U.S. patent application number 17/656825 was filed with the patent office on 2022-07-07 for zeaxanthin formulations with additional ocular-active nutrients, for protecting eye health and treating eye disorders.
The applicant listed for this patent is ZeaVision LLC. Invention is credited to Dennis L. Gierhart.
Application Number | 20220211639 17/656825 |
Document ID | / |
Family ID | |
Filed Date | 2022-07-07 |
United States Patent
Application |
20220211639 |
Kind Code |
A1 |
Gierhart; Dennis L. |
July 7, 2022 |
Zeaxanthin Formulations With Additional Ocular-Active Nutrients,
For Protecting Eye Health And Treating Eye Disorders
Abstract
Oral formulations for promoting eye health, and in particular
for preventing or treating macular degeneration, are disclosed,
containing zeaxanthin, a carotenoid pigment, and at least two or
more additional ocular-active nutrients selected from lipoic acid,
omega-3 fatty acids, plant-derived compounds such as flavonoids,
anthocyanins, or polyphenolics, taurine, carnitine, Coenzyme-Q10,
carnosine, and nutrients that stimulate the production of
glutathione. Processes are disclosed for identifying ocular-active
nutrients that will interact in a synergistic and potentiating
manner with zeaxanthin, to provide better and more effective
protection, for eye health, than can be provided by zeaxanthin
alone. Additional optional agents include zinc, vitamin E, and
vitamin C.
Inventors: |
Gierhart; Dennis L.;
(Chesterfield, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ZeaVision LLC |
Chesterfield |
MO |
US |
|
|
Appl. No.: |
17/656825 |
Filed: |
March 28, 2022 |
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Application
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16949955 |
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17656825 |
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16429817 |
Jun 3, 2019 |
10842757 |
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16949955 |
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15990269 |
May 25, 2018 |
10307384 |
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16429817 |
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15331706 |
Oct 21, 2016 |
9980922 |
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15990269 |
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14861803 |
Sep 22, 2015 |
9474724 |
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15331706 |
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10746403 |
Dec 23, 2003 |
9192586 |
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14861803 |
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International
Class: |
A61K 31/047 20060101
A61K031/047; A61K 31/07 20060101 A61K031/07; A61K 9/00 20060101
A61K009/00 |
Claims
1-4. (canceled)
5. A multivitamin supplement for eye health presented as a capsule
for oral ingestion, comprising: (a) an oily carrier; (b) vitamin E;
(c) vitamin C; (d) zinc in an amount that does not exceed 40 mg;
(e) selenium; (f) riboflavin; and (g) carotenoids selected from the
group consisting of lutein and 3R-3R' zeaxanthin such that the
multivitamin supplement is substantially free of other carotenoids,
and wherein the 3R-3R' zeaxanthin is present in an amount that is
at least 0.5 mg.
6. The multivitamin eye-health supplement of claim 5, wherein the
composition further includes omega-3 fatty acids.
7. The multivitamin eye-health supplement of claim 5, wherein the
composition further includes a lipoic acid.
8. The multivitamin eye-health supplement of claim 5, wherein the
composition further includes mixed tocopherols.
9. The multivitamin eye-health supplement of claim 5, further
including pyridoxine.
10. The multivitamin eye-health supplement of claim 5, wherein the
nutritional supplement is for reducing the risk of progression of
the macular degeneration for the user.
11. The multivitamin eye-health supplement of claim 5, wherein
vitamin C is in the form of ascorbic acid.
12. The multivitamin eye-health supplement of claim 5, wherein the
capsule provides a daily dosage of the ingredients to the user that
is released following the oral ingestion.
13. The multivitamin eye-health supplement of claim 12, wherein
zeaxanthin is present in an amount of at least 3 milligrams.
14. The multivitamin eye-health supplement of claim 5, wherein the
oily carrier is for enhancing the uptake of the zeaxanthin.
15. The multivitamin eye-health supplement of claim 5, wherein the
supplement excludes beta-carotene for a user who is a current or
former smoker.
16. The multivitamin eye-health supplement of claim 5, wherein the
composition further comprises at least one of taurine, carnitine
and carnosine.
17. A multivitamin eye-health supplement, comprising: (a) fish oil
providing omega-3 fatty acids, the omega-3 fatty acids including
docosa-hexaenoic acid (DHA) and eicosa-pentaenoic acid (EPA); (b)
carotenoids selected from the group consisting of lutein and 3R-3R'
zeaxanthin such that the multivitamin eye-health supplement is
substantially free of other carotenoids, and wherein the 3R-3R'
zeaxanthin is present in an amount that is at least 0.5 mg; (c)
zinc in an amount that does not exceed 40 mg; (d) vitamin E; (e)
vitamin C; and wherein the multivitamin eye-health supplement is in
the form of a tablet or capsule for oral ingestion.
18. The multivitamin eye-health supplement of claim 17, wherein
vitamin C is in the form of ascorbic acid.
19. The multivitamin eye-health supplement of claim 17, wherein the
tablet or capsule provides a daily dosage of the ingredients to the
user that is released following the oral ingestion.
20. The multivitamin eye-health supplement of claim 19, wherein the
supplement excludes beta-carotene for a user who is a current or
former smoker.
21. The multivitamin eye-health supplement of claim 17, wherein the
multivitamin eye-health supplement is for reducing the risk of
progression of the macular degeneration for the user.
22. The multivitamin eye-health supplement of claim 17, wherein
zeaxanthin is present in an amount of at least 3 milligrams.
23. A multivitamin supplement for eye health for oral ingestion,
comprising: (a) vitamin E; (b) vitamin C; (c) zinc in an amount
that does not exceed 40 mg; (d) selenium; (e) riboflavin; and (f)
carotenoids selected from the group consisting of lutein and 3R-3R'
zeaxanthin such that the multivitamin supplement is substantially
free of other carotenoids, and wherein the 3R-3R' zeaxanthin is
present in an amount that is at least 0.5 mg.
24. The multivitamin eye-health supplement of claim 23, further
including pyridoxine.
Description
RELATED APPLICATION
[0001] This application claims the benefit under 35 USC 119(e) of
provisional application No. 60/453,522, filed on Dec. 23, 2002.
FIELD OF THE INVENTION
[0002] This invention is in the fields of biochemistry,
pharmacology, and nutritional supplements, and relates to
orally-ingested formulations for treating or preventing eye
diseases and vision problems.
BACKGROUND OF THE INVENTION
[0003] Hundreds of different dietary supplements, under thousands
of different brand and product names, are being marketed to the
public in the U.S. and elsewhere, by means of advertising promises
and claims which suggest that these products can help prevent or
treat eye diseases, and maintain eye health. Faced with an
overwhelming glut of competing promises and products, nearly all of
which are unproven and many of which have only tenuous and flimsy
support, it has become effectively impossible for people who are
concerned about eye health to know which products will help, and
which are merely preying on innocent victims whose vision is
deteriorating, either because of general aging problems, or due to
specific diseases, infections or injuries.
[0004] Indeed, severe uncertainties and doubts about which dietary
supplements are effective extend to full-time professionals who
specialize in eye research, or in treating eye diseases. Many
examples to support this assertion can be cited, including numerous
current and recent articles, in respected scientific and medical
journals, stating that not enough evidence is available to allow
physicians to know whether to recommend various candidate dietary
supplements to their patients.
[0005] Along those same lines, the recent AREDS (Age-Related Eye
Disease Study) study, which was organized and carried out by the
National Eye Institute at a cost of tens of millions of dollars,
tested vitamins C and E (as well as beta-carotene) at high dosages.
They offered a low and weak level of protection against macular
degeneration, in sonic but not all of the patient categories, in
the AREDS-1 trial. Similarly, zinc at very high dosages (80
mg/day), by itself, offered a low and weak level of protection in
some categories of patients. When vitamins A/C/E and zinc were
combined, the level of protection increased, especially among
late-stage macular degeneration sufferers. Accordingly, the results
and findings of the AREDS-1 trial are not regarded as strong or
compelling, when compared with the potential benefits of
zeaxanthin, and in recent years it also has become clear that high
dosages of vitamin A or its precursor, beta carotene, offer little
or no serious hope for providing any significant protection against
macular degeneration, or any other serious eye disorders among
people who receive minimal baseline levels of vitamin A.
[0006] As a direct response to the positive claims of the AREDS
managers, one skilled observer (Siegel 2002) publicly and openly
complained that the purported benefits could be teased out of the
data only by massaging the data in ways that, instead of being
objective, impartial, and scientific, were instead biased and
intended to locate something positive to report, to offset the fact
that the entire remainder of the study had spent many millions of
dollars but had come up empty. in the words of that expert. "In my
opinion the AREDS investigators promoted a nonsignificant result
into a conclusive recommendation. Here is how they did it . . . the
message that should have emerged from AREDS is that these
treatments failed to demonstrate efficacy in preventing AMD and are
not recommended for that use." Even reviewers who endorsed the
AREDS findings had to include various cautions and caveats; as one
example, in an editorial that accompanied the AREDS report, in the
same issue of the same journal, the reviewer had to include
statements such as, "The exclusion of the subgroup of patients in
Category 2 from many of the analyses because of the low incidence
of primary outcome events in troubling because it came after review
of the data."
