U.S. patent application number 12/734013 was filed with the patent office on 2010-09-16 for compositions comprising unsaturated fatty acids and nitric oxide releasing compounds and use thereof for enhancing cognitive and related functions.
Invention is credited to Yuanlong Pan.
Application Number | 20100233304 12/734013 |
Document ID | / |
Family ID | 40853324 |
Filed Date | 2010-09-16 |
United States Patent
Application |
20100233304 |
Kind Code |
A1 |
Pan; Yuanlong |
September 16, 2010 |
COMPOSITIONS COMPRISING UNSATURATED FATTY ACIDS AND NITRIC OXIDE
RELEASING COMPOUNDS AND USE THEREOF FOR ENHANCING COGNITIVE AND
RELATED FUNCTIONS
Abstract
Compositions comprising one or more unsaturated fatty acids and
one or more nitric oxide releasing compounds, and methods for using
such compositions for enhancing cognitive function, reducing or
preventing a decline of social interaction, reducing or preventing
age-related behavioral changes, increasing trainability,
maintaining optimal brain function, facilitating learning and
memory, reducing memory loss, retarding brain aging, preventing or
treating strokes, and preventing or treating dementia in an animal.
Preferably, the compositions are food compositions useful for
enhancing cognitive function in humans and companion animals.
Inventors: |
Pan; Yuanlong;
(Chesterfield, MO) |
Correspondence
Address: |
WENDELL RAY GUFFEY;NESTLE PURINA PETCARE GLOBAL RESOURCES, INC.
1 CHECKERBOARD SQUARE, 11-T
ST. LOUIS
MO
63164
US
|
Family ID: |
40853324 |
Appl. No.: |
12/734013 |
Filed: |
December 19, 2008 |
PCT Filed: |
December 19, 2008 |
PCT NO: |
PCT/US2008/013870 |
371 Date: |
April 1, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60010097 |
Jan 17, 1996 |
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61137382 |
Jul 30, 2008 |
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Current U.S.
Class: |
424/752 ; 426/2;
426/601; 514/102; 514/108; 514/119; 514/17.5; 514/171; 514/215;
514/263.31; 514/283; 514/315; 514/324; 514/560; 514/89 |
Current CPC
Class: |
A61K 31/202 20130101;
A61P 9/10 20180101; A61K 31/663 20130101; A61K 31/54 20130101; A23K
20/158 20160501; A23K 50/40 20160501; A23D 9/007 20130101; A61K
31/683 20130101; A61K 31/675 20130101; A61K 31/198 20130101; A61P
3/02 20180101; A61K 31/522 20130101; A61K 35/60 20130101; A23L
33/115 20160801; A61K 31/22 20130101; A61K 31/20 20130101; A61K
31/445 20130101; A61P 25/28 20180101; A61K 31/4375 20130101; A61K
31/56 20130101; A61K 31/454 20130101; A61K 31/55 20130101; A23L
33/175 20160801; A23K 10/18 20160501; A61P 25/00 20180101; A61K
36/16 20130101; A61K 45/06 20130101; A61P 39/06 20180101; A23L
33/12 20160801; A61K 31/20 20130101; A61K 2300/00 20130101; A61K
31/22 20130101; A61K 2300/00 20130101; A61K 31/54 20130101; A61K
2300/00 20130101; A61K 31/202 20130101; A61K 2300/00 20130101; A61K
31/4375 20130101; A61K 2300/00 20130101; A61K 31/445 20130101; A61K
2300/00 20130101; A61K 31/454 20130101; A61K 2300/00 20130101; A61K
31/522 20130101; A61K 2300/00 20130101; A61K 31/55 20130101; A61K
2300/00 20130101; A61K 31/56 20130101; A61K 2300/00 20130101; A61K
31/663 20130101; A61K 2300/00 20130101; A61K 31/675 20130101; A61K
2300/00 20130101; A61K 31/683 20130101; A61K 2300/00 20130101; A61K
36/16 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/752 ;
514/560; 514/119; 514/263.31; 514/215; 514/283; 514/315; 514/102;
514/324; 514/171; 514/12; 514/89; 514/108; 426/601; 426/2 |
International
Class: |
A61K 36/16 20060101
A61K036/16; A61K 31/202 20060101 A61K031/202; A61K 31/683 20060101
A61K031/683; A61K 31/522 20060101 A61K031/522; A61K 31/55 20060101
A61K031/55; A61K 31/4375 20060101 A61K031/4375; A61K 31/445
20060101 A61K031/445; A61K 31/663 20060101 A61K031/663; A61K 31/454
20060101 A61K031/454; A61K 31/56 20060101 A61K031/56; A61K 38/23
20060101 A61K038/23; A61K 31/675 20060101 A61K031/675; A61P 25/28
20060101 A61P025/28; A23K 1/16 20060101 A23K001/16; A23K 1/18
20060101 A23K001/18; A23L 1/30 20060101 A23L001/30; A23D 9/00
20060101 A23D009/00 |
Claims
1. A composition suitable for enhancing cognitive and related
functions in an animal comprising one or more unsaturated fatty
acids (UFA) and one or more nitric oxide releasing compounds (NORC)
in an amount effective for enhancing cognitive and related
functions in an animal.
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26. A method for enhancing cognitive function in an animal
comprising administering a composition comprising one or more
unsaturated fatty acids (UFA) and one or more nitric oxide
releasing compounds (NORC) to the animal in an amount effective for
enhancing cognitive function in the animal.
27. (canceled)
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29. The method of claim 26 wherein the animal is an aging
animal.
30. The method of claim 26 wherein the UFA comprises one or more of
a natural fish oil, ALA, EPA, DPA, DHA, or another n-3 fatty acid
from any source.
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32. The method of claim 26 wherein the composition comprises from
about 0.1% to about 50% UFA.
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36. The method of claim 26 wherein the composition comprises from
about 0.1% to about 20% NORC.
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45. The method of claim 26 wherein the composition is administered
to the animal in conjunction with one or more cognitive drugs in an
amount effective for enhancing cognitive function.
46. The method of claim 45 wherein the cognitive drug is one or
more of selegiline, nicerogoline, a phosphatidylserine,
propentofyline, galantamine, vinpocetine, donepezil, a Ginkgo
biloba extract, a bisphosophonate, raloxifene, an estrogen, a
phytoestrogen, calcitonin, risedronate, or alendronate.
47. (canceled)
48. The method of claim 26 wherein the composition is administered
on an extended regular basis.
49. The method of claim 48 wherein the composition is administered
to the animal on a daily basis.
50. The method of claim 26 wherein the animal is an aging
animal.
51. The method of claim 50 wherein the animal has a phenotype
associated with age-related cognitive impairment.
52. The method of claim 51 wherein the phenotype includes one or
more of decreased ability to recall, short-term memory loss,
decreased learning rate, decreased capacity for learning, decreased
problem solving skills, decreased attention span, decreased motor
performance, increased confusion, or dementia, as compared to a
control animal not having the phenotype.
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110. A method for preventing or treating strokes in an animal
comprising administering a composition comprising UFA and NORC to
the animal in an amount effective to prevent or treat strokes.
111. The method of claim 110 wherein the animal is a human or
companion animal.
112. The method of claim 110 wherein the animal is an aging
animal.
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196. The method of claim 26 wherein the NORC is arginine,
citrulline, citrulline, or a nitric oxide-releasing derivatives
thereof.
197. The method of claim 26 wherein the composition further
comprises one or more B vitamins in an amount effective for
enhancing cognitive function, one or more antioxidants in an amount
effective for enhancing cognitive function, or both.
198. The method of claim 197 wherein the composition comprises from
about 0.1 to 40 times the recommended daily requirement of B
vitamins, from about 0.0001% to about 25% of antioxidants, or
both.
199. The method of claim 110 wherein the NORC is arginine,
citrulline, citrulline, or a nitric oxide-releasing derivatives
thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a national stage application under 35
U.S.C. .sctn.371 of PCT/US2008/013870 filed Oct. 2, 2008, which
claims priority to U.S. Provisional Application Ser. No. 61/010,097
filed Jan. 4, 2008, and U.S. Provisional Application Ser. No.
61/137,382 filed Jul. 30, 2008, the disclosures of which are
incorporated herein by this reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates generally to compositions and methods
for enhancing cognitive function and particularly to compositions
comprising unsaturated fatty acids and nitric oxide releasing
compounds and their use for enhancing cognitive function in
animals.
[0004] 2. Description of Related Art
[0005] Aged or aging animals frequently suffer some degree of
cognitive impairment. Changes, including decline in cognitive
function that progresses with age, and age-related changes in brain
morphology and cerebrovascular function are commonly observed,
e.g., brain aging. Age-related or age-associated cognitive
impairment may manifest itself in many ways, e.g., short-term
memory loss, diminished capacity to learn, diminished rate of
learning, diminished attention, diminished motor performance,
and/or dementia, among other indicia. In some cases, a specific
etiology of such cognitive decline is unknown. In other cases,
cognitive impairment results from the onset or progression of
recognized diseases, disorders, or syndromes, for example,
Alzheimer's disease (AD). It is known that age-associated cognitive
decline is distinct from and can occur independently of AD.
[0006] Animal models of cognitive impairment greatly facilitate the
study of such conditions including their physiology, neurology,
anatomy, and pathology. Dogs are useful model animals that
demonstrate age-associated cognitive decline in learning and memory
that varies depending on the function of the cognitive task (Adams
B et al., 2000a; Chan A D F et al., 2002; Su M-Y et al., 1998; and,
Tapp P D et al., 2003). While the study of such decline in dogs is
useful in its own right because of their role as companion animals,
the fact that the observed decline mirrors age-related cognitive
declines seen in humans (Adams B et al. 2000b) makes the studies
even more valuable. Aged dogs develop neuropathology that is
related to that seen in both successfully aging humans and patients
with AD, such as beta amyloid protein (Cotman C W and Berchtold,
2002; and Cummings B J et al., 1996). However, dogs do not
demonstrate every hallmark of AD, in particular, tau-containing
neurofibrillar tangles (Dimakopoulos A C et al., 2002) have not
been observed. Therefore, the condition in dogs is distinct and
referred to as Canine Cognitive Dysfunction Syndrome (CCDS).
[0007] Both healthy dogs and unhealthy dogs such as those diagnosed
with CCDS may present clinically with progressive cognitive
impairment and neuropathological changes (London E D et al., 1983).
In addition, aging dogs and those diagnosed with CCDS exhibit
various behavioral disorders. For example, they may not respond to
their name or familiar commands, may get lost or confused even in
familiar surroundings, may no longer greet or respond to their
owners or visitors, may exhibit diminished daytime activity, may
walk in circles, may shun affection, and may lose bladder or bowel
control.
[0008] Though advances have been made, there remains a need to
develop compositions and methods that improve cognition,
particularly in aging humans and other animals. Compositions and
methods for the treatment and/or prevention of cognitive
impairment, neurodegeneration conditions, stroke, and dementia are
also needed. Such therapies would be useful to improve the overall
quality of life for all involved. For companion animals, these
therapies would lead to improved owner satisfaction and would
improve the owner-companion animal bond.
SUMMARY OF THE INVENTION
[0009] It is, therefore, an object of the present invention to
provide compositions and methods useful for enhancing cognitive
function in an animal.
[0010] It is another object of the present invention to provide
methods for reducing or preventing a decline of social interaction,
reducing or preventing age-related behavioral changes, increasing
trainability, maintaining optimal brain function, facilitating
learning and memory, reducing memory loss, retarding brain aging,
preventing or treating strokes, and preventing or treating dementia
in an animal.
[0011] It is a further object of the invention to provide articles
of manufacture in the form of kits that contain one or more of the
compounds useful to produce the composition of the present
invention in combination with foods or other ingredients and
devices useful for enhancing cognitive function in an animal.
[0012] It is another object of the invention to provide a package
comprising a composition of the present invention and a label
affixed to the package indicating the contents of the package
and/or the benefits of administering the composition to an
animal.
[0013] One or more of these other objects are achieved using novel
compositions and methods for enhancing cognitive function.
Generally, the compositions comprise one or more unsaturated fatty
acids and nitric oxide releasing compounds. The methods generally
comprise administering the compositions in an amount effective for
enhancing cognitive function, particularly to prevent, reduce
and/or delay the age-related cognitive-decline, cognitive
impairment, neurodegeneration conditions, stroke, and dementia in
an animal.
