amount
of a therapeutic agent which induces utilization of fatty acids and
development of ketosis to a patient in need thereof.
13. A method of treating or preventing dementia of Alzheimer's
type, or other loss of cognitive function caused by reduced
neuronal metabolism, comprising coadministering an effective amount
of an agent selected from the group consisting of medium chain
triglycerides, medium chain fatty acids, and ketone bodies, and
Lcamitine or a derivative of L-camitine to a patient in need
thereof.
14. The method of claim 13, wherein s aid coadministration is
intravenous, and said agent selected from the group consisting of
medium chain triglycerides, medium chain fatty acids, and ketone
bodies is administered at a dose of about 0.5 g/kg/day to about 10
g/kg/day and said L-camitine or said derivative of L-camitine is
administered at a dose of about 0.5 mg/kg/day to about 10
mg/kg/day.
15. The method of claim 13, wherein said agent selected from the
group consisting of medium chain triglycerides, medium chain fatty
acids, and ketone bodies and L-camitine or a derivative of
L-carnitine are administered in a formulation comprising 10-500 g
of said agent and 10-2000 mg L-carnitine or derivative of
L-camitine.
16. A therapeutic agent for the treatment of prevention or dementia
of Alzheimer's type, or other loss of cognitive function caused by
reduced neuronal metabolism comprising medium chain
triglycerides.
17. A therapeutic agent for the treatment of prevention or dementia
of Alzheimer's type, or other loss of cognitive function caused by
reduced neuronal metabolism comprising free fatty acids derived
from medium chain triglycerides .
18. A therapeutic agent for the treatment of prevention or dementia
of Alzheimer's type, or other loss of cognitive function caused by
reduced neuronal metabolism comprising a medium chain triglyceride
prodrug.
19. A therapeutic agent for the treatment of prevention or dementia
of Alzheimer's type, or other loss of cognitive function caused by
reduced neuronal metabolism comprising an agent which induces
utilization of fatty acids and development of ketosis to a patient
in need thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 60/200,980 filed May 1, 2000, entitled "Use of
Medium Chain Triglycerides for the Treatment and Prevention of
Alzheimer's Disease and Other Diseases Resulting from Reduced
Neuronal Metabolism."
FIELD OF THE INVENTION
[0002] This invention relates to the field of therapeutic agents
for the treatment of Alzheimer's Disease, and other diseases
associated with reduced neuronal metabolism.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's Disease (AD) is a progressive neurodegenerative
disorder, which primarily affects the elderly. There are two forms
of AD, early-onset and late-onset. Early-onset AD is rare, strikes
susceptible individuals as early as the third decade, and is
frequently associated with mutations in a small set of genes. Late
onset AD is common, strikes in the seventh or eighth decade, and is
a multifactorial disease with many genetic risk factors. Late-onset
AD is the leading cause of dementia in persons over the age of 65.
An estimated 7-10% of the American population over 65, and up to
40% of the American population greater than 80 years of age is
afflicted with AD (McKhann et al., 1984; Evans et al. 1989). Early
in the disease, patients experience loss of memory and orientation.
As the disease progresses, additional cognitive functions become
impaired, until the patient is completely incapacitated. Many
theories have been proposed to describe the chain of events that
give rise to AD, yet, at time of this application, the cause
remains unknown. Currently, no effective prevention or treatment
exists for AD. The only drugs to treat AD on the market today,
Aricept.RTM. and Cognex.RTM., are acetylcholinesterase inhibitors.
These drugs do not address the underlying pathology of AD. They
merely enhance the effectiveness of those nerve cells still able to
function. Since the disease continues, the benefits of these
treatments are slight.
[0004] Early-onset cases of AD are rare (.about.5%), occur before
the age of 60 and are frequently associated with mutations in three
genes, presenilin1 (PS1), presenilin2 (PS2) and amyloid precursor
protein (APP) (for review see Selkoe, 1999). These early-onset AD
cases exhibit cognitive decline and neuropathological lesions that
are similar to those found in late-onset AD. AD is characterized by
the accumulation of neurofibrillar tangles (NFT) and .beta.-amyloid
deposits in senile plaques (SP) and cerebral blood vessels. The
main constituent of senile plaques is the .beta.-amyloid peptide
(A.beta.), which is derived from the APP protein by proteolytic
processing. The presenilin proteins may facilitate the cleavage of
APP. The A.beta. peptide is amyloidagenic and under certain
conditions will form insoluble fibrils. However, the toxicity of
A.beta. peptide and fibrils remains controversial. In some cases
A.beta. has been shown to be neurotoxic, while others find it to be
neurotrophic (for reviews see Selkoe, 1999). The cause of
early-onset AD is hypothesized to be accumulation of aggregated
proteins in susceptible neurons. Mutations in APP are hypothesized
to lead to direct accumulation of fibrillar A.beta., while
mutations in PS1 or PS2 are proposed to lead to indirect
accumulation of A.beta.. How a variety of mutations in PS1 and PS2
lead to increased A.beta. accumulation has not been resolved.