[0007] Other experts in eye research, and ophthalmologists who
specialize in treating patients with serious eye problems, do not
and cannot agree on the roles of either or both of two carotenoid
pigments that are known to exist naturally in the retina. Those two
pigments are called lutein and zeaxanthin. However, even though
nearly 20 years have passed since Bone et al 1985 identified those
two carotenoid pigments as the agents that give the "macula" (a
small yellowish spot in the center of the retina, which is crucial
for clear vision) its yellowish color, experts in eye research and
eye diseases cannot and do not agree on what roles those two
carotenoids play in the retina, or whether either or both of them
should be recommended as dietary supplements. Evidence to support
and prove this conclusion is available from numerous sources, both
published and unpublished. As one example of a published report, a
large panel of highly respected experts who specialize in retinal
diseases was brought together in 1998 by the National Eye Institute
(NEI), and the experts were asked to develop strategic proposals
and recommendations that would guide the NEI's funding for eye
research over the next five years. That panel reviewed a wide range
of options and candidate treatments, and specifically identified
and named about 60 candidate treatments that the experts thought
were deserving of careful scientific study and research grants.
Even though that panel of experts identified nearly 60 specific
research leads, it never even mentioned lutein or zeaxanthin. That
omission could not have been a mere oversight due to a lack of
available information, since a number of members of that panel had
previously written and published papers that had explicitly
discussed lutein and zeaxanthin.
[0008] Numerous other researchers who specialize in eye and vision
studies also have stated that no reliable conclusions can yet be
reached on whether lutein and/or zeaxanthin can actually benefit
the eyes to a point where they should be recommended as nutritional
supplements. Examples of such recently-published conclusions
include Schalch 2000, and Jampol 2001. Schalch 2000 states, at page
38, "Epidemiological studies therefore cannot provide definite
proof of the efficacy of lutein and zeaxanthin in MR Such studies
can provide evidence of possible relationships but cannot determine
whether an effect is causal. The situation is different with
intervention studies in which agents are administered on a
double-masked, placebo-controlled, randomized basis and results are
evaluated using predefined efficacy parameters. In the case of
supplementation with lutein and zeaxanthin, where only small to
moderate responses can be expected, only studies such as these are
likely to provide a definite answer as to an effect of lutein and
zeaxanthin on AMD. However, the specific time-course and nature of
this disease makes the design of such trials difficult." Jampol
2001, at page 1534, states, "In view of previous studies suggesting
that beta-carotene might be harmful in smokers and may be
associated with a greater risk of lung cancer, beta carotene should
probably not be used by smokers and recent ex-smokers. An argument
could be made that another carotenoid, lutein or zeaxanthin, could
be substituted for beta carotene, but the values and risks of other
carotenoids [apparently referring again to lutein and zeaxanthin]
is unknown at this time."
[0009] As another example of the uncertainties and doubts that
surround zeaxanthin among skilled physicians who treat eye
diseases, the Inventor has personal knowledge of a patient who has
the "wet" (or "exudative") form of macular degeneration. This
disease is characterized by aggressive growth of capillaries in and
around certain layers of the retina, and it leads to rapid and
devastating loss of vision. The best known treatment for wet AMD is
called laser photocoagulation, or photodynamic therapy. It uses a
drug called verteporfin, which is activated by a laser that is
shone directly into the eyes of patients who have taken the drug.
In October of 2003, a ZeaVision customer (a male in his late 70's)
who was taking zeaxanthin capsules on a daily basis was scheduled
to have a laser treatment using verteporfin, at the Wilmer Eye
Institute in Baltimore, which is affiliated with the Johns Hopkins
School of Medicine. This patient told his treating physician, who
is one of the top experts in the world on treating macular
degeneration, that he was taking zeaxanthin capsules on a daily
basis. The treating physician suggested that the patient should
stop taking zeaxanthin, since it probably would not help. Despite
that suggestion, the patient continued taking zeaxanthin, up
through the date of the treatment and continuing thereafter. The
results of that treatment, as measured up until the date this is
being written, have been outstanding, and have been much better
than was expected by the treating physician. That discovery is the
subject of a recently-filed provisional patent application that
will be disclosed to the companies that manufacture and sell
verteporfin, and to a number of physicians who perform
laser-verteporfin treatments, so they can evaluate it in a clinical
trial using numerous patients, For now, the point worth noting is
this: when advised that a patient suffering from wet macular
degeneration was taking zeaxanthin, one of the top eye experts in
the world advised the patient that he should stop taking it.
[0010] This current invention centers on zeaxanthin, which is
believed by the Inventor to be an essential and crucial ingredient
in any optimal or near-optimal pharmaceutical formulations and/or
dietary supplements that will be truly effective in protecting,
treating, and otherwise improving various aspects of eye health. A
number of reasons for believing and asserting that zeaxanthin is
and will be the essential and crucial ingredient in such
formulations (including factors indicating that zeaxanthin will
perform substantially better than lutein, in this role) are set
forth below, to justify these assertions and beliefs by the
Inventor despite lingering refusals by other skilled researchers
and eye care companies to recognize zeaxanthin's role as a crucial
and essential agent for protecting and preserving eye health.
[0011] It might be asserted that each factor summarized in the next
section is already known and published, in the prior art. However,
it must also be recognized that (i) these factors have never
previously been combined and correlated, in the manner set forth
herein; and, (ii) the non-obviousness of the invention disclosed
herein must also be evaluated in light of evidence which clearly
shows that numerous highly-skilled experts do not believe
zeaxanthin has any proven role in protecting or restoring eye
health.
Information on Zeaxanthin in Eye Health
[0012] The use of zeaxanthin for treating and preventing macular
degeneration is described in several US patents, including U.S.
Pat. No. 5,747,544 (Garnett et al 1997) on methods of use, and
reissue patent Re-38,009 (Garnett et al 2003, which replaced U.S.
Pat. No. 5,827,652, Garnett et al 1998) on formulations for human
ingestion. The contents and teachings of those patents are
incorporated herein by reference, as though fully set forth
herein.
[0013] Additional review articles that discuss the roles and the
assumed, purported, or likely effects of zeaxanthin and lutein, in
mammalian eyes, is provided in a number of articles, including
Snodderly 1995, Landrum et al 1997, Schalch et al 1999, Schalch
2000, and Semba et al 2003.
[0014] Zeaxanthin and lutein both belong to a class of molecules
called carotenoids, which are created by plants. "Carotenoids" were
given that name, because they were first isolated from carrots.
[0015] Carotenoids have two traits that make them very important in
nature and nutrition: (1) they're very good at absorbing
ultraviolet (UV) and blue light; and (2) just like vitamins, they
cannot be synthesized inside the cells or bodies of humans, or
other mammals. Therefore, humans and other mammals must eat
carotenoids in food, or in dietary supplements, to get the amounts
they need,
[0016] Since the UV radiation in direct sunlight, shining directly
on cells for numerous hours each day, is strong enough to kill any
type of unprotected cell, carotenoids play crucially important role
in plants, and in many types of bacteria. Hundreds of slightly
different types of carotenoids have evolved in different species of
plants and bacteria; over 600 distinct types of carotenoids have
been identified in nature, and every year another dozen or more are
announced. All of those carotenoids are synthesized only in plants
or bacteria, Animals (including humans) simply cannot make
carotenoids; instead, we must eat the carotenoids we need, in our
diets.
[0017] An important fact of physics is that light rays with very
short wavelengths, in the ultraviolet ("UV"), near-ultraviolet, and
deep blue parts of the spectrum, contain the most energy of any
wavelengths in or near the visible spectrum. UV and near-UV rays
are what turn sunburned skin a painful shade of red. Sunburn is a
defense mechanism; when the outer layers of skin become damaged,
they respond by swelling up, becoming engorged with blood,
histamine, and other agents, and generating and recruiting higher
levels of pigment in an effort to reduce the amount of additional
damage. UV rays will kill the outermost layers of cells of the
skin; when sunburned skin begins to peel, those are dead skin
cells, coming off.
[0018] In the same way, UV rays are a very effective way to
sterilize surfaces, because they will kill nearly any types of
viruses or bacteria they can reach and hit.
[0019] UV rays inflict this type of damage by breaking apart
biomolecules more or less randomly. When a ray or photon of UV
radiation hits various types of chemical bonds that hold together
adjacent atoms in biomolecules, it typically breaks the bond
between those two atoms, thereby splitting the molecule into two
fragments.
[0020] By splitting apart biomolecules on a random basis, UV
radiation inflicts two different types of toxic and potentially
lethal damage on cells. First, UV radiation will directly break
apart the long molecular strands that make up protein and DNA.
Since protein and DNA are crucial to any cell, this type of damage
will directly kill cells, if it continues long enough. The second
mechanism is this: when UV radiation hits a molecule that contains
oxygen, it often causes an oxygen-containing fragment to be broken
off of the molecule, in a way that creates a highly unstable and
reactive "oxygen free radical". Because of complicated factors
involving the electrons in an oxygen atom's "valence shell", these
unstable free radicals will attack, alter, and damage nearly any
type of biomolecule.
[0021] To minimize that type of damage from oxygen free radicals,
cells use various types of anti-oxidants, which are molecules that
will attract and react with oxygen free radicals. A good
anti-oxidant molecule will bind any oxygen free radicals into
larger molecules, which are stable and will not attack other
molecules. This type of neutralizing reaction, by antioxidant
molecules which absorb and neutralize oxygen free radicals, is
often referred to as "quenching," in a manner similar to quenching
a fire.