[0014] Other and further objects, features, and advantages of the
present invention will be readily apparent to those skilled in the
art.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0015] The following abbreviations may be used herein: AA,
arachidonic acid; ALA, alpha-linolenic acid; ANOVA, analysis of
variance; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid;
EPA, eicosapentaenoic acid; LA, linoleic acid; UFA, unsaturated
fatty acids (as used herein UFA refers to one or more such fatty
acids); NO, nitric oxide; NORC, nitric oxide releasing compound or
compounds; and L-Arg, L-arginine.
[0016] The term "animal" means any animal that could benefit from
one or more of the methods of the present invention including
enhancing cognitive function; altering cognitive, motor, or
behavioral function; reducing or preventing a decline of social
interaction; reducing or preventing age-related behavioral changes;
increasing trainability; maintaining optimal brain function;
facilitating learning and memory; reducing memory loss; retarding
brain aging; preventing or treating strokes; preventing or treating
dementia; and/or maintaining mental clarity and alertness.
Generally, the animal is a human, avian, bovine, canine, equine,
feline, hicrine, lupine, murine, ovine, and porcine animal.
Preferably, the term "animal" means an animal for which an
enhancement of cognitive function is desired or would benefit from
an improvement in cognitive function. A "companion animal" is any
domesticated animal, and includes, without limitation, cats, dogs,
rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses,
cows, goats, sheep, donkeys, pigs, and the like. Preferably, the
animal is a human or a companion animal such as a dog or cat.
[0017] The term "enhancing cognitive function" means one or more of
increasing cognitive, motor, or behavioral function in an animal or
preventing, reducing, or delaying a decline in cognitive, motor, or
behavioral function in an animal.
[0018] The term "unsaturated fatty acids" or "UFA" means
polyunsaturated fatty acids or monounsaturated fatty acids,
including monocarboxylic acids having at least one double bond.
UFAs include (n-6) fatty acids such as linoleic acid (LA) and
arachidonic acid (AA) and (n-3) fatty acids such as
eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA),
docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). UFAs
also include myristoleic acid, palmitoleic acid, oleic acid,
linoleic acid, cis-vaccenic acid, and erucic acid.
[0019] The term "fish oil" means a fatty or oily extract,
relatively rich in UFA, whether crude or purified, obtained from a
sea animal, preferably a cold-water fish such as, but not limited
to, salmon, tuna, mackerel, herring, sea bass, striped bass,
halibut, catfish, and sardines, as well as shark, shrimp, and
clams, or any combination thereof. Fish oil is generally a term of
art used by ingredient suppliers and encompasses a range or
products of varying UFA content and purity.
[0020] The term "nitric oxide releasing compounds" or "NORC" means
any compound or compounds that cause or can result in the release
of nitric oxide in an animal. Examples of such compounds include
L-arginine, L-arginine-containing peptides and proteins, and
analogs or derivatives thereof that are known or determined to
release nitric oxide, such as arginine alpha-ketoglutarate, GEA
3175, sodium nitroprusside, glyceryl trinitrate,
S-nitroso-N-acetyl-penicillamine, nitroglycerin, S-NO-glutathione,
NO-conjugated non-steroidal anti-inflammatory drugs (e.g.,
NO-naproxen, NO-aspirin, NO-ibuprofen, NO-Diclofenac,
NO-Flurbiprofen, and NO-Ketoprofen), NO-releasing compound 7,
NO-releasing compound 5, NO-releasing compound 12, NO-releasing
compound 18, diazenium diolates and derivatives thereof,
diethylamine NONOate, and any organic or inorganic compound,
biomolecule, or analog, homolog, conjugate, or derivative thereof
that causes the release of nitric oxide, particularly "free" NO, in
an animal. NORC is also defined to include supplements that can be
converted to nitric oxide releasing compounds when metabolized in
the body, e.g., citrulline and ornithine.
[0021] The term "effective amount" means an amount of a compound,
material, composition, medicament, or other material that is
effective to achieve a particular biological result. Such results
include, but are not limited to, one or more of the following:
enhancing cognitive function, increasing daytime activity,
improving learning (either the rate or ease of learning), improving
attention, improving social behavior, improving motor performance,
and/or improving cerebrovascular function, particularly in aging
animals. In various embodiments, "effective amount" refers to an
amount suitable to prevent a decline in any one or more of the
above qualities, or, in certain embodiments, to improve any one or
more of the above qualities, for example, cognitive function or
performance, learning rate or ability, problem solving ability,
attention span and ability to focus on a task or problem, motor
function or performance, social behavior, and the like. In other
embodiments, an effective amount is suitable to reduce either the
extent or rate of decline in an animal's cognitive skills or
functioning, and/or the effective amount is suitable to delay the
onset of such decline. Such effectiveness may be achieved, for
example, by administering the compositions of the present invention
to an animal or to a population of animals. Preferably the
prevention, reduction, or delay of such a decline, or the
improvement in an individual or population is relative to a cohort,
e.g., a control animal or a cohort population that has not received
the treatment, or been administered the composition or
medicament.
[0022] The term "cognitive function" refers to the special, normal,
or proper physiologic activity of the brain, including one or more
of the following: mental stability, memory/recall abilities,
problem solving abilities, reasoning abilities, thinking abilities,
judging abilities, ability to discriminate or make choices,
capacity for learning, ease of learning, perception, intuition,
attention, and awareness. "Enhanced cognitive function" or
"improved cognitive function" refers to any improvement in the
special, normal, or proper physiologic activity of the brain,
including one or more of the following: mental stability,
memory/recall abilities, problem solving abilities, reasoning
abilities, thinking abilities, judging abilities, ability to
discriminate or make choices, capacity for learning, ease of
learning, perception, intuition, attention, and awareness, as
measured by any means suitable in the art.
[0023] The term "behavior" means anything that an animal does in
response or reaction to a given stimulation or set of conditions.
"Enhanced behavior" or "improved behavior" means any improvement in
anything that an animal does in response or reaction to a given
stimulation or set of conditions. "Behavior" is used synonymously
with "behavioral function" herein.
[0024] The term "motor function" or "motor performance" means the
biological activity of the tissues that affect or produce movement
in an animal. Such tissue include, without limitation, muscles and
motor neurons. "Enhanced motor performance (or function)" or
"improved motor performance (or function)" refers to any
improvement in the biological activity of the tissues that affect
or produce movement in an animal.
[0025] The term "decline" of any of the foregoing categories or
specific types of qualities or functions in an individual
(phenotypes) is generally the opposite of an improvement or
enhancement in the quality or function. An "effective amount" of a
composition may be an amount required to prevent decline altogether
or to substantially prevent decline ("prevent" decline), to reduce
the extent or rate of decline ("reduce" decline) over any time
course or at any time point, or delay the onset, extent, or
progression of a decline ("delay" a decline). Prevention,
reduction, or delay of "decline" is frequently a more useful
comparative basis when working with non-diseased aging animals
(e.g., "healthy aging animals"). Prevention, reduction, and delay
can be considered relative to a control or cohort which does not
receive the treatment, for example, the diet or supplement of
interest. Prevention, reduction, or delay of either the onset of a
detrimental quality or condition, or of the rate of decline in a
particular function can be measured and considered on an individual
basis, or in some embodiments on a population basis. The net effect
of preventing, reducing, or delaying decline is to have less
decrease in cognitive, motor, or behavioral functioning per unit
time, or at a given end point. In other words, ideally, for an
individual or in a population, cognitive, motor, and behavioral
functioning is maintained at the highest possible level for the
longest possible time. Thus, it is not required that there be a net
increase in cognitive, motor, or behavioral function for any
embodiment. For purposes herein, an individual can be compared to a
control individual, group, or population. A population can likewise
be compared to an actual individual, to normalized measurements for
an individual, or to a group or population, as is useful.
[0026] The term "aging" means being of advanced age such that the
animal has exceeded 50% of the average lifespan for its particular
species and/or breed within a species. For example, if the average
lifespan for a given breed of dog is 10 years, then a dog within
that breed greater than 5 years old would be considered "aging" for
purposes herein. "Healthy aging animals" are those with no known
diseases, particularly diseases relating to loss of cognitive
impairment such as might confound the results. In studies using
healthy aging animals, cohort animals are preferably also healthy
aging animals, although other healthy animals with suitable
cognitive, motor, or behavioral functioning may be suitable for use
as comparative specimens. If animals with specific disease
diagnoses, or cognitive, motor, or behavioral limitations are used,
then the cohort animals should include animals that are similarly
diagnosed, or which present with similar indicia of the disease or
cognitive, motor, or behavioral limitation.
[0027] The term "food" or "food product" or "food composition"
means a product or composition that is intended for ingestion by an
animal, including a human, and provides nutrition to the
animal.
[0028] As used herein, a "food product formulated for human
consumption" is any composition specifically intended for ingestion
by a human being. The term "pet food" or "pet food composition"
means a composition intended for consumption by animals, preferably
by companion animals. A "complete and nutritionally balanced pet
food" is one that contains all known required nutrients for the
intended recipient or consumer of the food, in appropriate amounts
and proportions, based for example on recommendations of recognized
authorities in the field of companion animal nutrition. Such foods
are therefore capable of serving as a sole source of dietary intake
to maintain life or promote production, without the addition of
supplemental nutritional sources. Nutritionally balanced pet food
compositions are widely known and used in the art. The term
includes any food, feed, snack, food supplement, treat, meal
substitute, or meal replacement, whether intended for a human or
another animal. Animal food includes food or feed intended for any
domesticated or wild species. In preferred embodiments, a food for
an animal represents a nutritionally complete food composition,
e.g., a pelleted, extruded, or dry food. Examples of such animal
foods include extruded pet foods, such as foods for dogs and
cats.
[0029] The term "dietary supplement" means a product that is
intended to be ingested in addition to the normal animal diet.
Dietary supplements may be in any form, e.g., solid, liquid, gel,
tablets, capsules, powder, and the like. Preferably they are
provided in convenient dosage forms. In some embodiments they are
provided in bulk consumer packages such as bulk powders, liquids,
gels, or oils. In other embodiments, supplements are provided in
bulk quantities to be included in other food items such as snacks,
treats, supplement bars, beverages and the like.
[0030] The term "long-term administration" means periods of
repeated administration or consumption in excess of one month.
Periods of longer than two, three, or four months are preferred for
certain embodiments. Also preferred are more extended periods that
include longer than 5, 6, 7, 8, 9, or 10 months. Periods in excess
of 11 months or 1 year are also preferred. Longer term use
extending over 1, 2, 3, or more years are included in the
invention. For certain aging animals, the animal will continue
consuming on a regular basis for the remainder of its life.
Sometimes this is referred to as consumption for "extended"
periods.
[0031] The term "regular basis" means at least monthly dosing with
the compositions or consumption of the compositions, more
preferably weekly dosing. More frequent dosing or consumption, such
as twice, three, or seven times weekly, is preferred in certain
embodiments. Still more preferred are regimens that comprise at
least once daily consumption. The skilled artisan will appreciate
that the blood level of a compound or certain metabolites of that
compound or which result after the consumption of that compound,
may be a useful tool for assessing or determining dosing frequency.
A frequency, regardless of whether expressly exemplified herein,
that allows maintenance of a desired blood level of the measured
compound within acceptable ranges is useful herein. The skilled
artisan will appreciate that dosing frequency will be a function of
the composition that is being consumed or administered, and some
compositions may require more or less frequent administration to
maintain a desired blood level of the measured compound.
[0032] The term "oral administration" or "orally administering"
means that the animal ingests, or a human is directed to feed, or
does feed, the animal one or more of the compositions described
herein. Wherein a human is directed to feed the composition, such
direction may be that which instructs and/or informs the human that
use of the composition may and/or will provide the referenced
benefit, for example, enhancing cognitive function, improving liver
function, increasing daytime activity, improving learning,
improving attention, improving social behavior, improving motor
performance, and/or improving cerebrovascular function, or
preventing, reducing, or delaying a decline in such foregoing
functions or qualities. Such direction may be oral direction (e.g.,
through oral instruction from, for example, a physician,
veterinarian, or other health professional, or radio or television
media (i.e., advertisement), or written direction (e.g., through
written direction from, for example, a physician, veterinarian, or
other health professional (e.g., prescriptions), sales professional
or organization (e.g., through, for example, marketing brochures,
pamphlets, or other instructive paraphernalia), written media
(e.g., internet, electronic mail, website, or other
computer-related media), and/or packaging associated with the
composition (e.g., a label present on a container holding the
composition), or a combination thereof (e.g., label or package
insert with directions to access a website for more
information).