Accumulation of aggregated proteins is common to many progressive
neurodegenerative disorders, including Amyloid Lateral Sclerosis
(ALS) and Huntington's disease (for review see Koo et al., 1999).
Evidence suggests that accumulation of aggregated proteins inhibits
cellular metabolism and ATP production. Consistent with this
observation is the finding that buffering the energy capacity of
neurons with creatine will delay the onset of ALS in transgenic
mouse models (Klivenyi et al., 1999). Much of the prior art on AD
has focused on inhibiting production of or aggregation of A.beta.
peptides; such as U.S. Pat. No. 5,817,626, U.S. Pat. No. 5,854,204,
and U.S. Pat. No. 5,854,215. Other prior art to treat AD include,
U.S. Pat. No. 5,385,915 "Treatment of amyloidosis associated with
Alzheimer disease using modulators of protein phosphorylation",
patent U.S. Pat. No. 5,538,983, "Method of treating amyloidosis by
modulation of calcium." Attempts to increase neuronal survival by
use of nerve growth factors have dealt with either whole cell, gene
or protein delivery, such as described in U.S. Pat. No. 5,650,148
"Method of grafting genetically modified cells to treat defects,
disease or damage of the central nervous system", and U.S. Pat. No.
5,936,078 "DNA and protein for the diagnosis and treatment of
Alzheimer's disease."
[0005] The vast majority (.about.95%) of AD cases are late-onset,
occurring in the seventh or eighth decade. Late-onset AD is not
associated with mutations in APP, PS1 or PS2, yet exhibits
neuropathological lesions and symptoms that are similar to those
found in early-onset AD. Since late-onset AD is the most common
form, it will be referred to herein as AD, while early-onset AD
will be referred to as such. The similar neuropathology and outward
symptoms of early-onset and late-onset AD have led to the "amyloid
cascade hypothesis of AD"(Selkoe, 1994). This model holds that both
early and late onset AD result from accumulation of toxic amyloid
deposits. The model speculates that in early onset cases, amyloid
accumulates rapidly, while in late onset, amyloid accumulates
slowly. Much of the research on prevention and treatment of AD has
focused on inhibition of amyloid accumulation. However, the amyloid
cascade hypothesis remains controversial. Amyloid deposits may be a
marker for the disease and not the cause. Translation of Dr.
Alzheimer's original work on the neuropathology of AD, relates that
he did not favor the view that senile plaques were causative. He
states "These changes are found in the basal ganglia, the medulla,
the cerebellum and the spinal cord, although there are no plaques
at all in those sites or only isolated ones. So we have to conclude
that the plaques are not the cause of senile dementia but only an
accompanying feature of senile involution of the central nervous
system." The italics are his own (Davis and Chisholm, 1999). Many
years of research have not resolved this issue (for review of
amyloid hypothesis see Selkoe, 1999, for counter argument see Neve
et al., 1998). Since the present invention addresses the decreased
neuronal metabolism associated with AD, it does not rely on the
validity of the amyloid cascade hypothesis.
[0006] Several genetic risk factors have been proposed to
contribute to the susceptibility to late-onset AD. However, only
allelic variation in the lipid transport molecule apolipoprotein E
(apoE) has been reproducibly defined as a genetic risk factor for
late onset AD. ApoE functions as a ligand in the process of
receptor mediated internalization of lipid-rich lipoproteins. These
lipoprotein complexes contain phosopholipids, triglycerides,
cholesterol and lipoproteins. Several well-characterized allelic
variations exist at the apoe locus, and are referred to as apoE2,
E3 and E4. ApoE4 is associated with an increased risk of AD, while
apoE2 and E3 are not. Increasing the dosage of the E4 allele
increases the risk of AD, and lowers the age of onset. However,
apoE4 is not an invariant cause of AD. Some individuals, who are
homozygous for the E4 allele, do not show AD symptoms even into the
ninth decade (Beffert et al., 1998).
[0007] A prediction of the observation that apoE4 is associated
with AD is that populations with a high prevalence of the E4 allele
would also have a high incidence of AD. Yet, the opposite appears
to be true. Geographically distinct populations have differing
frequencies of apoe alleles. For example, the E4 variant is much
more common in Africa versus the UK. In a study of black South
Africans and Caucasians from Cambridge England, the apoE4 allele
was present in 48% of Black South Africans compared to 20.8% of
Caucasians (Loktionov et al, 1999). In fact, the E4 allele is
widespread throughout Africa (Zekraoui et al, 1997). Studies on AD
are difficult to do in developing countries, but the studies that
have been done show a very low incidence of AD in African
communities, 1% versus 6% in US populations (Hall et al, 1998).
Even more striking is that the normally robust association between
AD and apoE4 is absent in African cases (Osuntokun et al, 1995).
This suggests that something is different between native Africans,
and US citizens, who are largely of European descent. Perhaps the
African populations have some other genetic factor that protects
them from AD. This is unlikely, since the incidence of AD in a
population of African-Americans from Indianapolis, Indiana USA
(6.24%) was found to be much higher than an ethnically similar
population in Ibadan, Nigeria (1.4%) (Hall et al, 1998). This
suggests that the link between apoE4 and AD has some strong
environmental component.