[0022] Carotenoids are very effective anti-oxidants, and they can
quench and neutralize oxygen free radicals. Therefore, plants
evolved with carotenoids as a special class of protective
molecules, which can minimize damage that otherwise would be cause
by ultraviolet radiation. The surface cells that cover plant leaves
contain large quantities of carotenoids. Indeed, carotenoids are
what cause tree leaves to turn red, orange, and gold in the fall.
Since carotenoids absorb light with blue and violet wavelengths,
the wavelengths that bounce off and are reflected and emitted, by
the leaves, are at the other end of the color spectrum, in the red,
orange, and yellow region. When cold weather arrives and tree
leaves become inactive, any green chlorophyll which remains in the
leaves is degraded more rapidly than carotenoids, which are rather
stable molecules. This causes the red, yellow and orange
carotenoids to become the dominant colors in leaves, during the
fall.
[0023] Bacteria growing in places exposed to direct sunlight for
hours require the same type of protection against toxic UV rays.
This is why scum that grows on rocks in a river (if it is not made
of green algae with chlorophyll) is usually some shade of yellow,
brown, or orange. Bacteria that can survive in such locations have
evolved the ability to synthesize carotenoids, to protect the
bacteria from being killed by UV radiation.
[0024] Carotenoids can absorb UV radiation and neutralize oxygen
free radicals, without being broken apart, because they contain
numerous "conjugated bonds". This is a complicated term, but it can
be explained by pointing out an important fact in FIG. 1, which is
a drawing of the chemical structures of zeaxanthin and lutein (with
beta-carotene also shown, for comparative purposes).
[0025] In the straight chain portion (i.e., the chain that
stretches between the two "end rings") of all three carotenoids
shown in FIG. 1, the double bonds alternate with single bonds. This
pattern of alternating single-bonds and double-bonds is referred to
by chemists as "conjugation". It is important, because when a
series of single and double bonds, all in a row or circle, are
conjugated, the electrons that form the bonds between adjacent
atoms do not remain attached to specific atoms. Instead, the
electrons become mobile, and they form an "electron cloud" that
covers and surrounds the molecule. This same type of semi-mobile
electron cloud also surrounds and stabilizes benzene rings and
other "aromatic" organic molecules.
[0026] This type of semi-mobile electron cloud is important,
because it leads to a remarkable result. When a carotenoid molecule
is hit by a UV ray or an oxygen free radical, the molecule doesn't
break. Instead, the electron cloud is able to flex and yield, in a
way that cushions and absorbs the blow. This is comparable to
someone hitting a wooden board, or a rubber tire, with a
sledgehammer. The board will break, because it cannot bend or
deflect. The rubber tire will not break, because it can flex and
yield in a way that allows it to absorb the force of the blow.
[0027] Because their semi-mobile electron clouds are flexible and
yielding rather than rigid, carotenoid molecules can absorb
numerous "hits" from UV rays and oxygen free radicals, without
being broken apart. When a UV photon or an oxygen free radical hits
a carotenoid, the destructive power of that photon or free radical
is used up and absorbed by the electron cloud. The photon or free
radical is "quenched", so it cannot attack and damage any other
molecules, such as protein or DNA. In this manner, by absorbing and
neutralizing UV radiation and oxygen free radicals, carotenoids
protect DNA, proteins, and other crucially important molecules in
cells.
[0028] These facts about conjugation apply to zeaxanthin and
lutein, and they lead to a crucially important difference between
zeaxanthin versus lutein, the only two carotenoids that are found
in the macula, a crucially-important part of the retina that sits
at the very center of the retina. As can be seen by examining their
structures, in FIG. 1, the double-bond in the right end ring of
zeaxanthin is perfectly conjugated, since it continues and extends
the same alternating double-single sequence that appears in the
straight-chain portion. Therefore, the semi-mobile "electron cloud"
created by the conjugated bonds extends over part of zeaxanthin's
right end ring.
[0029] By contrast, in lutein, the double-bond in the right end
ring is misplaced, and there is no conjugation at all, in the right
end ring of lutein. Therefore, one of lutein's end rings has no
electron cloud.
[0030] It should also be noted, from the chemical structures in
FIG. 1, that the other end rings (shown on the left side of FIG. 1)
of both zeaxanthin and lutein are identical. In both molecules, the
left end rings are conjugated, and have partial electron clouds
covering them. This points out another important reason why
zeaxanthin appears to be better and more effective than lutein, in
protecting human retina cells. Zeaxanthin is perfectly symmetrical,
end-to-end. If rotated so that its two end rings swap places, there
is absolutely no change. By contrast, lutein is not symmetric,
since its two end rings have different structures. If lutein is
rotated, it leads to a different alignment, or structure.
[0031] That difference between zeaxanthin and lutein (i.e., the
misplaced double-bond in one of lutein's end rings) may seem minor,
from looking at the chemical drawings in FIG. 1. However, chemical
tests have clearly shown that zeaxanthin is more potent and
effective than lutein, in absorbing and "quenching" oxygen free
radicals. This presumably is one of the reasons why the macula, in
human retinas, evolved in a way that clearly favors zeaxanthin over
lutein, as described below.
[0032] Two other points involving the structures of zeaxanthin and
lutein also deserve mention. both zeaxanthin and lutein have
"hydroxy" (HO--) groups attached to both of their end rings. By
contrast, beta-carotene, also shown in FIG. 1, is made entirely of
carbon and hydrogen atoms, with no oxygen atoms anywhere.
[0033] The fact that beta-carotene is made entirely of hydrocarbon
leads to a crucial fact: it is non-polar, which means it is soluble
in oily liquids, most of which also are made only of hydrocarbons.
By contrast, the presence of hydroxy groups, at both ends of
zeaxanthin and lutein, leads to a crucially important difference in
the way zeaxanthin and lutein behave, compared to how beta-carotene
behaves, when any of those three carotenoids, formed in plants, are
eaten by animals.
[0034] The outer membrane of any animal cell is made of molecules
that are oil-soluble at one end, and water-soluble at the other
end. These molecules are called phospho-lipids, since they have a
water-soluble "head" (which contains phosphorous) bonded to an
oil-soluble "tail" (made entirely of hydrocarbons). Because of
these structures, phospho-lipid molecules will spontaneously line
up together, when they are placed in a watery fluid, in a way that
gives them a "bilayer" arrangement, shown in FIG. 2A. A layer that
contains the water-soluble "heads" of the phospho-lipids line up so
that they cover the outside of the cell membrane. This allows the
water-soluble "heads" of the phospho-lipids to coat the outermost
surface of the cell membrane with a layer that is completely
comfortable in the watery liquids that surround the cell (including
blood, lymph, and tissue gel). The center layer of the bilayer
membrane is made of the oily hydrocarbon tails, which are attracted
to each other. The inner surface of the membrane is another layer
of water-soluble heads, which will comfortably contact the watery
fluid (called cytoplasm) that fills the cell.
[0035] Because beta-carotene has an entirely oily structure, made
of nothing but oily hydrocarbons with no oxygen atoms or hydroxy
groups, it will align itself in a way that causes it to remain
fully inside a cell membrane, once it reaches that position. This
configuration is shown in FIG. 2B.
[0036] By contrast, because zeaxanthin and lutein have
water-soluble hydroxy groups at their ends, they will align
themselves perpendicular to a cell membrane, in a direction that
causes them to "straddle" or "span" the cell membrane. This
"membrane-spanning" alignment is illustrated in FIG. 2C.
[0037] This crucial difference, in how these carotenoids will align
themselves in animal cell membranes, is a major difference between
beta-carotene, versus oxygen-containing carotenoids such as
zeaxanthin and lutein. Because of how carotenoids and animal cell
membranes evolved, in ways that allowed them to survive on earth
despite constant bombardment by potentially lethal dosages of
ultraviolet radiation from the sun, it is no mere coincidence that
most of the oxygen-containing carotenoids (including zeaxanthin,
lutein, and various other carotenoids such as canthaxanthin,
astaxanthin, etc.) have molecular lengths that allow them to
perfectly span the thickness of an animal cell membrane, with their
end rings sticking out from both the inner and outer surfaces of
the cell membrane.
[0038] However, it should also be recognized that this same factor
(i.e., the alignment of zeaxanthin or lutein in a direction that
causes them to straddle and span an animal cell membrane) makes the
difference between the end rings of zeaxanthin, versus lutein, even
more important. As mentioned above, both of the end rings of
zeaxanthin have conjugated electron clouds that extend into, and
cover, parts of both of zeaxanthin's end rings. Therefore, in
zeaxanthin, the conjugated electron cloud (which can help absorb
and quench UV rays, and oxidative free radicals), extends and
protrudes partway out from both sides of an animal cell membrane,
when a zeaxanthin molecule settles into the cell membrane.
[0039] By contrast, as mentioned above, one of the end rings of
lutein has no conjugation, and no electron cloud. Therefore, lutein
cannot extend a protective electron cloud, out beyond one side of
the cell membrane.
[0040] The perfect end-to-end symmetry of zeaxanthin (compared to
the lack of symmetry in lutein), and the presence of a conjugated
and protective electron cloud over both end rings of zeaxanthin
(while lutein has a protective cloud over only one end ring), are
presumed to be the primary reasons why the human retina prefers
zeaxanthin over lutein.