[0033] The term "cognitive drugs" means any compound, composition,
or drug useful for affecting cognitive function, e.g., monoamine
oxidase B inhibitors such as selegiline; vasodilators such as
nicerogoline and vinpocetine; phosphatidylserine; propentofyline;
anticholinesterases (cholinesterase inhibitors) such as tacrine,
galantamine, rivastigmine, vinpocetine, donepezil (ARICEPT.RTM.
(donepezil hydrochloride)), metrifonate, and physostigmine;
lecithin; choline cholinomimetics such as milameline and
xanomeline; ionotropic N-methyl-D-aspartate (NMDA) receptor
antagonists such as memantine; anti-inflammatory drugs such as
prednisolone, diclofenac, indomethacin, propentofyline, naproxen,
rofecoxin, ibruprofen and suldinac; metal chelating agents such as
cliquinol; Ginkgo biloba; bisphosophonates; selective oestrogen
receptor modulators such as raloxifene and estrogen; a
phytoestrogen; beta and gamma secretase inhibitors;
cholesterol-lowering drugs such as statins; calcitonin;
risedronate; alendronate; and combinations thereof.
[0034] The term "in conjunction" means that a composition
comprising UFA, NORC, a food composition, cognitive drug, or other
compound or composition of the present invention are administered
to an animal (1) together in a food composition or (2) separately
at the same or different frequency using the same or different
administration routes at about the same time or periodically.
"Periodically" means that the agent is administered on a dosage
schedule acceptable for a specific agent and that the food is fed
to an animal routinely as appropriate for the particular animal.
"About the same time" generally means that the food and agent are
administered at the same time or within about 72 hours of each
other. "In conjunction" specifically includes administration
schemes wherein a cognitive drug is administered for a prescribed
period and the compositions comprising UFA and NORC are
administered indefinitely.
[0035] The term "individual" when referring to an animal means an
individual animal of any species or kind.
[0036] The term "microorganism" encompasses at least bacteria,
molds and other fungi, and yeasts. Probiotics are beneficial
microorganisms that can survive or even multiply and thrive in the
gastrointestinal tract of an animal. Probiotics can contribute to
the overall health of an animal generally and particularly to the
gastrointestinal health of the animal.
[0037] The term "single package" means that the components of a kit
are physically associated, in or with one or more containers, and
considered a unit for manufacture, distribution, sale, or use.
Containers include, but are not limited to, bags, boxes or cartons,
bottles, packages of any type or design or material, over-wrap,
shrink-wrap, affixed components (e.g., stapled, adhered, or the
like), or combinations of any of the foregoing. For example, a
single package kit may provide containers of individual
compositions and/or food compositions physically associated such
that they are considered a unit for manufacture, distribution,
sale, or use.
[0038] The term "virtual package" means that the components of a
kit are associated by directions on one or more physical or virtual
kit components instructing the user how to obtain the other
components, e.g., in a bag or other container containing one
component and directions instructing the user to go to a website,
contact a recorded message or a fax-back service, view a visual
message, or contact a caregiver or instructor to obtain, for
example, instructions on how to use the kit, or safety or technical
information about one or more components of a kit. Examples of
information that can be provided as part of a virtual kit include
instructions for use; safety information such as material safety
data sheets; poison control information; information on potential
adverse reactions; clinical study results; dietary information such
as food composition or caloric composition; general information on
cognitive, behavioral, or motor function; diseases that effect
cognitive, behavioral, or motor function; treating cognitive,
behavioral, or motor function; or general information on treatment
or preservation of cognitive, behavioral, or motor function;
self-help relating to cognitive, behavioral, or motor function;
caregiver information for those caring for animals with cognitive,
behavioral, or motor function challenges; and use, benefits, and
potential side-effects or counter-indications for cognitive
drugs.
[0039] The term "health and wellness of an animal" means the
complete physical, mental, and social well being of the animal, not
merely the absence of disease or infirmity.
[0040] The term "extending the prime" means extending the number of
years an animal lives a healthy life and not just extending the
number of years an animal lives, e.g., an animal would be healthy
in the prime of its life for a relatively longer time.
[0041] All percentages expressed herein are by weight of the
composition on a dry matter basis unless specifically stated
otherwise. The skilled artisan will appreciate that the term "dry
matter basis" means that an ingredient's concentration or
percentage in a composition is measured or determined after any
free moisture in the composition has been removed.
[0042] As used throughout, ranges are used herein in shorthand, so
as to avoid having to set out at length and describe each and every
value within the range. Any appropriate value within the range can
be selected, where appropriate, as the upper value, lower value, or
the terminus of the range.
[0043] As used herein and in the appended claims, the singular form
of a word includes the plural, and vice versa, unless the context
clearly dictates otherwise. Thus, the references "a", "an", and
"the" are generally inclusive of the plurals of the respective
terms. For example, reference to "a puppy", "a method", or "a food"
includes a plurality of such "puppies", "methods", or "foods".
Reference herein, for example to "an antioxidant" includes a
plurality of such antioxidants, whereas reference to "pieces"
includes a single piece. Similarly, the words "comprise",
"comprises", and "comprising" are to be interpreted inclusively
rather than exclusively. Likewise the terms "include", "including"
and "or" should all be construed to be inclusive, unless such a
construction is clearly prohibited from the context. Where used
herein the term "examples," particularly when followed by a listing
of terms is merely exemplary and illustrative, and should not be
deemed to be exclusive or comprehensive.
[0044] The methods and compositions and other advances disclosed
here are not limited to particular methodology, protocols, and
reagents described herein because, as the skilled artisan will
appreciate, they may vary. Further, the terminology used herein is
for the purpose of describing particular embodiments only, and is
not intended to, and does not, limit the scope of that which is
disclosed or claimed.
[0045] Unless defined otherwise, all technical and scientific
terms, terms of art, and acronyms used herein have the meanings
commonly understood by one of ordinary skill in the art in the
field(s) of the invention, or in the field(s) where the term is
used. Although any compositions, methods, articles of manufacture,
or other means or materials similar or equivalent to those
described herein can be used in the practice of the present
invention, the preferred compositions, methods, articles of
manufacture, or other means or materials are described herein.
[0046] All patents, patent applications, publications, technical
and/or scholarly articles, and other references cited or referred
to herein are in their entirety incorporated herein by reference to
the extent allowed by law. The discussion of those references is
intended merely to summarize the assertions made therein. No
admission is made that any such patents, patent applications,
publications or references, or any portion thereof, are relevant,
material, or prior art. The right to challenge the accuracy and
pertinence of any assertion of such patents, patent applications,
publications, and other references as relevant, material, or prior
art is specifically reserved. Full citations for publications not
cited fully within the specification are set forth at the end of
the specification.
The Invention
[0047] In one aspect, the invention provides compositions suitable
for enhancing cognitive function in an animal. The compositions
comprise one or more unsaturated fatty acids (UFA) and one or more
nitric oxide releasing compounds (NORC) in an amount effective for
enhancing cognitive function in an animal. In certain embodiments,
the compositions further comprise one or more B vitamins, one or
more antioxidants, or combinations thereof. The invention is based
upon the discovery that compositions comprising UFA and NORC, with
or without B vitamins and/or antioxidants, are effective for
enhancing cognitive function in animals. The compositions are
useful for affecting one or more cognitive, motor, or behavioral
functions in animals regardless of health or age, e.g., juvenile,
adult, or senior animals. The compositions increase one or more
cognitive, motor, or behavioral functions in animals, including
healthy animals of all ages or animals that are susceptible to or
suffering from a decline in cognitive function brought about by the
aging process or by disease. Similarly, the compositions prevent,
reduce, or delay a decline in cognitive function in animals,
particularly aging animals susceptible to or suffering from a
decline in cognitive function brought about by the aging process or
by disease. The compositions are particularly effective for
reducing or delaying the effects of age-related and disease-related
cognitive decline in humans and companion animals, particularly
dogs and cats. The compositions are also useful for enhancing
cognitive function when cognitive decline is caused by changes in
brain function, particularly brain aging, or damage from disease,
particularly strokes.
[0048] The UFA can be any UFA suitable for administration to an
animal. UFAs can be obtained from any suitable source, synthetic or
natural. Preferred sources of UFA are natural sources of such fatty
acids and include, without limitation, primrose; dark green
vegetables such as spinach; algae and blue-green algae such as
spirulina; plant seeds and oils from plants such as flax, canola,
soybean, walnut, pumpkin, safflower, sesame, wheat germ, sunflower,
corn, and hemp; and fish such as salmon, tuna, mackerel, herring,
sea bass, striped bass, halibut, catfish, sardines, shark, shrimp,
and clams; and the extracted oils of any one or more of the
foregoing. The UFA may also be synthetic, and as such may be
produced according to any means suitable in the art, from any
suitable starting material. The UFA may comprise a blend of any one
or more UFA from any one or more sources, such as those exemplified
above, whether natural or synthetic. In preferred embodiments, the
UFA are long chain polyunsaturated fatty acids (LCPUFA) comprising
one or more monocarboxylic acids having at least 20 carbon atoms
and at least two double bonds. Preferably, the UFAs are (n-6) fatty
acids or (n-3) fatty acids, most preferably n-3 LCPUFAs.
[0049] The NORC can be any NORC suitable for administration to an
animal. NORC can be obtained from any suitable source, synthetic or
natural. In various embodiments, the NORC comprises arginine.
Presently preferred sources of arginine include, without
limitation, animal and plant proteins. Examples of plants
considered rich in arginine content and suitable for use herein
include, but are not limited to, legumes such as soy, lupins, and
carob; grains such as wheat and rice; and fruits such as grapes.
Seeds and nuts of plants such as cacao and peanut are also
considered rich in arginine content and are therefore useful
herein. Some examples of suitable animal proteins considered rich
in arginine content are poultry and fish products. The NORC can
also be synthetically produced, according to any suitable means in
the art. As with UFA, the NORC content of any composition disclosed
herein can include a blend of any natural or synthetic NORC. Both
UFA and NORC, whether natural or synthetic, can be obtained
directly or provided by a commercial source.
[0050] In one aspect, the compositions further comprise one or more
B vitamins, one or more antioxidants, or combinations thereof. The
B vitamins can be any B vitamin suitable for administration to an
animal. B vitamins include vitamins B1 (thiamine), B2 (riboflavin),
B3 (aka P or PP) (niacin, including nicotinic acid and/or
nicotinamide), B5 (pantothenic acid), B6 (pyridoxine), B7 (aka H)
(biotin), B8 (myo-inositol), B9 (aka M or B-c) (folic acid), B12
(cobalamin), or salts, conjugates, or derivatives thereof
recognized of found to have B vitamin activity. Combinations of any
of the foregoing are also useful herein and are sometimes referred
to herein as "mixtures" of B vitamins. Since the vitamin
requirements vary for different species, not all of the listed
compounds are deemed vitamins for all species. For example, since
it is known that myo-inositol can be synthesized by humans, it is
no longer deemed a vitamin, as it is not required for adequate
human nutrition.
[0051] The antioxidants can be any antioxidant suitable for
administration to an animal. Antioxidants are well known in the
art, particularly the art of food technology and food formulation.
Natural antioxidant compounds include vitamins (such as A, C and E,
and derivative, conjugates, or analogs thereof), as well as plant
extracts, including extracts from fruit, vegetables, herbs, seeds,
and other types and/or parts of plants. Compounds such as
.alpha.-lipoic acid, chlorophyll and derivatives thereof,
glutathione, ubiquinols (e.g., coenzyme Q10), carotenoids (e.g.,
lycopene), flavonoids, phenolic acids and polyphenols, and
pycnogenol are known to be excellent antioxidants. Some examples of
plant sources of antioxidants include those from fruits such as
berries (cherry, blackberry, strawberry, raspberry, crowberry,
blueberry, bilberry/wild blueberry, black currant), pomegranate,
grape, orange, plum, pineapple, kiwi fruit, and grapefruit; those
from vegetables including kale, chili pepper, red cabbage, peppers,
parsley, artichoke, Brussels sprouts, spinach, lemon, ginger,
garlic, and red beets; those from dry fruits like apricots, prunes,
and dates; from legumes including broad beans, pinto beans, and
soybeans. Also nuts and seeds such as pecans, walnuts, hazelnuts,
ground nut, and sunflower seeds; cereals such as barley, millet,
oats, and corn. Many natural antioxidants are also available from a
wide variety of spices including cloves, cinnamon, rosemary, and
oregano. Less widely known sources of antioxidants include Ginkgo
biloba, and tropical plants such as uyaku, and carica papaya.