[0008] ApoE4 is the ancestral allele, it is most similar to the
apoE found in chimpanzees and other primates, while the E2 and E3
alleles arose exclusively in the human lineage, (Hanlon and
Rubinsztein, 1995). The changes in apoE were probably brought about
by a change in diet in ancestral humans. The E2 and E3 alleles may
have arisen in populations as an adaptation to agriculture (Corbo
and Scacchi, 1999).
[0009] The metabolism of apoE4 in human circulation is different
from the non-AD associated apoE3 allele (Gregg et al., 1986). The
E4 allele is associated with unusually high levels of circulating
lipoproteins (Gregg et al., 1986). In particular, the E4 allele
results in decreased rates of VLDL clearance, which leads to higher
levels of VLDL and LDL particles in the blood (Knouff, et al.
1999). VLDL and LDL particles contain higher levels of
triglycerides than HDL particles. The increased levels of
circulating VLDL in individuals carrying apoE4 is due to decreased
fatty acid utilization caused by preferential binding of apoE4 to
chylomicron and VLDL particles. Prior art has suggested that apoE4
contributes to AD due to inefficient delivery of phospholipids to
neurons (for review see Beffert et al., 1998). Yet, apoE4 also
contributes to decreased triglyceride usage.
[0010] In the central nervous system (CNS), apoE plays a central
role in the transportation and redistribution of cholesterol and
lipids. The importance of apoe in the brain is highlighted by the
absence of other key plasma apolipoproteins such as apoA1 and apoB
in the brain (Roheim et al., 1979). ApoE mRNA is found
predominantly in astrocytes in the CNS. Astrocytes function as
neuronal support cells and can efficiently utilize fatty acids for
energy. Since the brain lacks other apolipoproteins, it is uniquely
dependent on apoE for lipid transport, including triglycerides.
While prior art on apoe's role in AD has focused on phospholipid
transport, apoe also delivers free fatty acids in the form of
triglycerides to astrocytes. Fatty acids delivered by lipoproteins
can be converted to ketone bodies by astrocytes for use as an
alternative energy source to glucose. An alternative to the
neuronal remodeling hypothesis, is that the preferential binding of
apoE4 to VLDL particles prevents efficient astrocyte access to
triglycerides. Decreased access to triglycerides results in
decreased availability of fatty acids and decreased production of
ketone bodies, and hence a decreased alternative energy source for
cerebral neurons. This reduction in energy supplies may become
critical when glucose metabolism in compromised.
[0011] Metabolism and Alzheimer's Disease
[0012] At the time of this application, the cause of AD remains
unknown, yet a large body of evidence has made it clear that
Alzheimer's Disease is associated with decreased neuronal
metabolism. In 1984, Blass and Zemcov proposed that AD results from
a decreased metabolic rate in subpopulations of cholinergic
neurons. However, it has become clear that AD is not restricted to
cholinergic systems, but involves many types of transmitter
systems, and several discrete brain regions. Positron-emission
tomography has revealed poor glucose utilization in the brains of
AD patients, and this disturbed metabolism can be detected well
before clinical signs of dementia occur (Reiman et al., 1996;
Messier and Gagnon, 1996; Hoyer, 1998). Additionally, certain
populations of cells, such as somatostatin cells of the cortex in
AD brain are smaller, and have reduced Golgi apparatus; both
indicating decreased metabolic activity (for review see Swaab et
al. 1998). Measurements of the cerebral metabolic rates in healthy
versus AD patients demonstrated a 20-40% reduction in glucose
metabolism in AD patients (Hoyer, 1992). Reduced glucose metabolism
results in critically low levels of ATP in AD patients. Also, the
severity of decreased metabolism was found to correlate with senile
plaque density (Meier-Ruge, et al. 1994).
[0013] Additionally, molecular components of insulin signaling and
glucose utilization are impaired in AD patients. Glucose is
transported across the blood brain barrier and is used as a major
fuel source in the adult brain. Consistent with the high level of
glucose utilization, the brains of mammals are well supplied with
receptors for insulin and IGF, especially in the areas of the
cortex and hippocampus, which are important for learning and memory
(Frolich et al., 1998). In patients diagnosed with AD, increased
densities of insulin receptor were observed in many brain regions,
yet the level of tyrosine kinase activity that normally is
associated with the insulin receptor was decreased, both relative
to age-matched controls (Frolich et al., 1998). The increased
density of receptors represents up-regulation of receptor levels to
compensate for decreased receptor activity. Activation of the
insulin receptor is known to stimulate phosphatidylinositol-3
kinase (P13K). P13K activity is reduced in AD patients (Jolles et
al., 1992; Zubenko et al., 1999). Furthermore, the density of the
major glucose transporters in the brain, GLUT1 and GLUT3 were found
to be 50% of age matched controls (Simpson and Davies 1994). The
disturbed glucose metabolism in AD has led to the suggestion that
AD may be a form of insulin resistance in the brain, similar to
type II diabetes (Hoyer, 1998). Inhibition of insulin receptor
activity can be exogenously induced in the brains of rats by
intracerebroventricular injection of streptozotocin, a known
inhibitor of the insulin receptor. These animals develop
progressive defects in learning and memory (Lannert and Hoyer,
1998). While glucose utilization is impaired in brains of AD
patients, use of the ketone bodies, beta-hydroxybutyrate and
acteoacetate is unaffected (Ogawa et al. 1996).