[0041] The retina is the thin layer of nerve cells located at the
back of the eye, where sight actually begins. When light enters a
mammalian eye, it passes through the cornea (a clear layer on the
front of the eye), a clear liquid called aqueous humor (which is
thin and watery), a focusing lens (which becomes cloudy, in people
with cataracts), and then another clear fluid (called vitreous
humor, since it has a consistency close to gelatin). All of those
are clear, and they allow light to pass through them, so that the
light can reach and activate nerve cells in the retina.
[0042] Using "rod and cone" structures that contain light-sensitive
chemicals, the nerve cells in the retina convert incoming light,
into chemically-driven nerve signals. Those nerve signals are sent
to the brain, where they are processed by the brain to form images
and sight. Therefore, the retina plays a crucial role in vision, If
the retina doesn't work properly, neither does vision.
[0043] The macula is the most important part of the retina, by far.
It is a small yellowish circle, only about an eighth of an inch
wide, located in the very middle of the retina, covering the exact
center of the field of vision. However, despite its small size, it
is crucially important to good vision, because of a factor most
people don't realize. The only part of the retina that provides
fine resolution is the macula, in the center of the retina. The
rest of the retina provides only coarse resolution.
[0044] Most people never notice that fact, because they are
accustomed to having both of their eyes flit rapidly across
moderately wide areas, in ways that allow the brain to rapidly
assemble a complete field of vision with good detail and accuracy.
However, the human brain has evolved an extraordinarily useful way
to speed up its ability to rapidly make sense of huge numbers of
incoming nerve impulses. It does so by using fine resolution only
in the very center of the retina, and coarse resolution in the
remainder of the retina.
[0045] As a simple demonstration of this feature of human vision,
if a person covers up one eye, with a hand or sheet of paper, while
looking at a page of text, and then looks through just one eye at a
single particular letter printed on the page, it becomes nearly
impossible to read any of the words directly above or below that
letter, in a line of text that is only three or four lines higher
or lower on the page. It is also nearly impossible to read any
words, through one eye, that are more than about an inch to the
left or right of the particular letter that is being stared at.
Most people are startled to realize how difficult that challenge
is, because they never notice that their vision has fine resolution
only in the center.
[0046] Indeed, the physical structure of the retinas of primates
(which evolved over many millions of years, in ways that helped
give primates substantially better vision than other classes of
mammals) helped create and drive that feature. In most of a human
or other primate retina, the capillaries and other blood vessels
that provide blood to the retinal cells (which need large
quantities of fresh blood, because they are so active) are placed
on the front side of the retina, where they interfere with incoming
light. That interference can be tolerated without harming vision
clarity, because vision is not very clear or high-resolution
anyway, in those parts of the retina. By contrast, in the macula,
the structure and placement of the blood vessels is entirely
different. In that small region, the blood vessels have moved to
the backside of the retina, so that they are positioned behind the
layer of nerve cells in the macula. In that one small portion of
the retina, they do not interfere with the incoming light before it
can reach the retina. Therefore, this placement of blood vessels,
behind the nerve cells in the small macular portion of the retina,
allows and promotes fine-resolution vision, but only in the very
center of the field of vision.
[0047] Because it is the only part of the retina that provides
vision with fine resolution, the macula must be healthy, for good
vision. If the macula degenerates, a person will lose the ability
to read, drive, recognize faces, or even be able to walk safely
down an unfamiliar sidewalk or hallway.
[0048] Loss of vision (up to a point that results in functional
blindness or major impairments), caused by macular degeneration,
happens to hundreds of thousands of people every year. Among the
elderly, macular degeneration is the leading cause of
blindness.
[0049] Furthermore, because of demographic and dietary shifts in
industrialized nations over the past decades (in particular, as the
population ages, and as people eat more processed and fatty foods
and fewer dark green vegetables), macular degeneration is becoming
even more widespread, at alarming rates. As briefly summarized in a
newsmagazine, "Eating doughnuts and other fatty treats doubles the
risk of going blind later in life" (Shute 2003, which briefly
summarized the results reported in Seddon et al 2003). Despite
every warning, many millions of people will continue to eat more
and more fatty treats, and fewer and fewer dark green
vegetables.
[0050] Studies of the retinas of people who suffer from macular
degeneration (including studies on living people, using
non-invasive measurements of "macular pigment optical density"
(MPOD), as well as chemical studies of retinas harvested from
macular degeneration sufferers who died of other causes) have made
it clear that low levels of macular pigment are strong correlated
with increased risk of macular degeneration. It is abundantly clear
that people with less-than-normal concentrations of zeaxanthin, in
the macular portions of their retinas, suffer higher risks and
rates of macular degeneration then people with normal levels of
zeaxanthin.
[0051] With regard to lutein, there is no clear data, and no clear
consensus. Since both pigments normally are found together, in
plant sources, it is difficult to distinguish between them, and it
generally has been presumed, for nearly two decades, that both
pigments are important. However, recent research that has been
specifically designed to distinguish between the concentrations and
effects of zeaxanthin and lutein has begun to suggest that
zeaxanthin plays a more important role than lutein, in protecting
the eyesight (e.g., Gale et al 2003).
[0052] As briefly mentioned above, another crucially important and
revealing fact of nature distinguishes zeaxanthin from lutein, in
human retinas. is clear that the human macula contains only
zeaxanthin and lutein, as the two pigments that give the macula its
distinctive yellowish color. However, the macula places those two
different carotenoids in different locations. It deposits
zeaxanthin at highest concentrations directly in the center of the
macula, in the most crucial part of the macula. Then, it surrounds
that high-concentration zeaxanthin zone in the center, with a ring
of higher lutein concentrations.
[0053] There is no sharp dividing line, between zeaxanthin in the
center of the macula, and lutein around the edges. Instead, there
is a transition zone, with zeaxanthin concentrations gradually
decreasing, and lutein concentrations gradually increasing, as the
distance from the center of the macula increases.
[0054] This fact about the retina must be considered in view of an
important and well-established fact of nature: lutein is relatively
abundant in plant sources, while zeaxanthin is scarce. Lutein is a
dominant carotenoid, which is present in a fairly wide variety of
food sources. This dominance apparently arose because the structure
of lutein's non-conjugated end ring allows it to fit, in an ideal
manner, into certain structures in plant cells that are involved in
photosynthesis. As a result, even in plants that have unusually
high concentrations of zeaxanthin (such a spinach, kale, etc),
there is roughly 20 to 50 times more lutein, than zeaxanthin.
Therefore, lutein can be obtained much more easily and readily than
zeaxanthin, and in much higher quantities and concentrations, from
plant sources in the diet.
[0055] Nevertheless, despite the huge imbalance in favor of higher
lutein supplies, the retina somehow obtains and places the highest
concentrations of zeaxanthin directly in the center of the macula,
while it places lutein at high concentrations only around the
periphery of a zone that has higher zeaxanthin concentrations,
[0056] These items of evidence, placed together, strongly indicate
that human retinas have developed and evolved with a notable and
substantial preference for zeaxanthin, over lutein.
[0057] In addition, there is yet another important factor which
clearly indicates that the human retina prefers zeaxanthin over
lutein. Acting apparently through enzymatic and/or light-triggered
reactions that are not fully understood, the human retina attempts
to convert lutein into zeaxanthin. However, the retina cannot
convert lutein into the same isomer of zeaxanthin that exists in
the natural diet. The only isomer of zeaxanthin that is present in
dietary sources is the stereoisomer (also referred to as the R-R
isomer, for convenience), which means that the "right" (or
dextrorotatory, rather than left, or levorotatory) stereoisomer
arrangement is present on both of zeaxanthin's two end rings.
However, the human retina cannot form the normal R-R isomer, when
it converts lutein into zeaxanthin. Therefore, the retina converts
lutein into a different isomer, called meso-zeaxanthin, or S-R
zeaxanthin. Therefore, the presence of the non-dietary S-R (meso)
isomer of zeaxanthin, in human retinas, is clear evidence that the
human retina is attempting to convert lutein, into zeaxanthin.
[0058] In passing, it should be noted that the S-R (meso) isomer of
zeaxanthin has never been shown to exist in any known dietary
sources. Although a report from the mid-1980's (Maoka et al 1986)
asserted that meso-zeaxanthin had been found in certain types of
fish, that assertion was later contradicted by the discovery that
alkaline treatment of carotenoids (as used by Maoka et al) can
convert lutein into meso-zeaxanthin. Accordingly, the claim that
meso-zeaxanthin had been found in fish may have been, instead,
merely an artifact of the carotenoid extraction process they used,
and meso-zeaxanthin has never been shown to exist in any food
sources that humans eat. Its safety, as a food additive for humans
(or as a feed additive for poultry or farm-raised salmon) is not
known, and has not been evaluated. Accordingly, any efforts to add
meso-zeaxanthin (created by alkaline treatment of lutein) to any
human food source (either as a dietary supplement, or as a feed
additive that is fed to poultry or fish) raise serious questions as
to whether such additives are safe and legal, under the terms of
the United States' Dietary Supplement and Health Education Act.