Antioxidant properties of various teas and green tea, as well as
fermented products such as red wine, have become of great interest
in recent years and such would be suitable for use herein. Selenium
is an excellent oxygen scavenger and works well, especially with
vitamin or related tocopherol compounds. Synthetic dietary
antioxidants include butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT) which are commonly used in food products. Any
of the foregoing, alone or in combination, are suited for use
herein, as are combinations of natural and synthetic antioxidants.
In one embodiment, the antioxidants comprise astaxanthin alone or
in combination with other antioxidants.
[0052] The compositions comprise UFA and NORC, and B vitamins and
antioxidants if included in the composition, in an amount effective
for enhancing cognitive function. Generally, the compositions
comprise from about 0.1% to about 50% UFA, and from about 0.1% to
about 20% NORC. When included in the composition, the composition
comprises from about 0.1 to 40 times the recommended daily
requirement (RDA) of B vitamins and from about 0.0001% to about 25%
of antioxidants. In various embodiments, the compositions comprise
from about 1 to about 30% UFA, preferably from about 1 to about 15%
UFA; and from about 1 to about 15% NORC, preferably from about 1 to
about 10% NORC. In various embodiments, the B vitamins comprise
from about 1 to 20 times the RDA, preferably from about 1 to 10
times the RDA, and antioxidants comprise from about 0.0001% to
about 15%, most preferably from about 0.001% to about 5%, most
preferably from about 0.001% to about 2%. In one embodiment, the
compositions comprise UFA, NORC, and a mixture of one or more B
vitamins and one or more antioxidants in such amounts. In one
embodiment, the composition comprises from about 0.5 g to about 10
g UFA, and from about 0.5 g to about 10 g NORC, with or without the
RDA for B vitamins and antioxidants.
[0053] The compositions may further comprise substances such as
minerals, other vitamins, salts, functional additives including,
for example, palatants, colorants, emulsifiers, antimicrobial or
other preservatives. Minerals that may be useful in such
compositions include, for example, calcium, phosphorous, potassium,
sodium, iron, chloride, boron, copper, zinc, magnesium, manganese,
iodine, selenium and the like. Examples of additional vitamins
useful herein include such fat soluble vitamins as A, D, E, and K.
Inulin, amino acids, enzymes, coenzymes, and the like may be useful
to include in various embodiments.
[0054] In one embodiment, the compositions are food compositions,
including human and pet food compositions. Such compositions
include foods intended to supply the necessary dietary requirements
for an animal, animal treats (e.g., biscuits), or dietary
supplements. The compositions may be a dry composition (e.g.,
kibble), semi-moist composition, wet composition, or any mixture
thereof. In another embodiment, the composition is a dietary
supplement such as a gravy, drinking water, beverage, yogurt,
powder, granule, paste, suspension, chew, morsel, treat, snack,
pellet, pill, capsule, tablet, or any other suitable delivery form.
The dietary supplement can comprise a high concentration of the UFA
and NORC, and optional B vitamins and antioxidants. This permits
the supplement to be administered to the animal in small amounts,
or in the alternative, can be diluted before administration to an
animal. The dietary supplement may require admixing, or preferably
be admixed with water or other diluent prior to administration to
the animal.
[0055] In one embodiment, the compositions are refrigerated or
frozen compositions. In another embodiment, the UFA and NORC are
pre-blended with the other components to provide the beneficial
amounts needed. In yet other embodiments, the UFA and NORC are used
to coat a food, snack, pet food composition, or pet treat. In one
embodiment, the UFA and NORC are added to the composition just
prior to offering it to the animal, e.g., using a sprinkled powder
or a mix. Such compositions can further comprise B vitamins and/or
antioxidants.
[0056] The compositions can optionally comprise one or more
supplementary substances that promote or sustain general health.
Preferred substances may be associated with improved mental health
or enhanced cognitive function or may be substances that inhibit,
delay, or decrease loss of cognitive function, e.g., herbs or
plants that enhance cognitive function.
[0057] In various embodiments, pet food or pet treat compositions
comprise from about 15% to about 50% crude protein. The crude
protein material may comprise vegetable proteins such as soybean
meal, soy protein concentrate, corn gluten meal, wheat gluten,
cottonseed, and peanut meal, or animal proteins such as casein,
albumin, and meat protein. Examples of meat protein useful herein
include pork, lamb, equine, poultry, fish, and mixtures
thereof.
[0058] The compositions may further comprise from about 5% to about
40% fat. The compositions may further comprise a source of
carbohydrate. The compositions may comprise from about 15% to about
60% carbohydrate. Examples of such carbohydrates include grains or
cereals such as rice, corn, milo, sorghum, alfalfa, barley,
soybeans, canola, oats, wheat, and mixtures thereof. The
compositions may also optionally comprise other materials such as
dried whey and other dairy by-products.
[0059] In some embodiments, the ash content of the composition
ranges from less than 1% to about 15%, preferably from about 5% to
about 10%.
[0060] The moisture content can vary depending on the nature of the
composition. In a preferred embodiment, the composition is a
complete and nutritionally balanced pet food. In this embodiment,
the pet food may be a "wet food", "dry food", or food of
intermediate moisture content. "Wet food" describes pet food that
is typically sold in cans or foil bags, and has a moisture content
typically in the range of about 70% to about 90%. "Dry food"
describes pet food which is of a similar composition to wet food,
but contains a limited moisture content, typically in the range of
about 5% to about 15% or 20%, and therefore is presented, for
example, as small biscuit-like kibbles. In one presently preferred
embodiment, the compositions have moisture content from about 5% to
about 20%. Dry food products include a variety of foods of various
moisture contents, such that they are relatively shelf-stable and
resistant to microbial or fungal deterioration or contamination.
Also preferred are dry food compositions which are extruded food
products, such as pet foods, or snack foods for either humans or
companion animals.
[0061] The compositions may also comprise one or more fiber
sources. The term "fiber" includes all sources of "bulk" in the
food whether digestible or indigestible, soluble or insoluble,
fermentable or nonfermentable. Preferred fibers are from plant
sources such as marine plants but microbial sources of fiber may
also be used. A variety of soluble or insoluble fibers may be
utilized, as will be known to those of ordinary skill in the art.
The fiber source can be beet pulp (from sugar beet), gum arabic,
gum talha, psyllium, rice bran, carob bean gum, citrus pulp,
fructooligosaccharide, pectin, short chain oligofructose,
mannanoligofructose, soy fiber, arabinogalactan,
galactooligosaccharide, arabinoxylan, or mixtures thereof.
[0062] Alternatively, the fiber source can be a fermentable fiber.
Fermentable fiber has previously been described to provide a
benefit to the immune system of a companion animal. Fermentable
fiber or other compositions known to skilled artisans that provide
a prebiotic to enhance the growth of probiotics within the
intestine may also be incorporated into the composition to aid in
the enhancement of the benefit provided by the present invention to
the immune system of an animal.
[0063] In other embodiments, the compositions further comprise
prebiotics, probiotics, or a combination thereof. Probiotics are
live microorganisms that have a beneficial effect in the prevention
and treatment of specific medical conditions when ingested.
Probiotics are believed to exert biological effects through a
phenomenon known as colonization resistance. The probiotics
facilitate a process whereby the indigenous anaerobic flora limits
the concentration of potentially harmful (mostly aerobic) bacteria
in the digestive tract. Other modes of action, such as supplying
enzymes or influencing enzyme activity in the gastrointestinal
tract, may also account for some of the other functions that have
been attributed to probiotics. Prebiotics are nondigestible food
ingredients that beneficially affect host health by selectively
stimulating the growth and/or activity of bacteria in the colon.
Prebiotics include fructooligosaccharides (FOS),
xylooligosaccharides (XOS), galactooligosaccharides (GOS), and
mannooligosaccharides (typically for non-human foods such as
petfoods). The prebiotic, fructooligosaccharide (FOS) is found
naturally in many foods such as wheat, onions, bananas, honey,
garlic, and leeks. FOS can also be isolated from chicory root or
synthesized enzymatically from sucrose. FOS fermentation in the
colon results in a large number of physiologic effects including
increasing the numbers of bifidobacteria in the colon, increasing
calcium absorption, increasing fecal weight, shortening of
gastrointestinal transit time, and possibly lowering blood lipid
levels. The increase in bifidobacteria has been assumed to benefit
human health by producing compounds to inhibit potential pathogens,
by reducing blood ammonia levels, and by producing vitamins and
digestive enzymes. Probiotic bacteria such as Lactobacilli or
Bifidobacteria are believed to positively affect the immune
response by improving the intestinal microbial balance leading to
enhanced antibody production and phagocytic (devouring or killing)
activity of white blood cells. Bifidobacterium lactis could be an
effective probiotic dietary supplement for enhancing some aspects
of cellular immunity in the elderly. Probiotics enhance systemic
cellular immune responses and may be useful as a dietary supplement
to boost natural immunity in otherwise healthy adults. Probiotics
include many types of bacteria but generally are selected from four
genera of bacteria: Lactobacilllus acidophillus, Bifidobacteria,
Lactococcus, and Pediococcus. Beneficial species include
Enterococcus and Saccharomyces species. The amount of probiotics
and prebiotics to be administered to the animal is determined by
the skilled artisan based upon the type and nature of the prebiotic
and probiotic and the type and nature of the animal, e.g., the age,
weight, general health, sex, extent of microbial depletion,
presence of harmful bacteria, and diet of the animal. Generally,
probiotics are administered to the animal in amounts of from about
one to about twenty billion colony forming units (CFUs) per day for
the healthy maintenance of intestinal microflora, preferably from
about 5 billion to about 10 billion live bacteria per day.
Generally, prebiotics are administered in amounts sufficient to
positively stimulate the healthy microflora in the gut and cause
these "good" bacteria to reproduce. Typical amounts are from about
one to about 10 grams per serving or from about 5% to about 40% of
the recommended daily dietary fiber for an animal. The probiotics
and prebiotics can be made part of the composition by any suitable
means. Generally, the agents are mixed with the composition or
applied to the surface of the composition, e.g., by sprinkling or
spraying. When the agents are part of a kit, the agents can be
admixed with other materials or in their own package.
[0064] The compositions and dietary supplements may be specially
formulated for the intended recipients or consumers, such as for
adult animals or for older or young animals. For example, a
composition adapted for puppies or kittens or adapted for active,
pregnant, lactating, or aging animals can be prepared. In general,
specialized compositions will comprise energy and nutritional
requirements appropriate for animals at different stages of
development or age.
[0065] Certain aspects of the invention are preferably used in
combination with a complete and balanced food. According to certain
embodiments provided herein, the compositions comprising the UFA
and NORC, are preferably used with a high-quality commercial food.
As used herein, "high-quality commercial food" refers to a diet
manufactured to produce the digestibility of the key nutrients of
80% or more, as set forth in, for example, the recommendations of
the National Research Council above for dogs, or in the guidelines
set forth by the Association of American Feed Control Officials.
Similar high nutrient standards would be used for other
animals.
[0066] In one embodiment, the food compositions comprise any of a
variety of ingredients or combinations thereof selected for their
contributions to the overall composition. Thus a skilled food
technologist may choose from among natural (e.g., plant or
plant-derived, animal, or animal-derived, and microbial or
microbially-derived), and synthetic ingredients or components. In
particular embodiments, the ingredients may include any of the
cereal grains and/or fractions or components thereof, meat and meat
by-products, fish, shellfish, or other seafood, other animal
products or by-products, eggs from any source, vitamins, minerals,
salts, sweeteners, fiber, flavoring or other palatants, coloring,
and functional ingredients such as emulsifiers, stabilizers,
softeners, functional coatings, and the like. Cereals useful in the
invention include all plants recognized as "cereal" crops, whether
currently used in commercial agriculture or merely known
practically or botanically as being a "cereal". For example,
"cereals" includes corn, wheat, rice, barley, sorghum, millet,
oats, rye, triticale, buckwheat, fonio, and quinoa. The skilled
artisan will appreciate that in a given food composition, it is not
uncommon to use one or more such cereal products. Meats useful in
the invention include products from any animal, preferably muscle
tissue such as chicken or other poultry, lamb, sheep, veal, beef,
or pork. Other animal products and by-products useful in the
invention include dairy products or by-products derived from the
milk of any species. Other important components or ingredients
include fats and the skilled artisan will appreciate that many
sources of vegetable, animal, or microbial fats are available for
formulating food compositions. In one embodiment, the source of fat
is a plant fat such as corn, soy, or canola oil, preferably one
that is readily available. In another embodiment, an animal fat,
such as tallow, is useful for providing calories from fat, as well
as enticing flavor to meat-eating animals. Of course, combinations
of any of the foregoing ingredients, such as fats, are known in the
art and useful for optimizing the food compositions based on
functional properties as well as price and availability.