[0014] The cause of decreased neuronal metabolism in AD remains
unknown. Yet, aging may exacerbate the decreased glucose metabolism
in AD. Insulin stimulation of glucose uptake is impaired in the
elderly, leading to decreased insulin action and increased insulin
resistance (for review see Finch and Cohen, 1997). For example,
after a glucose load, mean plasma glucose is 10-30% higher in those
over 65 than in younger subjects. Hence, genetic risk factors for
AD may result in slightly compromised neuronal metabolism in the
brain. These defects would only become apparent later in life when
glucose metabolism becomes impaired, and thereby contribute to the
development of AD. Since the defects in glucose utilization are
limited to the brain in AD, the liver is "unaware" of the state of
the brain and does not mobilize fatty acids (see Brain Metabolism
section below). Without ketone bodies to use as an energy source,
the neurons of the AD patient brain slowly and inexorably starve to
death.
[0015] Attempts to compensate for reduced cerebral metabolic rates
in AD patients has met with some success. Treatment of AD patients
with high doses of glucose and insulin increases cognitive scores
(Craft et al., 1996). However, since insulin is a polypeptide and
must be transported across the blood brain barrier, delivery to the
brain is complicated. Therefore, insulin is administered
systemically. Large dose of insulin in the blood stream can lead to
hyperinsulinemia, which will cause irregularities in other tissues.
Both of these shortcomings make this type of therapy difficult and
rife with complications. Accordingly, there remains a need for an
agent that may increase the cerebral metabolic rate and
subsequently the cognitive abilities of a patient suffering from
Alzheimer's disease.
[0016] Brain Metabolism
[0017] The brain has a very high metabolic rate. For example, it
uses 20 percent of the total oxygen consumed in a resting state.
Large amounts of ATP are required by neurons of the brain for
general cellular functions, maintenance of an electric potential,
synthesis of neurotransmitters and synaptic remodeling. Current
models propose that under normal physiologic conditions, neurons of
the adult human brain depend solely on glucose for energy. Since
neurons lack glycogen stores, the brain depends on a continuous
supply of glucose from the blood for proper function. Neurons are
very specialized and can only efficiently metabolize a few
substrates, such as glucose and ketone bodies. This limited
metabolic ability makes brain neurons especially vulnerable to
changes in energy substrates. Hence, sudden interruption of glucose
delivery to the brain results in neuronal damage. Yet, if glucose
levels drop gradually, such as during fasting, neurons will begin
to metabolize ketone bodies instead of glucose and no neuronal
damage will occur.
[0018] Neuronal support cells, glial cells, are much more
metabolically diverse and can metabolize many substrates, in
particular, glial cells are able to utilize fatty acids for
cellular respiration. Neurons of the brain cannot efficiently
oxidize fatty acids and hence rely on other cells, such as liver
cells and astrocytes to oxidize fatty acids and produce ketone
bodies. Ketone bodies are produced from the incomplete oxidation of
fatty acids and are used to distribute energy throughout the body
when glucose levels are low. In a normal Western diet, rich in
carbohydrates, insulin levels are high and fatty acids are not
utilized for fuel, hence blood ketone body levels are very low, and
fat is stored and not used. Such a scenario explains the prevalence
of obesity.
[0019] Current models propose that only during special states, such
as neonatal development and periods of starvation, will the brain
utilize ketone bodies for fuel. The partial oxidation of fatty
acids gives rise to D-beta-hydroxybutyrate (D-3-hydroxybutyrate)
and acetoacetate, which together with acetone are collectively
called ketone bodies. Neonatal mammals are dependent upon milk for
development. The major carbon source in milk is fat (carbohydrates
make up less then 12% of the caloric content of milk). The fatty
acids in milk are oxidized to give rise to ketone bodies, which
then diffuse into the blood to provide an energy source for
development. Numerous studies have shown that the preferred
substrates for respiration in the developing mammalian neonatal
brain are ketone bodies. Consistent with this observation is the
biochemical finding that astrocytes, oligodendrocytes and neurons
all have capacity for efficient ketone body metabolism (for review
see Edmond, 1992). Yet only astrocytes are capable of efficient
oxidation of fatty acids.
[0020] The body normally produces small amounts of ketone bodies.