[0059] Accordingly, the major points discussed above can be briefly
summarized as follows:
[0060] 1. Zeaxanthin has been shown to be a better and more potent
anti-oxidant than lutein, in lab tests;
[0061] 2. Zeaxanthin is completely symmetrical, while lutein is
not;
[0062] 3. Zeaxanthin is able to extend a "conjugated electron
cloud" (which is useful and protective, since it can absorb UV rays
as well as destructive oxygen free radicals) beyond both sides of a
cell membrane, while lutein can extend that type of protective
electron cloud beyond only one side of a cell membrane.
[0063] 4. Even though lutein is far more abundant in plant sources,
zeaxanthin is deposited at higher concentrations in the crucially
important center of the macula. Lutein is deposited only at low
concentrations in the center of the macula, and at higher
concentrations around the less-important periphery.
[0064] At one level of analysis, one might presume that these four
factors suggest two logical conclusions: (i) the macula wants and
prefers zeaxanthin, over lutein; and, (ii) when the macula cannot
obtain enough zeaxanthin (because zeaxanthin is so scarce in food
sources), it will make up the deficit by using lutein, because of
lutein's close structural similarity to zeaxanthin.
[0065] However, that is only one possible analysis, and it appears
that no one, prior to the inventor herein, has ever cleanly and
concisely assembled all four of those factors, into a fully
cohesive, consistent, and persuasive argument for zeaxanthin.
Instead, any analyses of this invention must also take into account
several additional and equally compelling facts and factors, which
center around the following:
[0066] (i) numerous published reports, in respected and refereed
journals, assert that there is no solid and reliable evidence that
zeaxanthin actually can help protect the retina;
[0067] (ii) numerous published reports explicitly advise physicians
who treat patients suffering from eye diseases that it is premature
and ill-advised for any physician to instruct patients to begin
taking any unproven and potentially dangerous supplements;
[0068] (iii) when a large panel of world-class retinal experts was
asked, in 1998, by the National Eye Institute, to list the best and
most promising candidate agents for fixture research to help
prevent or treat retinal diseases, that entire panel, in its
collective wisdom and expertise, completely omitted both zeaxanthin
and lutein as candidates that should be considered for research,
even though the members of that panel were aware of both zeaxanthin
and lutein and had even published articles on them prior to 1998;
and,
[0069] (iv) in October 2003, when one of the world's top experts in
treating macular degeneration was informed that one of his patients
was taking zeaxanthin, the physician specifically advised the
patient to stop taking zeaxanthin, since it might interfere with a
different treatment that the physician was planning to give the
patient.
[0070] These factors oiler powerful evidence that the invention
disclosed herein, which rests upon zeaxanthin as the crucial and
essential ingredient in multi-component formulations for preventing
or treating eye diseases, is not obvious to those who are truly
skilled in the art, and who in fact have devoted their careers to
trying to prevent and treat eye diseases.
[0071] This current invention arises from substantial additional
readings and research into eye health, by the Inventor herein,
during the past several years. Despite his realization that
zeaxanthin appears to be the crucial and essential key to good eye
health, he continued to carefully study and analyze both: (i)
hundreds of published reports and product claims, for literally
hundreds of products and ingredients that are being sold or touted
as being able to benefit eye health, and (ii) hundreds of published
articles, on various aspects of eye physiology, anatomy, and
structure, and on eye diseases and disorders.
[0072] Those readings and research, followed by extensive thought
and efforts to synthesize everything he had read on the subject of
eye health and eye products, led him to several realizations that
are discussed in more detail below. One of the key realizations can
be briefly summarized as follows: the eye is designed to serve as
an interface, between two entirely different realms of nature (one
realm is outside the body, where light begins, and the other realm
is inside the body, where sight begins), and even between two
completely different realms of science (the eye must be able to
convert physics, in the form of electromagnetic radiation, into
chemistry, in the form of neurotransmitters and nerve impulses).
The eye can accomplish these results, only by being able to
combine, into a single unit, multiple types of tissues, cells, and
structures (including two different types of clear tissues, two
different types of clear liquids, two different types of
photoreceptors, and nearly a dozen distinct layers, in and behind
the retina).
[0073] One of the factors that enabled and promoted the evolution
and development of an extraordinary level of complexity, in human
eyes, relates to the fact that carotenoids are multi-functional
agents, and can perform more than just one role or task. In
addition to being highly effective in absorbing ultraviolet light,
they are also highly effective in quenching oxidative free
radicals.
[0074] However, the multifunctionality of carotenoids doesn't stop
there. They also have mild yet potentially helpful and useful
ability to control and reduce inflammation. This is a crucial
benefit, in many types of eye disorders, since inflammation can
lead to severe adverse results, if it lasts for a number of days,
weeks, or months in succession. One mechanism for potentially
serious damage to the eyesight, cause by inflammation, arises from
the effects of increased fluid pressures inside the eyeball. This
fluid pressure will be imposed on the exterior surfaces of the
capillaries that provide blood to the retina. Since capillary walls
must be extremely thin (in order to promote rapid exchange of
oxygen, nutrients, and metabolites), they cannot resist and push
back against elevated fluid pressures on their exterior walls. As a
result, elevated pressures inside the eye, if they arise as a
result of inflammation after an injury or infection, can act in a
manner comparable to a severe and accelerated case of glaucoma (a
disease that also involves elevated fluid pressures inside the eye,
which causes reduced blood flow through the retinal capillaries,
and which can cause severe and permanent damage to retinal nerve
cells). Therefore, the ability of certain carotenoids to help
control and reduce inflammation can become crucially important, and
extremely helpful, in response to injuries, infections, or other
events that can trigger inflammation of one or more types of eye
tissues.
[0075] Similarly, carotenoids also have a mild yet potentially
useful and helpful level of activity in preventing and reducing
"sclerosis". This term refers to hardening, stiffening, and loss of
flexibility (for example, arteriosclerosis refers to hardening of
the arteries, and atherosclerosis is a related process in which the
insides of the arteries become coated with cholesterol or other
fatty deposits), In the eyes, sclerosis and loss of flexibility
(which can also arise when substantial quantities of drusin,
lipofuscin, and other debris accumulate) can adversely affect
certain membranes, such as the Bruch's membrane, which is a
crucially important layer in the back of the eye, behind the
retina. Therefore, the ability of carotenoids to help prevent and
reduce sclerosis is yet another way in which carotenoids can help
protect eye health and good vision.
[0076] After the inventor herein had read about and recognized
those additional roles of carotenoids, he then began to actively
notice still more different roles and activities that are being
played by carotenoids. A complete list must include (but is not
limited to) the following:
[0077] (1) Carotenoids have mild yet potentially useful levels of
activity in controlling and regulating angiogenesis (i.e., the
formation of new blood vessels, which can lead to extremely severe
problems in the wet or exudative form of macular degeneration).
[0078] (2) Carotenoids have mild yet potentially useful levels of
activity in helping to modulate and regulate the functioning of
mitochondria, which are crucial to oxygen usage, respiration, and
energy utilization by a cell.
[0079] (3) Carotenoids have mild yet potentially useful levels of
activity in helping to modulate and regulate apoptosis, a form of
"programmed cell death," in which cells that receive certain
signals or that enter into certain states trigger a process that
leads to fairly rapid death of the cell. This process effectively
allows other specialized cells (glial cells in the nervous system,
and immune cells in the remainder of the body) to clean up and
remove the cell debris, so that the system in that locality can go
back to functioning properly, without being hindered by a lingering
cell that is crippled, useless, and a drain on resources.
[0080] (4) Carotenoids have mild yet potentially useful levels of
activity in helping to regulate and control certain types of
actions and responses of the immune system.
[0081] It must be kept in mind that this brief listing (immediately
above) of four different "peripheral" activities, by carotenoids,
must be added to two other peripheral activities (i.e., modulation
of inflammatory responses, and modulation of sclerotic hardening),
and all six of those activities must then be added to the two
"primary" activities of carotenoids (i.e., absorbing and quenching
destructive ultraviolet photons, and absorbing and quenching
destructive oxygen free radicals).
[0082] There are also various other scientific reasons for
believing that (i) many eye disorders are multi-factorial, and (ii)
the best treatments or preventive agents for such disorders will
also be multi-factorial. These factors are highly complex, and
involve, for example: (i) the fact that inflammation and immune
responses can both create oxygen free radicals and "reactive oxygen
species"; (ii) various types of signaling pathways that cells use,
to effectively communicate with each other; and (iii) the crucial
involvement of mitochondria in many of these processes, and in
processed involving apoptosis and programmed or signaled cell
death.
[0083] Upon reading and realizing that carotenoids must be able to
perform two absolutely crucial primary and central roles
(neutralizing UV photons and free radicals), while also being
called upon to perform at least six known secondary and peripheral
activities, the inventor herein gradually reached several
conclusions about carotenoids in human eyes. Those two conclusions
can be summarized as follows:
[0084] 1. If carotenoids are being asked to perform eight different
tasks (and possibly even more) in a single eye, they are more
likely to become "stretched thin", and unable to adequately handle
all of those tasks simultaneously, than other molecules that only
need to perform fewer numbers of tasks;
[0085] 2. Research reports have indeed shown that people who are
suffering from certain types of eye problems do indeed suffer from
low carotenoid concentrations in their blood (as shown by tests on
blood serum) and/or their eyes (as shown by inadequate levels of
zeaxanthin in people with macular degeneration, and reduced
zeaxanthin densities in the lenses of people suffering from
cataracts);
[0086] 3. If any or all of the "secondary demands" that are being
imposed on carotenoids in the eyes can be reduced, by ingesting or
administering other nutrients that can provide a balanced regimen
that will help address and satisfy those secondary demands, then
any newly-arriving carotenoids will be more likely to actually
arrive at locations where they can carry out their essential
primary roles, and provide the most overall benefit.