[0067] The skilled artisan will also appreciate that in formulating
the food compositions of the invention, the formulation may vary
slightly, so as to allow consideration by the formulator of the
price and/or availability of certain ingredients in the
compositions, as well as the batch-to-batch variation in the
analysis of certain ingredients. Thus a given food composition or
formulation may vary slightly from batch to batch, plant to plant,
or even season to season depending on such factors. Notwithstanding
such variation in specific ingredients selected for manufacturing a
particular batch of a food composition, the overall composition
(for example, analysis of protein, carbohydrate, fat, fiber, or
other component) may be held constant or at least substantially
constant, for example, in accordance with a label claim, such as a
claim or guarantee of a minimum or maximum percent of a particular
component.
[0068] In other embodiments, the compositions of the invention
comprise UFA and NORC, and, if included in the composition, B
vitamins and antioxidants in an amount effective for one or more of
reducing or preventing a decline of social interaction, reducing or
preventing age-related behavioral changes, increasing trainability,
maintaining optimal brain function, facilitating learning and
memory, reducing memory loss, retarding brain aging, preventing or
treating strokes, preventing or treating dementia, and maintaining
mental clarity and alertness in an animal.
[0069] The skilled artisan will understand how to determine the
appropriate amount of UFA, NORC, B vitamins, antioxidants, and any
other ingredients to be added to a given composition. The skilled
formulator may consider important the animal's species, age, size,
weight, health, and the like in determining how best to formulate a
particular composition, food, or pharmaceutical composition
comprising the UFA, NORC, and other components. Other factors that
may be taken into account for formulation include the type of
composition (e.g., pet food composition versus dietary supplement),
the desired dosage of each component (UFA, NORC), the average
consumption of specific types of compositions by different animals
(e.g., based on species, body weight, activity/energy demands, and
the like) and the manufacturing conditions under which the
composition is prepared. Preferably, the concentrations of UFA and
NORC to be added to the composition are calculated on the basis of
the energy and nutrient requirements of the animal. When
formulating the compositions of the present invention, a skilled
can determine the amounts of the UFA, NORC, and other components of
the compositions and of other compounds or ingredients, in for
example a food composition, based upon the desired dosages and the
characteristics of the animal.
[0070] For pet foods and food products formulated for human
consumption, the amount of UFA as a percentage of the composition
is preferably in the range of about 0.1% to about 13% of the
composition, although a greater percentage can be supplied. In
various embodiments, the amount of UFA is about 0.1%, 0.2%, 0.3%,
0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%,
1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,
2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%,
3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%,
4.8%, 4.9%, 5.0%, or more, e.g., 6%, 7%, 8%, 9%, 10%, 11%, 12%,
13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or more, of the composition.
Up to 30, 40, or 50% UFA may be used in certain embodiments.
[0071] For pet foods and food products formulated for human
consumption, the amount of NORC as a percentage of the composition
is in the range of about 0.1% to about 12% of the composition,
although a greater percentage can be supplied. In various
embodiments, the amount of NORC is about 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%,
1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%,
2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%,
3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%,
4.9%, 5.0%, or more, e.g., 6%, 7%, 8%, 9%, 10%, 11%, 12% or more,
up to about 15% or even 20% of the composition. In specific
embodiments, 2-2.5% UFA and 2-2.5% NORC are used. In such
embodiments, pure L-arginine is a preferred NORC compound. Dietary
supplements may be formulated to contain several-fold higher
concentrations of UFA and NORC, to be amenable for administration
to an animal in the form of a tablet, capsule, liquid concentrate,
emulsion, suspension, gel, or other dosage form, or to be diluted
before administration, such as by dilution in water, or adding to a
pet food (for example, by spraying or sprinkling thereon), and
other modes of administration suitable for administering such
dietary supplements.
[0072] In an alternative embodiment, the amount of UFA and NORC in
the composition is a function of an amount required to establish
specified concentrations, or a desired range of concentrations, of
UFA and/or NORC, or a metabolite thereof, in the blood serum of the
animal. The specified concentrations, or desired ranges of UFA
and/or NORC in the blood serum may be calculated by determining the
blood serum levels of animals fed the recommended amounts of UFA
and NORC specified above, as would be appreciated by one of skill
in the art.
[0073] In a preferred embodiment, the food compositions comprise a
macronutrient composition suitable for the type of food being
designed. In one embodiment, the food composition has about 20 to
32% protein, about 30 to 50% carbohydrate, about 5% to 20% fat, and
about 15% to 25% moisture. In another embodiment, the food
composition is a pet food composition such as a premium or
super-premium pet food composition. In one embodiment, the pet food
is formulated for canines and has a protein content of about
20-30%, preferably about 24-28%, and more preferably about 25-27%.
In one embodiment, the protein content of a dog food composition is
about 26% by weight. In another embodiment, the formulation is for
felines and has a protein content of about 35-45%, preferably about
37-42%, and more preferably about 39-41%. In one embodiment, the
protein content of a cat food composition is about 40%. In a
preferred embodiment, the composition is a food product comprising
UFA and NORC, and further comprising about 15% to about 50%
protein, about 5% to about 40% fat, about 5% to about 10% ash
content, and having a moisture content of about 5% to about
20%.
[0074] In one embodiment, the food composition is a wet food, such
as a canned food, frozen food, or fresh food product. In one
embodiment, the food composition is shelf stable. In another, it
must be refrigerated. In other embodiments, the food composition is
an intermediate moisture product or a dry food product as described
above.
[0075] In a preferred embodiment, the UFA is a fish oil and the
NORC is arginine or a nitric oxide-releasing derivative thereof. In
certain embodiments, the compositions comprise from about 0.1% to
about 50% fish oil and from about 0.1% to about 20% arginine. In
preferred embodiments, both UFA and NORC are within the preferred
ranges provided herein when the composition is a food product. Such
ranges offer improved palatability and functional properties that
will enhance acceptance of the food product.
[0076] In various embodiments, the composition is a human food
composition, pet food composition, or a dietary supplement. The
composition that is a dietary supplement may contain vastly
different concentrations or amounts of the UFA and NORC than a food
product or pet food. Generally, the palatability and similar
sensory factors are not of concern with certain dietary
supplements, e.g., those that are swallowed.
[0077] In one embodiment, the UFA comprises one or more of a
natural fish oil, ALA, EPA, DPA, DHA, or another n-3 fatty acid
from any source. Combinations of UFA sources are of course
contemplated for use herein. UFA with n-3 or n-6 are also
contemplated for use in various embodiments.
[0078] Preferably, the composition is formulated for a companion
animal, e.g., a dog or cat. In other embodiments, the animal is a
human, with or without an age-related cognitive decline.
[0079] In one embodiment, the composition is formulated to provide
about 0.5 g to about 10 g each of UFA and NORC per day in one or
more portions of a recommended serving size. For example, if the
composition is intended for twice-per-day consumption, a 10 g dose
can be provided by formulating the composition such that each
recommended portion (e.g., 2 spoonsful, or one 20 g portion, or the
like) to provide 5 g each of UFA and NORC.
[0080] In a preferred embodiment, the compositions comprise from
about 0.1% to about 50% fish oil; and from about 0.1% to about 20%
arginine. Preferably, the compositions further comprise from about
0.1 to 40 times the recommended daily requirement of B vitamins,
from about 0.0001% to about 25% antioxidants, or both. In one
embodiment, the composition used in the methods comprises from
about 0.5 g to about 10 g UFA, and from about 0.5 g to about 10 g
NORC, with or without B vitamins and antioxidants.
[0081] In another aspect, the compositions further comprise one or
more cognitive drugs in an amount effective for enhancing cognitive
function. The skilled artisan can determine the amount of cognitive
drug to be added to the composition based upon the recommended
dosage for the drug given by its manufacturer or upon the animal's
weight, species, age, health status, and the like.
[0082] In another aspect, the invention provides pharmaceutical
compositions comprising a composition of the present invention and
one or more pharmaceutically-acceptable carriers, diluents, or
excipients. Generally, pharmaceutical compositions are prepared by
admixing a compound or composition with excipients, buffers,
binders, plasticizers, colorants, diluents, compressing agents,
lubricants, flavorants, moistening agents, and the like, including
other ingredients known to skilled artisans to be useful for
producing pharmaceuticals and formulating compositions that are
suitable for administration to an animal as pharmaceuticals.
Optionally, the pharmaceutical compositions further comprise one or
both of a B vitamin and an antioxidant.
[0083] In another aspect, the invention provides methods for
enhancing cognitive function in an animal. The methods generally
comprise administering to an animal a composition comprising one or
more unsaturated fatty acids (UFA) and one or more nitric oxide
releasing compounds (NORC) to the animal in an amount effective for
enhancing cognitive function in the animal. In certain embodiments,
the compositions further comprise one or more B one or more
antioxidants, or combinations thereof.
[0084] In some embodiments, the UFA, NORC, B vitamins, and
antioxidants are administered to the animal in amounts given herein
when describing the compositions. In one embodiment, the
composition is administered in an amount effective to increase one
or more cognitive, motor, or behavioral functions in animals,
including animals of all ages that are healthy or animals that are
susceptible to or suffering from a decline in cognitive function
brought about by the aging process or by disease. In another
embodiment, the composition is administered in an amount effective
to prevent, reduce, or delay a decline in cognitive function in
animals, particularly aging animals susceptible to or suffering
from a decline in cognitive function brought about by the aging
process or by disease. In certain embodiments, the daily dose for
the compositions ranges from about 5 mg/day to about 5,000 mg/day,
10,000 mg/day, or 20,000, or more per animal. Preferably, the daily
dose ranges from about 30 mg/day to about 10,000 mg/day per animal,
and more preferably from about 750 mg/day to about 7,500 mg/day per
animal. The daily dose of UFA and NORC can be measured in terms of
grams of UFA and NORC per kg of body weight (BW) of the animal. The
daily dose of UFA and NORC, therefore can range from about 0.001
g/kg to about 50 g/kg BW of the animal, although greater or lesser
doses can be provided. Preferably, the daily dose of UFA and NORC
is from about 0.001 g/kg to about 25 g/kg BW of the animal. More
preferably, the daily dose of UFA and NORC is from about 0.001 g/kg
to about 10 g/kg BW of the animal. More preferably, the daily dose
of UFA and NORC is from about 0.001 g/kg to about 5 g/kg BW of the
animal. More preferably, the daily dose of UFA and NORC is from
about 0.001 g/kg to about 1 g/kg BW of the animal. More preferably,
the daily dose of the UFA and NORC is from about 0.001 g/kg to
about 0.5 g/kg BW of the animal.
[0085] In another aspect, the invention provides methods for
enhancing cognitive function in an animal. The methods generally
comprise administering to an animal a composition comprising one or
more unsaturated fatty acids (UFA) and one or more supplements that
can be metabolized to produce nitric oxide releasing compounds
(NORC) to the animal in an amount effective for enhancing cognitive
function in the animal. In certain embodiments, the compositions
further comprise one or more B vitamins, one or more antioxidants,
or combinations thereof. The supplements are converted to NORC by
the metabolic processes in the animals and the NORC are involved in
enhancing cognitive function as described herein. In preferred
embodiments, the supplements are citrulline/citrulline and
ornithine. The supplements can be administered in any amount
sufficient to obtain the NORC amounts required herein upon
metabolism. Typically, the supplements are administered in a
composition comprising UFA and supplements, preferably about 0.1%
to about 50% UFA and 0.1% to about 20% supplement.