However, because they are rapidly utilized, the concentration of
ketone bodies in the blood is very low. Blood ketone body
concentrations rise on a low carbohydrate diet, during periods of
fasting, and in diabetics. In a low carbohydrate diet, blood
glucose levels are low, and pancreatic insulin secretion is not
stimulated. This triggers the oxidation of fatty acids for use as a
fuel source when glucose is limiting. Similarly, during fasting or
starvation, liver glycogen stores are quickly depleted, and fat is
mobilized in the form of ketone bodies. Since both a low
carbohydrate diet and fasting do not result in a rapid drop of
blood glucose levels, the body has time to increase blood ketone
levels. The rise in blood ketone bodies provides the brain with an
alternative fuel source, and no cellular damage occurs. Since the
brain has such high energy demands, the liver oxidizes large
amounts of fatty acids until the body becomes literally saturated
in ketone bodies. Therefore, when an insufficient source of ketone
bodies is coupled with poor glucose utilization severe damage to
neurons results. Since glial cells are able to utilize a large
variety of substrates they are less susceptible to defects in
glucose metabolism than are neurons. This is consistent with the
observation that glial cells do not degenerate and die in AD
(Mattson, 1998).
[0021] As discussed in the Metabolism and Alzheimer's Disease
section, in AD, neurons of the brain are unable to utilize glucose
and begin to starve to death. Since the defects are limited to the
brain and peripheral glucose metabolism is normal, the body does
not increase production of ketone bodies, therefore neurons of the
brain slowly starve to death. Accordingly, there remains a need for
an energy source for brain cells that exhibit compromised glucose
metabolism in AD patients. Compromised glucose metabolism is a
hallmark of AD; hence administration of such an agent will prove
beneficial to those suffering from AD.
[0022] Medium Chain Triglycerides (MCT)
[0023] The metabolism of MCT differs from the more common long
chain triglycerides (LCT) due to the physical properties of MCT and
their corresponding medium chain fatty acids (MCFA). Due to the
short chain length of MCFA, they have lower melting temperatures,
for example the melting point of MCFA (C8:0) is 16.7.degree. C.,
compared with 61.1.degree. C. for the LCFA (C16:0). Hence, MCT and
MCFA are liquid at room temperature. MCT are highly ionized at
physiological pH, thus they have much greater solubility in aqueous
solutions than LCT. The enhanced solubility and small size of MCT
also increases the rate at which fine emulsion particles are
formed. These small emulsion particles create increased surface
area for action by gastrointestinal lipases. Additionally, medium
chain 2-monoglycerides isomerize more rapidly than those of long
chain length, allowing for more rapid hydrolysis. Some lipases in
the pre-duodenum preferentially hydrolyze MCT to MCFA, which are
then partly absorbed directly by stomach mucosa (Hamosh, 1990).
Those MCFA which are not absorbed in the stomach, are absorbed
directly into the portal vein and not packaged into lipoproteins.
LCFA are packaged in chylomicrons and transported via the lymph
system, while MCFA are transported via the blood. Since blood
transports much more rapidly than lymph, the liver is quickly
perfused with MCFA.
[0024] In the liver the major metabolic fate of MCFA is oxidation.
The fate of LCFA in the liver is dependent on the metabolic state
of the organism. LCFA are transported into the mitochondria for
oxidation using camitine palmitoyltransferase I. When conditions
favor fat storage, malonyl-CoA is produced as an intermediate in
lipogenesis. Malonyl-CoA allosterically inhibits carnitine
palmitoyltransferase I, and thereby inhibits LCFA transport into
the mitochondria. This feedback mechanism prevents futile cycles of
lipolysis and lipogenesis. MCFA are, to large extent, immune to the
regulations that control the oxidation of LCFA. MCFA enter the
mitochondria largely without the use of carnitine
palmitoyltransferase I, therefore MCFA by-pass this regulatory step
and are oxidized regardless of the metabolic state of the organism.
Importantly, since MCFA enter the liver rapidly and are quickly
oxidized, large amounts of ketone bodies are readily produced from
MCFA.
[0025] Numerous patents relate to use of MCT. None of these patents
relate to the specific use of MCT for treatment and prevention of
Alzheimer's Disease. Patents such as U.S. Pat. No. 4,528,197
"Controlled triglyceride nutrition for hypercatabolic mammals" and
U.S. Pat. No. 4,847,296 "Triglyceride preparations for the
prevention of catabolism" relate to the use of MCT to prevent
body-wide catabolism that occurs in burns and other serious
injuries. Each patent described herein is incorporated by reference
herein in its entirety.
SUMMARY OF THE INVENTION
[0026] The present invention provides a method of treating or
preventing dementia of Alzheimer's type, or other loss of cognitive
function caused by reduced neuronal metabolism, comprising
administering an effective amount of medium chain triglycerides to
a patient in need thereof. Administration may be oral or
intravenous. The medium chain triglycerides may be emulsified, and
may be coadministered with L-carnitine or a derivative of
L-carnitine.
[0027] The present invention also provides a method of treating or
preventing dementia of Alzheimer's type, or other loss of cognitive
function caused by reduced neuronal metabolism, comprising
administering an effective amount of free fatty acids derived from
medium chain triglycerides to a patient in need thereof.
[0028] The present invention also provides a method of treating or
preventing dementia of Alzheimer's type, or other loss of cognitive
function caused by reduced neuronal metabolism, comprising
administering an effective amount of a medium chain triglyceride
prodrug to a patient in need thereof.
[0029] The present invention also provides a method of treating or
preventing dementia of Alzheimer's type, or other loss of cognitive
function caused by reduced neuronal metabolism, comprising
administering an effective amount of a therapeutic agent which
induces utilization of fatty acids and development of ketosis to a
patient in need thereof.