[0087] Accordingly, over a span of time that allowed careful
consideration and additional readings on related subjects, this
line of logic and analysis began to suggest, more and more
persuasively, that well-balanced eye-care preparations would be
able to do the greatest possible good, in protecting or restoring
the extraordinarily complex needs of human eyes, if those
formulations contain both: (i) zeaxanthin, as the ideal, symmetric,
fully-conjugated carotenoid that has been fully optimized (by
millions of years of evolution) for interacting in beneficial ways
with animal cells and animal cell membranes; and, (ii) one, two, or
more additional ocular-active nutrients that can directly and
efficiently address and correct any one or more "secondary
demands", which otherwise will tend to "siphon off" part of any
zeaxanthin that reaches the eye.
[0088] Viewed from another perspective, zeaxanthin can be regarded
as a form of "buffer", in a system that is constantly trying to
sustain an equilibrium (which is usually called "homeostasis", when
living biological systems are involved). Like buffer compounds,
carotenoids can respond to whatever is added to (or imposed upon)
the system, in a way that usually will help the system move back
toward its equilibrium (also referred to as the "set-point" of the
system). However, it must also be recognized that if the outer
limits of the buffering capacity of a certain buffer compound has
been reached in a certain system, addition of even a slight
quantity of additional acid or alkali can cause major swings and
upheavals, in the system. In an analogous manner, if the
carotenoids in a human eye are "stretched thin", by a combination
of multiple competing demands, all demanding responses at the same
time, then the overall protective system can fail, leading to a
variety of stresses, problems, and damage, all occurring at once,
and acting together in ways that are suggested by phrases such as
vicious circle, witch's brew, etc.
[0089] Subsequently, as the inventor pondered various approaches to
developing and optimizing ways to respond to complicated and
intertwined problems that lead to (or are caused by) complex,
difficult, and often intractable ocular diseases and disorders
(which lead to serious visual impairment, functional blindness, or
complete blindness in millions of people every year, despite the
best efforts of thousands of doctors and researchers), he
eventually arrived at a complex intersection, where roughly half a
dozen distinct themes all converge and cross each other. Briefly,
those themes include the following:
[0090] (i) Using nature and evolution as the best examples and the
best instructors, many and probably most of the best candidate
ocular-active nutrients are likely to be derived from plants;
[0091] (ii) In the same way and for the same reasons that occur in
plants, many and probably most of the best candidate ocular-active
nutrients are likely to have strong or even exclusive specificity
for certain stereoisomers, and racemic mixtures created by
non-specific chemical synthesis should be avoided wherever
possible;
[0092] (iii) Despite the dominance of plant nutrients as offering
the best candidates overall, humans evolved most efficiently as
omnivores, and diversity should be recognized, respected, and
valued. Accordingly, animal sources may well offer one or two
ocular-active nutrients that may provide good and useful
complements, when added to best-candidate plant nutrients for eye
health; and,
[0093] (iv) after a list has been developed that contains the best
candidates from the realm of naturally-occurring ocular-active
nutrients, the final step is to make good, shrewd, intelligent use
of technology, to get those natural products properly stored,
packaged, and delivered. In this context, appropriate technological
steps can include, for example: (i) the use of oily carrier
substances, to deliver active agents (including carotenoids) that
are naturally oil-soluble; (ii) the use of timed-release and/or
sustained-release technology, to establish sustained and lasting
increased blood concentrations of any compounds that otherwise
disappear rapidly from the gut or from circulating blood; and,
(iii) the use of various types of bioavailability enhancers (such
as bile salts, phospholipids, or pancreatic lipase), to increase
the uptake of oily compounds through the intestinal walls, and into
circulating blood.
[0094] After extensive thought, reading, research, and discussions
concerning various different factors listed above, the inventor
herein has reached a point where it is now time to convert these
concepts and ideas into detailed and specific tests, which must be
woven together .into a consistent and cohesive program that is
planned and organized to lead directly to a specific outcome that
can be clearly envisioned and described at this time, even though
the screening tests have not yet been commenced that will identify
those specific agents that will perform most potently,
synergistically, and beneficially, when combined with
zeaxanthin.
[0095] Accordingly, one object of this invention is to disclose
multi-component orally-ingestible formulations for protecting eye
health in mammals (including humans), which contain zeaxanthin as
an essential and critical ingredient, and which also contain at
least two or more other agents that have been proven, in tests on
humans or other primates, to act in a synergistic and potentiating
manner with zeaxanthin, to provide improved efficacy in preventing
or treating eye diseases.
[0096] Another object of this invention is to disclose a focused
method of approach that will be able to clearly identify
ocular-active nutrients that, when added to zeaxanthin, will be
able to improve the efficacy of zeaxanthin in preventing or
treating eye diseases.
[0097] Another object of this invention is to disclose a method
(which has intertwined aspects of both scientific research, and a
method of doing business) that will sort through hundreds of
competing and confusing products that are accompanied by
unsupported and unreliable advertising and marketing claims, and
which will provide (i) elderly people who are suffering from vision
loss; (ii) their families, caregivers, and insurance companies;
and, (iii) government and charitable institutions that will be
forced to bear the brunt of the costs of caring for millions of
elderly people who are at severe risk of becoming functionally
blind, with genuinely useful and reliable products and information
that will be truly effective in preventing an epidemic of
blindness, which otherwise will occur as the population ages, and
as the long-terms effects of unhealthy high-fat diets gradually
take their toll on the aging populace.
[0098] These and other objects of the invention will become more
apparent, through the following summary, description, and
claims.
SUMMARY OF THE INVENTION
[0099] A process is disclosed for identifying ocular-active
nutrients that will interact in a synergistic and potentiating
manner with a carotenoid called zeaxanthin, to provide better and
more effective protection, for eye health, than can be provided by
zeaxanthin alone. Product-by-process combinations of such
ocular-active nutrients that are identified as offering especially
potent and useful eye health benefits, when combined with
zeaxanthin, are also disclosed.
[0100] Eight categories of candidate ocular-active nutrients are
identified herein. These eight categories can be summarized as
follows:
[0101] (1) Lipoic acid, preferably in the form of a purified or
enriched naturally occurring "R` (dextrorotatory) stereoisomer
rather than a racemic mixture.
[0102] (2) At least one omega-3 fatty acid, such as
docoso-hexaenoic acid (commonly referred to as DHA) or one of its
linolenic acid precursors, preferably obtained from a natural
source such as fish oil or marine algae.
[0103] (3) Various plant-derived compounds that are referred to by
various scientists as flavonoids, bioflavonoids, anthocyanins,
plant polyphenolics, or phytonutrients. These compounds include
extracts from bilberry, grapeseed, or green tea, as well as soy
isoflavones, quercetin, genestein, diazedem, fisetin, luteolin,
resveretrol, and pycogenol.
[0104] (4) Taurine, the common name for amino-ethane-sulfonic acid,
a "conditionally essential nutrient" that is present in milk and
various tissue types.
[0105] (5) Carnitine, a sulfur-containing amino acid (not one of
the 20 primary amino acids used in protein synthesis) that is
formed in the liver and elsewhere, and various esters and/or
precursors of carnitine, such as acetyl-L-carnitine.
[0106] (6) An enzyme cofactor known as Coenzyme-Q10, which is a
known anti-oxidant that provides energy-related support to
mitochondria. In some situations, it can help prevent or reduce a
process called "apoptosis" that leads to a type of programmed cell
death.
[0107] (7) Carnosine, a di-peptide formed from alanine and
histidine, which can prevent reactive aldehydes from causing
unwanted glycosylation or crosslinking of proteins.
[0108] (8) Nutrients that can stimulate the production or
metabolism of glutathione, a tri-peptide that helps cells eliminate
waste products. One such agent is N-acetyl cysteine, an ester that
is metabolized to release the cysteine, the sulfur-containing amino
acid in the center of glutathione.
[0109] In addition to those eight categories (none of which were
tested during the AREDS-1 trial in the 1990's), three classes of
compounds that were tested in the AREDS-1 trial also may merit
attention. Two of those categories include tocopherol compounds,
such as alpha-tocopherol (vitamin E), and ascorbic acid (vitamin C)
or a salt or ester thereof, such as ascorbyl palmitate. The third
category includes zinc. When vitamins C and E (as well as
beta-carotene) were combined at high dosages, they offered a low
and weak level of protection against macular degeneration, in some
but not all of the patient categories, in the AREDS-1 trial.
Similarly, zinc at very high dosages (80 mg/day), by itself,
offered a low and weak level of protection in some categories of
patients. When vitamins A/C/E and zinc were combined, the level of
protection increased, especially among late-stage macular
degeneration sufferers.