[0086] Only a portion of the arginine consumed by an individual
remains available for metabolization to NO. Arginine is metabolized
into citrulline and NO via the enzyme nitric oxide synthase (NOS).
As much as 60% of ingested arginine is metabolized in the liver by
arginase before entering the circulation, where any remaining
arginine may be metabolized to citrulline and NO. An alternative
source for arginine is the endogenous production of arginine from
the amino acid citrulline. This route contributes about 20% to
whole body arginine production. Citrulline is produced in the
intestine and enters the circulation without being metabolized by
the liver, with almost complete conversion to arginine in the
kidneys. Citrulline passes through the liver with little or no
metabolization and is converted to arginine in the mitochondria.
The majority of circulating citrulline is converted in the kidneys,
which are comprised of highly metabolically active tissue.
Citrulline circulating in the bloodstream is first converted to
arginine and then in cells to citrulline and NO. Citrulline can be
administered via the gastrointestinal (GI) tract in oral and
enteral products. Citrulline, endogenously, is a product of the
metabolism of glutamine in the gut, generated from ornithine as
part of the urea cycle, and formed by nitric oxide synthases
distributed in the body. Arginine is generated from citrulline,
mainly in the kidney, through its metabolism by argininosuccinate
synthase (EC 6.3.4.5) and argininosuccinate lyase (EC 4.3.2.1).
Significantly, the conversion of citrulline to arginine occurs
continuously, as long as citrulline is circulating in the
bloodstream. As a result, circulating citrulline makes it possible
to maintain elevated concentrations of arginine over time, which in
turn makes it possible to maintain a steady release of NO in cells.
Since the amino acid citrulline is a precursor to L-arginine,
citrulline can substitute for L-arginine in nutritional
compositions. Unlike arginine, citrulline is not metabolized by the
liver following entry into the bloodstream through absorption from
the diet or de novo intestinal production. Citrulline is
enzymatically converted to arginine by mitochondria via a part of
the urea cycle.
[0087] Similarly, ornithine is a precursor to L-arginine. As a
result, ornithine can substitute for L-arginine in nutritional
compositions. Unlike arginine, ornithine is not metabolized by the
liver following entry into the bloodstream through absorption from
the diet or de novo intestinal production. Ornithine is
enzymatically converted to arginine by mitochondria via a part of
the urea cycle.
[0088] Administration in accordance with the methods can be on an
as-needed or as-desired basis of varying or regular frequency. A
goal of regular ingestion is to provide the animal with a regular
and consistent dose of the composition or the direct or indirect
metabolites that result from such ingestion. Such regular and
consistent dosing will tend to create constant blood levels of the
components of the compositions or their direct or indirect
metabolites. Thus, regular administration can be once monthly, once
weekly, once daily, or more than once daily. Similarly,
administration can be every other day, week, or month, every third
day, week, or month, every fourth day, week, or month, and the
like. Administration can be multiple times per day. When utilized
as a supplement to ordinary dietetic requirements, the composition
may be administered directly to the animal, e.g., orally, or
otherwise. The compositions can alternatively be contacted with, or
admixed with, daily feed or food, including a fluid, such as
drinking water, or an intravenous connection for an animal that is
receiving such treatment. When utilized as a daily feed or food,
administration will be well known to those of ordinary skill.
[0089] Administration can also be carried out as part of a dietary
regimen for the animal. For example, a dietary regimen may comprise
causing the regular ingestion by the animal of a composition
described herein in an amount effective to prevent, reduce, or
delay a decline in one or more cognitive, motor, or behavioral
functions in the animal.
[0090] According to the methods of the invention, administration of
the compositions, including administration as part of a dietary
regimen, can span a period of time ranging from parturition through
the adult life of the animal. In various embodiments, the animal is
a human or companion animal such as a dog or cat. In certain
embodiments, the animal is a young or growing animal. In more
preferred embodiments, the animal is an aging animal. An animal
that has reached about 35% of its projected lifespan is generally
preferred. In presently preferred embodiments administration
begins, for example, on a regular or extended regular basis, when
the animal has reached more than about 30%, 40%, or 50% of its
projected or anticipated lifespan. In some embodiments, the animal
has attained 40, 45, or 50% of its anticipated lifespan. In yet
other embodiments, the animal is older having reached 60, 66, 70,
75, or 80% of its likely lifespan. A determination of lifespan may
be based on actuarial tables, calculations, estimates, or the like,
and may consider past, present, and future influences or factors
that are known to positively or negatively affect lifespan.
Consideration of species, gender, size, genetic factors,
environmental factors and stressors, present and past health
status, past and present nutritional status, stressors, and the
like may also influence or be taken into consideration when
determining lifespan.
[0091] A composition or method for enhancing cognitive function has
many effects on an animal. Many day-to-day life functions are
dependent upon or related to cognitive function. For example,
enhancing cognitive function is related to preventing a decline of
social interaction, reducing or preventing age-related behavioral
changes, increasing trainability, maintaining optimal brain
function, facilitating learning and memory, reducing memory loss,
retarding brain aging, preventing or treating strokes, and
preventing or treating dementia in an animal. Similarly, enhancing
cognitive function promotes the overall health and wellness of an
animal. Further, enhancing cognitive function is integral to
extending the prime for an animal. Therefore, enhancing cognitive
function results in a benefit to the animal in one or more of these
functions, e.g., an enhanced cognitive function allows the animal
to interact more desirably with other animals, permits the animal
to have a better memory, and counteract the affects of dementia.
Basically, enhancing cognitive function results in an improvement
in these and similar functions.
[0092] In various embodiments of the methods, the composition is a
human food composition, pet food composition, or a dietary
supplement. In other embodiments, the composition is a food
composition further comprising about 15% to about 50% protein,
about 5% to about 40% fat, about 5% to about 10% ash content, and
having a moisture content of about 5% to about 20%.
[0093] In certain embodiments, the UFA is a fish oil and the NORC
is arginine or a nitric oxide-releasing derivative thereof.
[0094] In certain embodiments, the composition being administered
comprises from about 0.1% to about 50% fish oil and from about 0.1%
to about 20% arginine. For embodiments of the methods, as with the
compositions above, the UFA comprises one or more of a natural fish
oil, ALA, EPA, DPA, DHA, another polyunsaturated fatty acid from
any source, or combinations thereof.
[0095] In one embodiment, the composition used in the methods is
formulated to provide about 0.5 g to about 10 g each of UFA and
NORC per day via one or more portions of a recommended serving
size. The composition can further comprise one or more B vitamins
and one or more antioxidants. The B vitamin preferably comprises
from about 0.1 to about 40 times the RDA and the antioxidant from
about 0.0001% to about 25% of the composition. Preferably, the
composition comprises a mixture of B vitamins.
[0096] In one embodiment, the composition is administered to the
animal in conjunction with one or more cognitive drugs in an amount
effective for enhancing cognitive and related functions as defined
herein. In a particular embodiment, the composition administered is
the pharmaceutical composition that includes a cognitive drug along
with UFA and NORC. In a preferred embodiment, the composition is
administered to the animal on a daily basis, preferably in a single
dose.
[0097] In certain embodiments, the animal is a healthy aging
animal. In others, the animal has a phenotype associated with
age-related cognitive impairment. For example, when compared to a
control animal not having the phenotype, the animal may have a
phenotype that includes one or more of decreased ability to recall,
short-term memory loss, decreased learning rate, decreased capacity
for learning, decreased problem solving skills, decreased attention
span, decreased motor performance, increased confusion, or dementia
(Alzheimer's in humans or its equivalent in other animals).
[0098] In another aspect, the composition comprises UFA and NORC in
an amount effective for improving one or more social behaviors. In
a preferred embodiment, the animal is a companion animal.
[0099] The compositions, after being administered to an animal, are
believed to increase the circulating concentrations of UFA and NORC
in the blood or blood plasma of the animal. In certain embodiments,
the blood concentration of a direct or indirect metabolite that
results from the consumption of UFA and/or NORC is increased, and
is useful as an indicator of dose. A decrease in concentration of
one or more compounds in the bloodstream of an animal receiving the
compositions can also occur in the normal course. Such decrease can
be also be a useful tool for monitoring or determining dosages.
Preferably, the change in amount of the bloodstream component to be
measured is dosage dependent. In some embodiments, the method
results in an increase in one or more ketone bodies in the animal's
blood. In embodiments where additional compounds are included in
the compositions, e.g., B vitamins or antioxidants, administration
results in an increase in circulating concentrations of these
compounds and is useful as an indication of dose.
[0100] The invention also provides other methods for affecting
various cognitive, motor, or behavioral related functions and for
affecting various physiological functions that relate to cognitive,
motor, or behavioral functions, e.g., social interaction and brain
aging. Generally, the methods comprise administering the
compositions of the present invention to an animal in amounts
defined herein for the compositions and methods.
[0101] In one aspect, the invention provides methods for reducing
or preventing a decline of social interaction in an animal
comprising administering a composition comprising UFA and NORC to
the animal in an amount effective to reduce or prevent a decline in
social interaction. In preferred embodiments, the compositions
further comprise one or more B vitamins, one or more antioxidants,
or both in amounts effective for reducing or preventing a decline
of social interaction in an animal. The methods ensure that an
aging animal remains involved in playtime, participates in group
activities, interacts with caregivers, and the like.
[0102] In one aspect, the invention provides methods for reducing
or preventing a decline of social interaction in an animal
comprising administering a composition comprising UFA and NORC to
the animal in an amount effective to reduce or prevent a decline in
social interaction. In preferred embodiments, the compositions
further comprise one or more B vitamins, one or more antioxidants,
or both in amounts effective for reducing or preventing a decline
of social interaction in an animal. The methods ensure that an
aging animal remains involved in playtime, participates in group
activities, interacts with caregivers, and the like.
[0103] In another aspect, the invention provides methods for
reducing or preventing age-related behavioral changes in an animal
comprising administering UFA and NORC to the animal in an amount
effective for reducing or preventing age-related behavioral changes
in the animal. Preferably, the age-related behavioral changes are
one or more of forgetfulness, disorientation, reduced social
interaction, changes in sleep and wake habits (particularly an
increase in nighttime activity), loss of "housetraining" that
results in changes in urination and defecation locations and
patterns, confusion, frustration, change in temperament such as
agitation and aggression, pacing, and wandering. Such changes have
been noted in response to cognitive declines in humans and other
animals. In preferred embodiments, the compositions further
comprise one or more B vitamins, one or more antioxidants, or both
in amounts effective for reducing or preventing age-related
behavioral changes in an animal.
[0104] In another aspect, the invention provides methods for
increasing trainability of an animal comprising administering a
composition comprising UFA and NORC to the animal in an amount
effective for increasing trainability. For example, administering
the composition while "potty training" babies, puppies, and kittens
permits the animal to learn the task more quickly than if the
training occurred without using the composition. Similarly,
training a dog or cat to obey verbal, signal, or other commands
permits the animal to learn the task more quickly than if the
training occurred without using the composition. Similarly, the
compositions could be useful for training feral or wild animals
such as animals used in a circus or pets raised in the wild. In
preferred embodiments, the compositions further comprise one or
more B vitamins, one or more antioxidants, or both in amounts
effective for increasing trainability of an animal.
[0105] In another aspect, the invention provides methods for
maintaining optimal brain function in an animal. The methods
comprise administering a composition comprising UFA and NORC to the
animal in an amount effective to prevent or delay a decline in
brain function, particularly over time. In preferred embodiments,
the compositions further comprise one or more B vitamins, one or
more antioxidants, or both in amounts effective for maintaining
optimal brain function in an animal. Generally, the methods ensure
that an aging animal maintains healthy and optimal brain function
throughout life and has a better quality of life, particularly in
older animals. The methods also slow the progression of mental
decline in aging dogs.
[0106] In another aspect, the invention provides methods for
facilitating learning and memory in an animal. The methods comprise
administering a composition comprising UFA and NORC to the animal
in an amount effective for facilitating learning and memory in the
animal. In one embodiment, the animal has reached at least about
50% of its life expectancy. The methods help an aging animal
remember facts and understand instructions. In preferred
embodiments, the compositions further comprise one or more B
vitamins, one or more antioxidants, or both in amounts effective
for facilitating learning and memory in an animal.
[0107] In another aspect, the invention provides methods for
reducing memory loss in an animal. The methods comprise
administering a composition comprising UFA and NORC to the animal
in an amount effective to reduce memory loss over time. In
preferred embodiments, the compositions further comprise one or
more B vitamins, one or more antioxidants, or both in amounts
effective for reducing memory loss in an animal.