[0030] The present invention further provides therapeutic agents
for the treatment or prevention of dementia of Alzheimer's type, or
other loss of cognitive function caused by reduced neuronal
metabolism.
DETAILED DESCRIPTION OF THE INVENTION
[0031] It is the novel insight of this invention that medium chain
triglycerides (MCT) and their associated fatty acids are useful as
a treatment and preventative measure for AD patients. MCT are
composed of fatty acids with chain lengths of between 5-12 carbons.
A diet rich in MCT results in high blood ketone levels. High blood
ketone levels will provide an energy source for brain cells that
have compromised glucose metabolism via the rapid oxidation of MCFA
to ketone bodies.
[0032] The background of this invention supports the present
invention in the following ways. (1) Neurons of the brain can use
both glucose and ketone bodies for respiration. (2) The neurons of
Alzheimer's Disease patients have well documented defects in
glucose metabolism. (3) Known genetic risk factors for Alzheimer's
Disease are associated with lipid and cholesterol transport,
suggesting defects in triglyceride usage may underlie
susceptibility to Alzheimer's Disease. (4) A diet rich in MCT will
lead to increased levels of blood ketone bodies and thereby provide
energy to starving brain neurons. Hence, supplementation of
Alzheimer's Disease patients with MCT will restore neuronal
metabolism.
[0033] The present invention provides a method of treating or
preventing dementia of Alzheimer's type, or other loss of cognitive
function caused by reduced neuronal metabolism, comprising
administering an effective amount of medium chain triglycerides to
a patient in need thereof. Generally, an effective amount is an
amount effective to either (1) reduce the symptoms of the disease
sought to be treated or (2) induce a pharmacological change
relevant to treating the disease sought to be treated. For
Alzheimer's Disease, an effective amount includes an amount
effective to: increase cognitive scores; slow the progression of
dementia; or increase the life expectancy of the affected patient.
As used herein, medium chain triglycerides of this invention are
represented by the following formula:
H.sub.2C--R1
H.sub.2C--R2
H.sub.2C--R3
[0034] wherein R1, R2 and R3 are fatty acids having 5-12 carbons in
the carbon backbone. The structured lipids of this invention may be
prepared by any process known in the art, such as direct
esterification, rearrangement, fractionation, transesterification,
or the like. For example the lipids may be prepared by the
rearrangement of a vegetable oil such as coconut oil.
[0035] In a preferred embodiment, the method comprises the use of
MCTs wherein R1, R2, and R3 are fatty acids containing a six-carbon
backbone (tri-C6:0). Tri-C6:0 MCT are absorbed very rapidly by the
gastrointestinal track in a number of model systems (Odle 1997).
The high rate of absorption results in rapid perfusion of the
liver, and a potent ketogenic response. Additionally, utilization
of tri-C6:0 MCT can be increased by emulsification. Emulsification
of lipids increases the surface area for action by lipases,
resulting in more rapid hydrolysis. Methods for emulsification of
these triglycerides are well known to those skilled in the art.
[0036] In another preferred embodiment, the invention provides a
method of treating or preventing dementia of Alzheimer's type, or
other loss of cognitive function caused by reduced neuronal
metabolism, comprising administering an effective amount of free
fatty acids, which may be derived from medium chain triglycerides,
to a patient in need thereof. Such fatty acids are referred to
herein as free medium chain fatty acids, or free fatty acids.
Because MCT are metabolized to produce medium chain fatty acids,
which are oxidized, the administration of free fatty acids and/or
ketone bodies have the same effect as the administration of MCT
themselves.
[0037] In another preferred embodiment, the invention comprises the
coadministration of emulsified tri-C6:0 MCT and L-camitine or a
derivative of Lcamitine. Slight increases in MCFA oxidation have
been noted when MCT are combined with L-camitine (Odle, 1997). Thus
in the present invention emulsified triC6:0 MCT are combined with
L-camitine at doses required to increase the utilization of said
MCT. The dosage of L-camitine and MCT will vary according to the
condition of the host, method of delivery, and other factors known
to those skilled in the art, and will be of sufficient quantity to
raise blood ketone levels to a degree required to treat and prevent
Alzheimer's Disease. Derivatives of L-camitine which may be used in
the present invention include but are not limited to
decanoylcamitine, hexanoylcamitine, caproylcarnitine,
lauroylcarnitine, octanoylcatnitine, stearoylcarnitine,
myristoylcamitine, acetyl-L-carnitine, O-Acetyl-L-carnitine, and
palmitoyl-L-carnitine.
[0038] Therapeutically effective amounts of the therapeutic agents
can be any amount or dose sufficient to bring about the desired
anti-dementia effect and depend, in part, on the severity and stage
of the condition, the size and condition of the patient, as well as
other factors readily known to those skilled in the art. The
dosages can be given as a single dose, or as several doses, for
example, divided over the course of several weeks.
[0039] In one embodiment, the MCT's or fatty acids are administered
orally. In another embodiment, the MCT's are administered
intravenously. Oral administration of MCT's and preparations
intravenous MCT solutions are well known to those skilled in the
art.