[0110] Accordingly, the results and findings of the AREDS-1 trial
are not regarded as strong or compelling, when compared with the
potential benefits of zeaxanthin, and in recent years it also has
become clear that high dosages of vitamin A or its precursor, beta
carotene, offer little or no serious hope for providing any
significant protection against macular degeneration, or any other
serious eye disorders among people who receive minimal baseline
levels of vitamin A. However, various general and specific benefits
of vitamins C and E, and of zinc, are well known and solidly
proven, especially among elderly people and people with poor diets.
Therefore, vitamins C and E, and zinc, remain of interest, and they
will be tested (possibly in the form of the complete AREDS
formulation, which is commercially available) in combination with
zeaxanthin, to determine whether they can provide a synergistic
benefit that will improve substantially on the results that can be
provided by zeaxanthin alone.
[0111] To evaluate and rank the efficacy and synergistic activities
of these candidate ocular-active nutrients, selected tests that
have been chosen to accommodate various animal models (including a
number of animal models described below) can be used. Each type of
animal model can provide different types of data, which will relate
to certain components of the eye and certain known ocular
disorders. Researchers who are experienced in designing and
carrying out such tests understand the types of data that can be
gathered from each such test, and from each type of animal species
that is well-suited for use in a particular type of test.
Accordingly, testing regimens with targeted data-gathering methods
can be developed, to gather specific types of data that will
indicate which ocular-active nutrients listed above are likely to
have the most valuable and beneficial effects, when combined with
zeaxanthin and then tested m human clinical trials.
[0112] Based on the results of the animal tests, candidate
formulations can be tested in clinical trials on humans who are
suffering from various types of eye disorders. Testing regimens are
known, and can be designed by skilled experts, for use with nearly
any type of eye disorder. At least some types of tests can be
designed to speed up the gathering of useful data, when testing
patients suffering from diseases that gradually manifest over a
span of multiple years. This type of accelerated data gathering can
be enabled by various approaches, such as by focusing on selected
patients who, at the point in time when they will be tested, are
entering or progressing through certain stages that involve
accelerated and rapid degeneration and loss of vision acuity. One
example, among most patients who suffer from the dry form of
macular degeneration, involves an intermediate stage called
"geographic atrophy", which occurs when distinct patches of
degeneration in or around the macula become clearly visible, in
certain types of diagnostic photographs. it is not yet known which
specific ocular-active nutrients in the candidate categories listed
above will act in the most potent, effective, and beneficial
synergistic manner, when combined with zeaxanthin. What is known,
instead, is that the uncontrolled and unsupported profusion of
eye-care nutritional products, all with their own competing and
confusing claims designed to sell products now (rather than support
research for the future), is not working adequately, and will not
work adequately in the future, unless something happens that alters
the landscape in an important and useful manner. Patients cannot be
sure what to take, physicians cannot be sure what to recommend, and
the largest and most powerful companies that sell eye care
nutrients have shown, by their actions, that they apparently are
determined to minimize zeaxanthin in their plans and products,
rather than recognizing its crucial role at the center of the
macula, and as the foundation and the single most important
ingredient in any nutrient formula that will be truly effective and
useful in protecting eye health and good vision.
[0113] The current system does not offer any realistic hope of
preventing dozens or even hundreds of millions of cases of
avoidable blindness, which will occur around the world over the
next 20 years unless a better approach can be found than the
approach that has been adopted and used so far by the largest
companies that sell eye care products, and by the National Eye
Institute. Accordingly, the testing and screening approach
disclosed herein should be regarded as a process, and the
synergistic compositions that will result will be
product-by-process compositions. Such product-by-process
compositions should be evaluated, not by pointing out that certain
items of prior art have been published on each of the candidate
nutrients listed above, but by comparing the testing and screening
method disclosed herein, which will treat zeaxanthin as an
essential "anchor" ingredient that will be included in all
formulations that will result from this approach, against: (i) the
research programs and eye-care nutritional products that have been
created by other companies that sell such products; and, (ii) the
actions of the National Eye Institute, which has stated in
communications to the inventor herein that it is planning to
deliberately exclude zeaxanthin from the so-called "AREDS-2" trial,
and focus on lutein instead.
BRIEF DESCRIPTION OF THE DRAWINGS
[0114] FIG. 1 depicts the chemical structures of zeaxanthin and
lutein and beta-carotene.
[0115] FIG. 2A depicts the bilayer structure of an animal cell
membrane, formed by two rows of phospho-lipids having water-soluble
phosphate "heads", and oil-soluble lipid "tails."
[0116] FIG. 2B depicts the way a molecule of beta-carotene, which
has no oxygen atoms or hydroxy groups, will align itself entirely
within the oily interior of a cell membrane.
[0117] FIG. 2C depicts how molecules of zeaxanthin and lutein will
align themselves to "span" or "straddle" a cell membrane, in a way
that causes their end rings and hydroxy groups to protrude and
extend out, beyond the cell membrane's outer and inner
surfaces.
DETAILED DESCRIPTION
[0118] As briefly summarized above, this invention relates to
"ocular-active nutrients" that can act in a synergistic and
potentiating manner with zeaxanthin, to protect and/or restore eye
health and good vision to a degree that rises substantially above
the levels of benefit that can be provided by zeaxanthin alone.
[0119] Several points of terminology need to be addressed, before
describing the testing and screening method, and the categories of
candidate nutrients, in more detail.
[0120] Ocular relates to the eye, and terms such as ocular-active
can be used interchangeably with other terms such as ophthalmic,
eye-related, vision-related, etc.
[0121] The term nutrients, as used herein, refers to compounds that
are found in the normal human diet. Under the various laws that
have been passed to regulate foods and drugs, nutrients that are
present in normal human diets are usually covered by the laws and
rules of the U.S. Dietary Supplement Health and Education Act. By
contrast, drugs and pharmaceuticals that are not found in the
normal diet are regulated separately, under different statues and
rules. However, as mentioned below, it should also be recognized
that some nutrients found in the normal diet can be regarded and
regulated as drugs or pharmaceuticals, if (and to the extent) they
are prescribed by physicians to treat specific and diagnosed
medical conditions.
[0122] Ocular-active nutrients, as used herein, refers to and is
limited to compounds developed for oral ingestion, to provide
active, substantial, and measurable benefits for one or more
aspects of eye health or vision quality. Although some of these
nutrients may also be useful (and indeed might have accelerated
effects) if administered by other means (such as by intravenous or
intraocular injection), all claims herein are limited to nutrient
formulations that are intended to be ingested orally. This is
deemed to be the relevant field of art and usage, and published art
on other, different types of formulations (such as, for example,
injectable drugs) are not deemed to be relevant herein.
[0123] The major use for orally-ingestible ocular-active nutrients,
as discussed herein, is to protect or treat human eyes, and vision.
However, if desired, such formulations may also be used to prevent
or correct eye-related problems in other mammalian species, such as
to prevent cataracts or retinopathies in dogs. The combined
formulations of this invention can be in the form of pharmaceutical
preparations, dietary supplements (also referred to interchangeably
as nutritional supplements), or foodstuffs.
[0124] Pharmaceutical preparations (which can be prescription-only,
over-the-counter, or any combination of the two) normally are used
to treat known and already-existing problems, while dietary
supplements (also referred to interchangeably herein as nutritional
supplements) normally are used to sustain a condition of good
health. While there is no clear dividing line between
pharmaceutical preparations versus dietary supplements (for
example, treating physicians often recommend dietary supplements to
patients who are suffering from specific diagnosed problems), a
practical difference nevertheless exists between the two
categories. This arises from the fact that pharmaceutical
preparations usually contain higher dosages of active agents, than
dietary supplements. Accordingly, for purposes of discussion and
description herein, terms such as "pharmaceutical preparations" and
"therapeutic dosages" are deemed to include any combinations of
ocular-active nutrients, as discussed herein, that contain at least
3 milligrams (mg) of zeaxanthin, either as a unitary dosage, or as
a recommended daily dosage. Preferred therapeutic dosages for most
patients who are suffering from diagnosed eye disorders usually
will comprise 10 or more mg of zeaxanthin per day.
[0125] Dietary (nutritional) supplements generally comprise
formulations and preparations that are designed to be taken by
people who wish to sustain a condition of good health, or at least
to prevent any further deterioration of their health, regardless of
whether they have been diagnosed with a particular disorder by a
physician. Accordingly, dietary supplements they usually have
unitary and/or daily dosages that are within a range that is (i)
higher than the minimal quantities (often called "trace amounts")
that are contained in naturally occurring foods, but (ii) lower
than the therapeutic dosages that are provided by drugs and
pharmaceuticals that are used to treat known medical problems.
Accordingly, for purposes of discussion and description herein,
dietary (nutritional) supplements are deemed to include
preparations that contain at least about 0.5 mg zeaxanthin, as
either a unitary dosage, or as a recommended daily dosage.