[0108] In another aspect, the invention provides methods for
retarding brain aging in an animal. The methods comprise
administering a composition comprising UFA and NORC to the animal
in an amount effective to retard brain aging. In preferred
embodiments, the compositions further comprise one or more B
vitamins, one or more antioxidants, or both in amounts effective
for retarding brain aging in an animal.
[0109] In another aspect, the invention provides methods for
preventing or treating strokes in an animal. The methods comprise
administering a composition comprising UFA and NORC to the animal
in an amount effective to prevent or treat strokes. In preferred
embodiments, the compositions further comprise one or more B
vitamins, one or more antioxidants, or both in amounts effective
for preventing or treating strokes in an animal. The methods are
based upon the discovery that reducing damage that results from
strokes is correlated to certain aspects of enhancing cognitive
function, e.g., reducing memory loss.
[0110] In another aspect, the invention provides methods for
preventing or treating dementia in an animal. The methods comprise
administering a composition comprising UFA and NORC to the animal
in an amount effective to prevent or treat dementia. In preferred
embodiments, the compositions further comprise one or more B
vitamins, one or more antioxidants, or both in amounts effective
for preventing or treating dementia in an animal. Dementia can be
Alzheimer's disease (AD) in humans, Canine Cognitive Dysfunction
Syndrome (CCDS) in canines, or similar diseases in other animals.
The methods are based upon the discovery that the compositions and
methods of the present invention prevent or reduce dementia by
reducing the effects of damage that results from the causes of
dementia, e.g., amyloid deposits or deterioration of artery
function.
[0111] In another aspect, the invention provides methods for
maintaining mental clarity and alertness in an animal. The methods
comprise administering a composition comprising UFA and NORC to the
animal in an amount effective for maintaining mental clarity and
alertness. In preferred embodiments, the compositions further
comprise one or more B vitamins, one or more antioxidants, or both
in amounts effective for maintaining mental clarity and alertness
in an animal.
[0112] In one aspect, the invention provides methods for promoting
the health and wellness of an animal comprising administering a
composition comprising UFA and NORC to the animal in an amount
effective to promote health and wellness. In preferred embodiments,
the compositions further comprise one or more B vitamins, one or
more antioxidants, or both in amounts effective for promoting
health and wellness.
[0113] In a further aspect, the invention provides methods for
extending the prime for an animal comprising administering a
composition comprising UFA and NORC to the animal in an amount
effective for extending the prime for the animal. In preferred
embodiments, the compositions further comprise one or more B
vitamins, one or more antioxidants, or both in amounts effective
for extending the prime for the animal.
[0114] In the methods for reducing or preventing a decline of
social interaction, reducing or preventing age-related behavioral
changes, increasing trainability, maintaining optimal brain
function, facilitating learning and memory, reducing memory loss,
retarding brain aging, preventing or treating strokes, preventing
or treating dementia, maintaining mental clarity and alertness,
promoting health and wellness, and extending the prime, the animal
is preferably a human or companion animal, most preferably a dog or
cat. The amounts of UFAs, NORC, B vitamins, antioxidants, and other
ingredients used in these methods are the same as the amounts or
within the ranges given for enhancing cognitive function.
[0115] In a further aspect, the invention provides kits suitable
for administering a composition comprising one or more UFA and NORC
to an animal. The kits comprise in separate containers in a single
package or in separate containers in a virtual package, as
appropriate for the kit component, (a) one or more UFAs, (b) one or
more NORC, and one or more of (1) one or more other ingredients
suitable for consumption by an animal; (2) one or more B vitamins;
(3) one or more antioxidants; (4) one or more cognitive drugs; (5)
one or more prebiotics; (6) one or more probiotics; (7) one or more
diagnostic devices suitable for determining whether an animal could
benefit from compositions and methods for enhancing cognitive
function and related functions; (8) instructions for how to combine
or prepare the UFA and NORC and any other ingredients provided in
the kit for administration to an animal; (9) instructions for how
to use the combined kit components, prepared kit components, or
other kit components for the benefit of an animal; and (10) a
device for administering the combined or prepared kit components to
an animal. The components are each provided in separate containers
in a single package or in mixtures of various components in
different packages. In preferred embodiments, the kits comprise the
UFAs, NORC, B vitamins, and antioxidants. The kits may comprise the
ingredients in various combinations. For example, the kit could
comprise a mixture of one or more B vitamins and one or more
antioxidants in one container and one or more other ingredients in
one or more other containers. Similarly, the kit could comprise a
mixture of UFA and NORC in one container and one or more other
ingredients in one or more other containers. Other such
combinations can be produced by the skilled artisan based upon the
characteristics of the ingredients and their physical and chemical
properties and compatibilities.
[0116] In another aspect, the invention provides a means for
communicating information about or instructions for one or more of
(1) using compositions of the present invention for enhancing
cognitive function; (2) admixing the UFAs, NORC, B vitamins,
antioxidants, or other components of the invention to produce a
composition suitable for enhancing cognitive function; (3) using
the kits of the present invention for enhancing cognitive function;
and (4) administering the compositions to an animal. The means
comprises one or more of a physical or electronic document, digital
storage media, optical storage media, audio presentation,
audiovisual display, or visual display containing the information
or instructions. Preferably, the means is selected from the group
consisting of a displayed website, a visual display kiosk, a
brochure, a product label, a package insert, an advertisement, a
handout, a public announcement, an audiotape, a videotape, a DVD, a
CD-ROM, a computer readable chip, a computer readable card, a
computer readable disk, a USB device, a FireWire device, a computer
memory, and any combination thereof.
[0117] In another aspect, the invention provides methods for
manufacturing a food composition comprising UFA, NORC, and one or
more other ingredients suitable for consumption by an animal, e.g.,
protein, fat, carbohydrate, fiber, B vitamins, and antioxidants.
The methods comprise admixing one or more ingredients suitable for
consumption by an animal with UFA and NORC, and possibly other
ingredients such as B vitamins and/or antioxidants. Alternatively,
the methods comprise applying UFA and NORC, and other ingredients
if desired, separately or in any combination onto the food
composition, e.g., as a coating or topping. The UFA and NORC can be
added at any time during the manufacture and/or processing of the
food composition. This includes, for example, admixing the UFA and
NORC as part of the core formulation of the "body" of the food
composition or applying them as a coating, i.e., primarily to the
surface of the food composition after its manufacture. The
compositions can be made according to any method suitable in the
art.
[0118] In another aspect, the present invention provides a package
comprising a composition of the present invention and a label
affixed to the package containing a word or words, picture, design,
acronym, slogan, phrase, or other device, or combination thereof,
that indicates that the contents of the package contains a
composition suitable for enhancing cognitive function, reducing or
preventing a decline of social interaction, reducing or preventing
age-related behavioral changes, increasing trainability,
maintaining optimal brain function, facilitating learning and
memory, reducing memory loss, retarding brain aging, preventing or
treating strokes, preventing or treating dementia, or maintaining
mental clarity and alertness in an animal, particularly an aging
animal. Typically, such device comprises the words "improves
cognitive function", "improves memory", "reduces memory loss in
aging animals", "maintains mental clarity and alertness" or an
equivalent expression printed on the package. Any package or
packaging material suitable for containing the composition is
useful in the invention, e.g., a bag, box, bottle, can, pouch, and
the like manufactured from paper, plastic, foil, metal, and the
like. In a preferred embodiment, the package contains a food
composition adapted for a particular animal such as a human, canine
or feline, as appropriate for the label, preferably a companion
animal food composition.
[0119] In another aspect, the invention provides for use of UFA and
NORC to prepare a medicament for enhancing cognitive function,
reducing or preventing a decline of social interaction, reducing or
preventing age-related behavioral changes, increasing trainability,
maintaining optimal brain function, facilitating learning and
memory, reducing memory loss, retarding brain aging, preventing or
treating strokes, preventing or treating dementia, and maintaining
mental clarity and alertness in an animal. The medicament can
further comprise one or more B vitamins, antioxidants, or
combinations thereof. Generally, medicaments are prepared by
admixing a compound or composition with excipients, buffers,
binders, plasticizers, colorants, diluents, compressing agents,
lubricants, flavorants, moistening agents, and other ingredients
known to skilled artisans to be useful for producing medicaments
and formulating medicaments that are suitable for administration to
an animal.
[0120] In the invention, the animal can be a juvenile, adult,
senior, or geriatric animal. Typically, for most embodiments, the
animal is an aging animal. Generally, animals are senior in the
last half of their expected lifespan and geriatric in the last
fourth of their expected lifespan. Lifespan definitions vary for
various animals and are known to skilled artisans. For example, an
animal is considered to be juvenile until about 16 years of age.
For a dog or cat, the animal is considered to be juvenile until 1
year of age.
[0121] The compositions of the invention, including the
pharmaceutical compositions and medicaments, are administered to
the animal using a variety of administration routes. Such routes
include oral, intranasal, intravenous, intramuscular, intragastric,
transpyloric, subcutaneous, rectal, and the like. Preferably, the
compositions are administered orally.
[0122] The compositions of the invention, including the
pharmaceutical compositions and medicaments, are administered to
the animal for a time required to accomplish one or more objectives
of the invention, e.g., enhancing cognitive function, reducing or
preventing a decline of social interaction, reducing or preventing
age-related behavioral changes, increasing trainability,
maintaining optimal brain function, facilitating learning and
memory, reducing memory loss, retarding brain aging, preventing or
treating strokes, preventing or treating dementia, and maintaining
mental clarity and alertness in an animal. The compositions are
suitable for long-term administration or administration on any
schedule compatible with the composition and objective.
[0123] In various embodiments of the methods and compositions of
the invention, the antioxidants comprise astaxanthin alone or in
combination with other antioxidants.
EXAMPLES
[0124] The invention can be further illustrated by the following
examples, although it will be understood that the examples are
included merely for purposes of illustration and are not intended
to limit the scope of the invention unless otherwise specifically
indicated.
Example 1
Animal and Test Groups
[0125] Cognitively-experienced beagle dogs (males and females
ranging from 7.5 to 11.6 years of age) were tested. The average age
of the dogs was 9.38 years. To qualify, the dogs must have had at
least 6 months of previous cognitive test experience, including
having been trained on the delayed non-matching-to position task
(DNMP) and the oddity task.
[0126] During an initial baseline phase, all dogs were tested on a
variable delay version of the DNMP task (or at 5 s if previously
unable to learn the task) that provided a means of assessing
visuo-spatial working memory and on a size discrimination and
reversal task. Performance on these tasks was used to place the
dogs into four cognitively equivalent treatment groups (twelve dogs
per group): (1) 2% fish oil, 2.5% arginine, 1 to 40 times RDA B
vitamins, 150 mg/kg vitamin C, 900 mg/kg vitamin E, and 0.5 mg/kg
selenium ("SPB Group"); and (2) the Control Group.
Feeding and Water
[0127] Dogs had free access to water via wall-mounted automatic
watering systems and/or water bowls. The animals were provided one
of five adult maintenance foods having approximately 32% protein,
20% fat, and 3% fiber once daily. Initial individual food amounts
were calculated using the formula "kcal requirement=110
kcal/day.times.(BW.times.0.75)", where BW is body weight. The
formula was intended to maintain a constant body weight at an
appropriate body condition.
[0128] Dogs were weighed weekly at the start of treatment and twice
monthly after food intake and body condition stabilization; food
intake was adjusted as needed to maintain a relatively constant
body weight. Animals were given approximately 30 minutes to eat the
food provided. The approximate amount of food remaining was
recorded in a food intake monitoring datasheet for each animal.
Housing Conditions
Cognitive Test Battery
[0129] Landmark discrimination learning (Days 7-99). Egocentric
learning and reversal (Days 100-163).
Landmark Discrimination Task
[0130] In this task, the dogs were trained to approach one of two
objects, based on their proximity to an external landmark. The task
was intended to assess allocentric spatial ability, which entails
utilization of external landmarks to localize objects in space. The
dogs were tested on successively more difficult versions of the
same general problem.