[0040] Oral and intravenous administration of MCT or fatty acids
result in hyperketonemia. Hyperketonemia results in ketone bodies
being utilized for energy in the brain even in the presence of
glucose. Additionally, hyperketonemia results in a substantial
(39%) increase in cerebral blood flow (Hasselbalch et al. 1996).
Hyperketonemia has been reported to reduce cognitive dysfunction
associated with systemic hypoglycemia in normal humans (Veneman et
al. 1994). Please note that systemic hypoglycemia is distinct from
the local defects in glucose metabolism that occur in AD. In
another embodiment, the invention provides the subject compounds in
the form of one or more prodrugs, which can be metabolically
converted to the subject compounds by the recipient host. As used
herein, a prodrug is a compound that exhibits pharmacological
activity after undergoing a chemical transformation in the body.
The said prodrugs will be administered in a dosage required to
increase blood ketone bodies to a level required to treat and
prevent the occurrence of Alzheimer's Disease. A wide variety of
prodrug formulations are known in the art. For example, prodrug
bonds may be hydrolyzable, such as esters or anhydrides, or
enzymatically biodegradable, such as amides.
[0041] This invention also provides a therapeutic agent for the
treatment or prevention of dementia of Alzheimer's type, or other
loss of cognitive function caused by reduced neuronal metabolism,
comprising medium chain triglycerides. In a preferred embodiment,
the therapeutic agent is provided in administratively convenient
formulations of the compositions including dosage units
incorporated into a variety of containers. Dosages of the MCT are
preferably administered in an effective amount, in order to produce
ketone body concentrations sufficient to increase the cognitive
ability of patients afflicted with AD or other states of reduced
neuronal metabolism. For example, for the ketone body
D-beta-hydroxybutyrate, blood levels are raised to about 1-10 mM or
as measured by urinary excretion in the range of about 5 mg/dL to
about 160 mg/dL, although variations will necessarily occur
depending on the formulation and host, for example. Effective
amount dosages of other MCTs will be apparent to those skilled in
the art. Convenient unit dosage containers and/or formulations
include tablets, capsules, lozenges, troches, hard candies,
nutritional bars, nutritional drinks, metered sprays, creams, and
suppositories, among others. The compositions may be combined with
a pharmaceutically acceptable excipient such as gelatin, an oil,
and/or other pharmaceutically active agent(s). For example, the
compositions may be advantageously combined and/or used in
combination with other therapeutic or prophylactic agents,
different from the subject compounds. In many instances,
administration in conjunction with the subject compositions
enhances the efficacy of such agents. For example, the compounds
may be advantageously used in conjunction with antioxidants,
compounds that enhance the efficiency of glucose utilization, and
mixtures thereof, (see e.g. Goodman et al. 1996).
[0042] In a preferred embodiment the human subject is intravenously
infused with MCT, MCFA (medium chain fatty acids) and/or ketone
bodies directly, to a level required to treat and prevent the
occurrence of Alzheimer's Disease. Preparation of intravenous
lipid, and ketone body solutions is well known to those skilled in
the art.
[0043] In a preferred embodiment, the invention provides a
formulation comprising a mixture of MCT and carnitine to provide
elevated blood ketone levels. The nature of such formulations will
depend on the duration and route of administration. Such
formulations will be in the range of 0.5 g/kg/day to 10 g/kg/day of
MCT and 0.5 mg/kg/day to 10 mg/kg/day of camitine or its
derivatives,. Variations will necessarily occur depending on the
formulation and/or host, for example.
[0044] A particularly preferred formulation comprises a range of
10-500 g of emulsified MCT combined with 10-2000 mg of carnitine.
An even more preferred formulation comprises 50 g MCT (95% triC8:0)
emulsified with 50 g of mono- and di-glycerides combined with 500
mg of L-carnitine. Such a formulation is well tolerated and induces
hyperketonemia for 3-4 hours in healthy human subjects.
[0045] In another embodiment, the invention provides the recipient
with a therapeutic agent which enhances endogenous fatty acid
metabolism by the recipient. The said therapeutic agent will be
administered in a dosage required to increase blood ketone bodies
to a level required to treat and prevent the occurrence of
Alzheimer's Disease. Ketone bodies are produced continuously by
oxidation of fatty acids in tissues that are capable of such
oxidation. The major organ for fatty acid oxidation is the liver.
Under normal physiological conditions ketone bodies are rapidly
utilized and cleared from the blood. Under some conditions, such as
starvation or low carbohydrate diet, ketone bodies are produced in
excess and accumulate in the blood stream. Compounds that mimic the
effect of increasing oxidation of fatty acids will raise ketone
body concentration to a level to provide an alternative energy
source for neuronal cells with compromised metabolism. Since the
efficacy of such compounds derives from their ability to increase
fatty acid utilization and raise blood ketone body concentration
they are dependent on the embodiments of the present invention.