[0131] General test procedures: Dogs were subject to ten (10)
trials per day, with an inter-trial interval of 30 seconds. Testing
was conducted once per day, approximately six days per week, such
that a total of 80 sessions were conducted. A partial correction
procedure was used. In this procedure, once each session the dogs
are permitted to correct their response after making an error. Each
dog was tested on up to four problems, depending upon the dog's
success at solving the problems. To move on from the first and
second problems, the dog had to complete a two-stage criterion. To
pass the first stage, the dog had to respond correctly in at least
9 of 10 trials, or on 8 of 10 trials over 2 consecutive days. Dogs
had to respond in all trials to pass the first stage. The second
criterion stage was completed when the dog responded correctly in
at least 70% of the next 30 trials over three consecutive sessions.
Dogs that had a non-response in any one trial were assigned a score
of 0.5, which was assumed to be the response based on random
choice, and were given one extra day of testing to complete the 30
trials. An average score of 70% over all test days was required to
pass the second stage.
[0132] The discriminanda were identical white coasters and a yellow
wooden peg, 2 cm.times.2 cm.times.9 cm, which served as the
landmark. The white circular coasters were placed over the two
lateral food wells on the presentation tray. Velcro tabs 2 cm in
diameter, to hold the landmark in place, were glued to the top
center of the coasters and to appropriate loci on the food
tray.
[0133] Initial Landmark Test (Land-0): On the initial test (L0),
the landmark was attached to the center of one of the two white
coasters. On each trial, the experimenter placed the food reward in
either the left or right food well and positioned the landmark
accordingly. The door was raised and the tray was moved to
approximately 25 cm from the dog for a brief inspection interval to
enable the dog to see the spatial arrangement on the tray. The tray
was then presented to the dog and the dog was allowed to respond.
In this and all subsequent levels, the dogs were required to
respond to the coaster closest to the landmark to obtain the food
reward. The correct side was determined randomly by the computer
with the constraint that each side was correct on half of the
trials of each test session. Each dog was allowed a maximum of 30
test sessions (300 trials) to learn to respond to stimulus
associated with the landmark during L0.
[0134] Remedial Training: Dogs that failed the initial L0 test were
given a remedial training program to help teach them the task. The
remedial training consisted of 5 additional training days, with 15
trials per day. At the start of the remedial training, the animals
were presented with a single rewarded stimulus on the majority of
the trials. With continued testing, additional paired stimulus
presentations were given. After completing the remedial learning
phase, the animals received additional training, up to a maximum of
10 sessions using the original protocol. This protocol was also
used for dogs that failed L1. Dogs that failed L0 were moved on to
L1. Dogs that failed remedial training after L1 were moved on to
the next task, if 80 test sessions had not elapsed. If fewer that
10 test sessions remained, the animals on L1 received extra
remedial training sessions.
[0135] Landmark-1 (L1): Once a dog learned the L0 task (either
during the initial training or after the remedial training), the
landmark was moved 1 cm medially and diagonally away from the edge
of the coaster, which constituted landmark 1 (L1). The landmark was
attached to the food tray with a black piece of 2 cm wide Velcro.
Dogs that did not learn within 30 sessions were given remedial
training, as described above for L0.
Egocentric Test Protocol
[0136] General Test Procedure: At the start of a trial the hinged
door was opened to present the stimulus tray to the dog and the dog
was allowed a maximum of 30-sec to make a response by displacing
one of the two identical stimuli. A correct response was counted
when the dog displaced a stimulus object covering food reward. An
error was counted when the dog displaced the non-rewarded stimulus.
The animals received 12 trials per session over a period of 63
sessions.
[0137] Preference Phase: On the first test day the dogs were given
a preference test consisting of 10 discrete trials with objects
covering both lateral food wells to determine if any side
preferences were present. The preferred side was used as the
positive side for the initial acquisition phase of testing. Thus,
if the animal chose the object to it's left most frequently, then
the animals' left side was designated its preferred side. For
animals that did not show a side preference (and responded five
times to each side), a coin toss was used to determine the rewarded
side.
[0138] Acquisition Phase: Each trial consisted of a single
presentation of the stimulus tray with a stimulus covering a reward
in the preferred side lateral well, or the center well. A second
non-rewarded stimulus object covered a well towards the dog's
non-preferred side. Consequently, the object furthest to the
animals' preferred side was always rewarded. On any given trial,
there were three possible spatial configurations (left-center,
left, right, or right-center). Each configuration occurred four
times per test session.
[0139] Criterion: The acquisition phase was successfully completed
once a dog scored a minimum of 90% correct (33/36 correct trials)
over three consecutive test sessions. A maximum of 12 sessions, or
144 trials, were given to meet this criterion. Animals that did not
learn within 12 sessions were given 5 sessions of remedial
training, which was followed by up to 10 additional sessions.
[0140] Reversal Phase: Once an animal passed the acquisition phase,
the rewarded position was switched to the opposite side. Thus, if
the object closest to a dog's right was rewarded in acquisition
testing, the object closest to its left was rewarded in the
reversal testing. For the first reversal test, the learning
criterion was the same as for the original acquisition. A maximum
of 15 sessions, or 180 trials, were given to meet this criterion.
If an animal did not satisfy the criterion within 15 sessions, 5
sessions of remedial training were given. The animals then received
10 additional sessions to reach the learning criterion.
[0141] Repeated (Multiple) Reversal Phase: Once an animal learned
the original reversal, the correct side was then be switched and
the animal retested until it relearned the task. This procedure was
repeated until the animals had completed a total of 52 sessions on
the egocentric protocol. The results are shown in Tables 1 to
5.
Landmark Test Results
TABLE-US-00001 [0142] TABLE 1 Landmark-0 test results Test Errors
to Criterion Group Means SE Control 45.42 12.85 SPB 29.38 8.10
[0143] Referring to the data, the SPB Group performed better than
the Control Group.
TABLE-US-00002 TABLE 2 Landmark-1 test results Test Errors to
Criterion Group Means SE Control 136.96 16.26 SPB 89.29 19.03
[0144] The Control Group differed significantly from the SPB
Group.
Egocentric Test Results
TABLE-US-00003 [0145] TABLE 3 Acquisition test results Test Errors
to Criterion Group Means SEM Control 25.58 2.96 SPB 20.41 2.71
[0146] Referring to the data, the Control Group differed from the
SPB group.
TABLE-US-00004 TABLE 4 Reversal test results Test Errors to
Criterion Group Means SEM Control 68.29 6.22 SPB 47.09 5.58
[0147] Referring to the data, the Control Group differed
significantly from the SPB Group.
TABLE-US-00005 TABLE 5 Repeated reversal test results Test
Reversals Learned Group Means SEM Control 2.42 0.40 SPB 4.42
0.48
Example 2
[0148] Male Charles Rivers Sprague-Dawley rats (250 g, Wilmington,
Mass.) were acclimatized to animal facilities 3 days prior to
surgery with a 12 hour light-dark cycle. Bilateral ovariectomy was
performed 2 weeks before diet feeding began. Four weeks after the
start of diet feeding, transient middle cerebral artery (tMCA)
occlusion under anesthesia was performed following intraperitoneal
injection of ketamine (60 mgkg) and xylazine (10 mg/kg). 15 rats
per group were randomly assigned to one of four treatment
groups:
[0149] Group 1--Neutered+Control Diet
[0150] Group 2--Neutered+Diet II
[0151] Group 3--Intact+Control Diet
[0152] Group 4--Intact+Diet II
[0153] The Control Diet was a standard rat diet containing 140 g/kg
casein, 100 g/kg sucrose, 50 g/kg fiber, 155 g/kg dextrin, 466 g/kg
corn starch, 35 g/kg standard salt mix, 40 g/kg soybean oil, 10
g/kg standard vitamin mix, 1.8 g/kg L-cystine and 2.5 g/kg choline
chloride. Diet II was the Control Diet plus 2% Arginine, 2%
Menhaden fish oil 4.times. B vitamins, and antioxidants (Vitamin E:
500 mg/kg diet, Vitamin C: 150 mg/kg diet, Astaxanthin:100 mg/kg,
selenium: 0.40 mg/kg).
[0154] Animals were anesthetized by an intraperitoneal injection of
ketamine (60 mg/kg) and xylazine (10 mg/kg). tMCA occlusion was
performed as previously described (Simpkins et al., 1997) with
slight modification. Briefly, the left common carotid artery,
external carotid artery and internal carotid artery were exposed
through a midline cervical incision. A 3.0 mono-filament suture was
introduced into the internal carotid artery lumen and gently
advanced until resistance was felt. The surgical procedure was
performed within 20 minutes, with minimal bleeding. The suture was
kept in place for 60 minutes and then withdrawn to allow
reperfusion. Rectal temperature was monitored and maintained
between 36.5 and 37.degree. C. with a heating pad throughout the
procedure. At 24 hours after the onset of reperfusion, the animals
were sacrificed and the brains were removed. The brains were then
dissected coronally into 2 mm sections using a metallic brain
matrix (ASI Instruments Inc.; Warren, Mich.) and stained by
incubation in a 2% solution of 2,3,5-triphenyltetrazolium chloride
(TTC) in physiological saline at 37OC, and then fixed in 10%
formalin. DNA fragmentation analysis with TdT-mediated dUTP
Nick-End Labeling (TUNEL) MCA occlusion is a widely used focal
ischemic stroke model (Bederson et al., 1986). This in vivo model
for neuronal death can rapidly induce a synchronized apoptotic
process in a large number of neurons and other cells (Li et al.,
1997). The effects of transient ischemia on apoptosis were
therefore examined by analyzing DNA fragmentation with the TUNEL
assay. TUNEL staining was performed according to the modified
manufacturer's instructions (Gavrieli et al., 1992).
Formalin-fixed, paraffin-embedded tissue sections were
deparaffinizated with xylene, rehydrated through graded ethanol
treatment, and given a final wash in PBS. The sections were
post-fixed in 4% paraformaldehyde for 20 minutes. Sections were
then washed and treated for 15 minutes with 100/pg/ml proteinase K
in PBS, equilibrated with equilibration buffer for 10 min, and then
incubated with buffer containing TdT enzyme and FITC-labeled dUTP
(Promega, Madison, Wis.) at 37OC in a humidified chamber. The
reaction was terminated by incubation in 2.times.SSC buffer for 15
min at room temperature. The sections were then mounted with
anti-fade reagents containing DAPI (Molecular Probes, Eugene,
Oreg.). Positive control sections were immersed in DNase I solution
for 10 min at room temperature before equilibration in TdT buffer.
The sections were observed under a fluorescent microscope with
appropriate excitation/emission filter pairs. After the surgery,
some animals died before the necropsy. The number of animals
quantified for lesion volume ranged from 12 to 15 per group. The
results are shown in Tables 6 and 7.
[0155] The results were analyzed with one-way analysis of variance
(ANOVA) using Prism software (Graphpad Inc; San Diego, Calif.). The
significance of differences among groups was determined by one-way
ANOVA followed by Tukey's multiple comparison tests. All values
were expressed as mean+/-SEM.
[0156] Referring to Tables 6 and 7, the results show that a diet
containing one or more of the ingredients given in Diet II has a
beneficial effect on preventing or treating ischemia and as such a
beneficial effect on many brain related functions, e.g., cognitive
function, social interaction, age-related behavioral changes,
decline in brain function, enhancing brain functions, preventing or
treating strokes, retarding brain aging, and preventing or treating
dementia such as Alzheimer's disease.
TABLE-US-00006 TABLE 6 The Effect of Diet II on the Lesion Volume
(mm.sup.3) Induced by Transient Focal Cerebral Ischemia Control +
Diet II + Intact + Intact + Castration Castration* Control Diet II
n 13 12 14 14 Mean 284.9 133.6 244.5 163.1 Std. Error 32.50 28.53
43.30 31.54 *p < 0.05 Diet II + Castration vs Control +
Castration
TABLE-US-00007 TABLE 7 The Effect of Diet II on the Apoptotic Index
(%) Induced by Cerebral Ischemia Control + Diet II + Intact +
Intact + Castration Castration* Control Diet II n 13 12 14 14 Mean
85.55 46.67 75.15 57.69 Std. Error 4.134 7.51 8.208 8.137
[0157] In the specification, there have been disclosed typical
preferred embodiments of the invention. Although specific terms are
employed, they are used in a generic and descriptive sense only and
not for purposes of limitation. The scope of the invention is set
forth in the claims. Obviously many modifications and variations of
the invention are possible in light of the above teachings. It is
therefore to be understood that within the scope of the appended
claims the invention may be practiced otherwise than as
specifically described.
* * * * *