[0046] From the description above, a number of advantages of the
invention for treating and preventing Alzheimer's Disease become
evident:
[0047] (a) Prior art on AD has largely focused on prevention and
clearance of amyloid deposits. The role of these amyloid deposits
in AD remains controversial and may only be a marker for some other
pathology. The present invention provides a novel route for
treatment and prevention of AD based on alleviating the reduced
neuronal metabolism associated with AD, and not with aspects of
amyloid accumulation.
[0048] (b) Current treatments for AD are merely palliative and do
not address the reduced neuronal metabolism associated with AD.
Ingestion of medium chain triglycerides as a nutritional supplement
is a simple method to provide neuronal cells, in which glucose
metabolism is compromised, with ketone bodies as a metabolic
substrate.
[0049] (c) Increase blood levels of ketone bodies can be achieved
by a diet rich in medium chain triglycerides.
[0050] (d) Medium chain triglycerides can be infused intravenously
into patients.
[0051] (e) Levels of ketone bodies can be easily measured in urine
or blood by commercially available products (i.e. Ketostix.RTM.,
Bayer, Inc.).
[0052] Accordingly, the reader will see that the use of medium
chain triglycerides (MCT) or fatty acids as a treatment and
preventative measure of Alzheimer's Disease (AD) provides a novel
means of alleviating reduced neuronal metabolism associated with
AD. It is the novel and significant insight of the present
invention that use of MCT results in hyperketonemia which will
provide increased neuronal metabolism for diseases associated with
reduced neuronal metabolism, such as AD, ALS, Parkinson's Disease
and Huntington's Disease. Although the description above contains
many specificities, these should not be construed as limiting the
scope of the invention but merely as providing illustrations for
some of the presently preferred embodiments of this invention. For
example, supplementation with MCT may prove more effective when
combined with insulin sensitizing agents such as vanadyl sulfate,
chromium picolinate, and vitamin E. Such agents may function to
increase glucose utilization in compromised neurons and work
synergistically with hyperketonemia. In another example MCT can be
combined with compounds that increase the rates of fatty acid
utilization such as L-camitine and its derivatives. Mixtures of
such compounds may synergistically increase levels of circulating
ketone bodies.
[0053] Thus the scope of the invention should be determined by the
appended claims and their legal equivalents, rather than by the
examples given.
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EXAMPLES
[0098] The following example is offered by way of illustration and
not by way of limitation.
Example 1: Nutritional drink
[0099] Nutritional drinks are prepared using the following
ingredients: emulsified MCT 100 gr/drink, L-camitine 1 gram/drink,
mix of daily vitamins at recommended daily levels, and a variety of
flavorings.
Example 2: Additional formulations
[0100] Additional formulations can be in the form of Ready to Drink
Beverage, Powdered Beverages, Nutritional drinks, Food Bars, and
the like. Formulations for such are clear to those skilled in the
art.
[0101] A. Ready to Drink Beverage
[0102] Ready to Drink Beverages are prepared using the following
ingredients: emulsified MCT 5-100 g/drink, L-camitine 250-1000
mg/drink, and a variety of flavorings and other ingredients used to
increased palatability, stability, etc.
[0103] B. Powdered Beverages
[0104] MCT may be prepared in a dried form, useful for food bars
and powdered beverage preparations. A powdered beverage may be
formed from the following components: dried emulsified MCT 10-50 g,
L-carnitine 250-500 mg, sucrose 8-15 g, maltodextrin 1-5 g,
flavorings 0-1 g.
[0105] C. Food bar
[0106] A food bar would consist of: dried emulsified MCT 10-50 g,
L-carnitine 250-500 mg, glycerin 1-5 g, corn syrup solids 5-25 g,
cocoa 2-7 g, coating 15-25 g.
[0107] D. Gelatin Capsules
[0108] Hard gelatin capsules are prepared using the following
ingredients: MCT 0.1-1000 mg/capsule, L-carnitine 250-500
mg/capsule, Starch, NF 0-600 mg/capsule; Starch flowable powder
0-600 mg/capsule; Silicone fluid 350 centistokes 0-20 mg/capsule.
The ingredients are mixed, passed through a sieve, and filled into
capsules.
[0109] E. Tablets
[0110] Tablets are prepared using the following ingredients: MCT
0.11000 mg/tablet; L-carnitine 250-500 mg/tablet; Microcrystalline
cellulose 20-300 mg/tablet; Starch 0-50 mg/tablet; Magnesium
stearate or stearate acid 0-15 mg/tablet; Silicon dioxide, fumed
0-400 mg/tablet; silicon dioxide, colloidal 0-1 mg/tablet, and
lactose 0-100 mg/tablet. The ingredients are blended and compressed
to form tablets.
[0111] F. Suspensions
[0112] Suspensions are prepared using the following ingredients:
0.1-1000 mg MCT; 250-500 mg L-camitine; Sodium carboxymethyl
cellulose 50-700 mg/5 ml; Sodium benzoate 0-10 mg/5 ml; Purified
water 5 ml; and flavor and color agents as needed.
[0113] G. Parenteral Solutions
[0114] A parenteral composition is prepared by stirring 1.5% by
weight of MCT and L-carnitine in 10% by volume propylene glycol and
water. The solution is made isotonic with sodium chloride and
sterilized.
* * * * *