[0126] As mentioned above, the categories of pharmaceutical
preparations and dietary (nutritional) supplements overlap, and
there is no specific upper limit for dosages that would cause a
dietary (nutritional) supplement to be reclassified as a
pharmaceutical preparation. Safety data that was gathered on
zeaxanthin, using high-dosage tests involving rats, indicated a "no
adverse effect limit" (NOEL) level of at least 1200 mg/day. These
data were disclosed in a "75-day Premarket Notification" for
zeaxanthin, which was submitted to the U.S. Food and Drug
Administration (FDA) by Roche Vitamins, Inc. (the only company that
is currently manufacturing the dietary isomer of zeaxanthin, for
human consumption), and which was opened for public inspection by
the FDA in June 2001 under FDA number 95S-0316. In addition,
small-scale tests involving human volunteers indicated that dosages
of zeaxanthin in a range of 50 to 80 mg/day appear to be entirely
safe, and were effective in reducing a person's risk and severity
of sunburn, when small areas of skin were exposed to controlled
dosages of high-intensity ultraviolet radiation from a
medical-grade UV lamp. These high dosages of zeaxanthin also
succeeded in creating slightly reddish skin tones, which turned a
darker brown or bronze color that completely resembled a healthy
tan, when subsequently exposed to the sun. Accordingly, people who
want tans, or who are planning to go on a vacation or other trip
that will involve exposure to abnormally high levels of sunlight,
may take large quantities of zeaxanthin (up to or even exceeding
100 mg/day), to help them avoid sunburn and obtain a deeper tanned
color on their skin. Such use, even at very high quantities, would
be regarded as taking a dietary supplement rather than a
pharmaceutical, and such dosages would still remain far below the
NOAEL levels that were determined by animal tests.
[0127] On the subject of unit dosages and daily dosages, unit
dosage forms involve discrete units. The most common forms are
capsules (which use an encapsulating material), tablets (which use
compressible binder materials), and various types of "hybrid" pills
that use encapsulating materials as well as compressible binders
(usually called caplets, coated tablets, etc). Other types of unit
dosages can also be provided by other means, such as sealed plastic
pouches containing measured amounts of a powder or liquid that is
to be added to a food or drink.
[0128] Daily dosage forms can include unitary dosage forms (such as
tablets or capsules, which normally are accompanied by a
recommendation to take a specified number of pills per day to
achieve a recommended daily dosage). Daily dosage forms also can
include liquids, powders, or similar preparations, which usually
are accompanied by instructions concerning a certain volume,
weight, or other quantity that should be ingested each day to
achieve a recommended daily dosage.
[0129] It should also be noted that unit dosages can be provided in
the form of capsules that will contain oily carrier materials, such
as a vegetable oil. This can enhance the uptake and bioavailability
of zeaxanthin, vitamin E, and various other oil-soluble nutrients
disclosed herein. If desired, such oily carriers can also be
formulated to carry microencapsulated beadlets or other
preparations, which can contain water-soluble nutrients or any
other components that are easier to handle if isolated or otherwise
coated in that manner.
[0130] Another class of compounds that can contain zeaxanthin
combined with other ocular-active agents is referred to herein by
the term "foodstuffs". This broad industry term includes compounds
that are designed to be eaten as a food or drink, having enough
volume and bulk to help satisfy an appetite or thirst (as distinct
from a tablet, capsule, or other low-volume drug-type preparation).
Foodstuffs can be complete and ready to eat (such as snack foods,
energy or nutrition bars or mixes, or desserts, or beverages that
are sold in cans, bottles, or pouches, etc.); they can require
cooking, mixing, or other preparation (such as frozen or
refrigerated snacks or entrees, soups or other foods sold in cans
or pouches, cooking ingredients, drink mixes, etc.); or, they can
involve any combination of or midway point between those categories
(such as peanut butter, cheese, vegetable dips, cracker spreads,
etc.). They also can be in the form of condiments (such as ketchup,
sauces, butter, margarine, etc), flavoring or coloring additives,
or any other preparations that are designed and intended to be
added to foods or beverages, or otherwise eaten or drunk as a food
or beverage.
[0131] In order to be covered by this invention, any such foodstuff
must contain zeaxanthin and at least two or more other
ocular-active nutrients, not merely as naturally-occurring
ingredients in one of the fruit, vegetable, or other materials used
to make the foodstuff, but as additives that were deliberately
added to the foodstuff, in a quantity intended to provide ocular
benefits to consumers. In most cases, this type of intent will be
made clear and explicit by labelling information on packaging,
advertising, or other marketing materials that advertise, enclose,
or otherwise accompany the foodstuff, which will claim or suggest
that an ocular benefit can be provided by the foodstuff or the
additives therein. Advertising and labelling is an essential part
of identifying and marketing foodstuffs having special
health-related benefits, since the additional costs of such agents
cannot be justified unless consumers know about the added benefits
and are therefore willing pay a correspondingly higher price for
products containing them.
[0132] The benefits of ocular-active combinations as disclosed
herein may include preventing, treating, or reducing the risks of
any one or more eye diseases, injuries, or infections or other
eye-related and/or vision-related problems. Such eye-related or
vision-related problems include, for example, retinal problems such
as macular degeneration, retinitis pigmentosa, and diabetic or
other retinopathies; lens-related problems, such as cataracts
(including cataracts relating to diabetes); fluid-related problems,
such as glaucoma, "dry eye" syndrome, tearing problems, etc;
problems related to hypersensitivity to light, as occur in people
with albinism, or who suffer from headaches, epileptic seizures, or
other disorders when exposed to certain types of light; and
undesired effects or problems arising from injury or infection, or
from a surgical or medical procedure that directly affects one or
both eyes of a patient or animal (such as a vitrectomy, repair of a
torn or detached retina, laser coagulation using verteporfin,
etc.). These and various other eye-related disorders are known to
ophthalmologists and other specialists.
[0133] While there is no specific reason to believe the treatments
herein can prevent, retard, or reverse focusing problems that are
normally corrected by glasses (near-sightedness, far-sightedness,
or astigmatism), such focusing problems may be aggravated and
increased, in at least some patients, by other types of stress or
damage imposed on the eye. As an illustration of this principle,
eye-related disorders frequently are accompanied (and brought to
the attention of a patient or physician) by unusually rapid changes
in the corrective strengths that must be provided by eyeglasses or
contact lenses. Accordingly, by establishing better, more stable,
and healthier overall conditions in the eye, the treatments herein
may be able to help retard the onset of, or reduce the need for,
lens correction.
[0134] It also should be noted that corrective lenses (including
bifocal lenses, etc.) are the standard treatment for presbyopia,
which refers to the decline in vision acuity that, in most people,
commences or accelerates in middle age. It is believed and
anticipated that, in at least some patients, by improving the
general health of the eyes, by reducing oxidative damage within the
eyes, and by reducing stresses imposed on various components of the
eyes, the nutrient formulations of this invention can help delay
the onset of presbyopia, and/or reduce its severity, especially if
taken over a span of years.
[0135] As used herein, terms such as treat, treatment, therapy, or
therapeutic are used broadly, and include the ingestion or
administration of pharmaceutical preparations, dietary or
nutritional supplements, or foodstuffs with additives as disclosed
herein, in an effort to respond to an existing and known ocular
disorder (which can include a disease, injury, infection, etc.).
Such treatments may retard or delay, fully or partially reverse, or
otherwise ameliorate, lessen, or benefit a known ocular disorder.
Such problems, when they arise, may be revealed by an ophthalmic
examination, vision test, or other medical examination, or they may
simply become apparent and troublesome to a sufferer (such as a
noticeable loss of clear vision). Such disorders may become known,
even though the sufferer or a treating physician may not have an
accurate diagnosis and may simply be aware that something is wrong
with either or both eyes or the vision of the sufferer.
[0136] As used herein, terms such as preventing or prophylaxis also
are used broadly, and include the ingestion of pharmaceutical
preparations, dietary or nutritional supplements, or foodstuffs
with additives, either (i) to sustain a general state of good
health and/or good vision, and/or to reduce a general risk of
health or vision problems, in a manner comparable to taking
vitamins; or, (ii) in a manner that is intended to reduce a known
elevated risk of one or more ocular diseases or disorders, by
someone with a family or personal history of a disease or disorder,
a known or suspected genetic defect, or some other factor that
indicates an elevated risk of one or more ocular disorders.
[0137] Just as there is no clear dividing line between vitamins and
drugs (for example, a vitamin becomes a drug when it is used to
treat someone suffering from a known vitamin deficiency), there is
no clear dividing line between preventive versus therapeutic usage
of ocular-active nutrients as discussed herein. As an example, if
someone who is relatively young suffers from a known genetic defect
that will affect his or her vision later in life, and if that
person begins to regularly take an ocular nutrient formulation
before any specific degeneration becomes apparent, then such usage
by that person can be classified either as preventive (since the
nutrients are being taken to prevent, delay, or reduce problems
that have not yet arisen), or therapeutic (since the nutrients are
being taken to treat a known genetic defect that already
exists).
[0138] Accordingly, while it is useful to bear in mind that this
invention relates to both pharmaceutical preparations (intended for
treating known problems, and typically involving high dosages) and
dietary/nutritional supplements (intended to sustain eye health,
and commonly but not necessarily involving lower dosages), those
two categories sometimes overlap and/or merge with each other, and
are not entirely separate and distinct from each other. It should
also be recognized that the category of foodstuffs containing
ocular-active additives, as described above, normally will fall
within the category of dietary or nutritional supplements, but may
be regarded as pharmaceutical and therapeutic, when ingested by
someone who is suffering from a known ocular problem.
[0139] While it is not claimed that any one particular
ocular-active formulation can be used to effectively treat all
eye-related disorders, the following points are asserted by the
inventor:
[0140] (1) Because of the central role that zeaxanthin plays in the
eye, in absorbing and quenching ultraviolet radiation as well as
oxidative free radicals, nutrient formulations that contain
zeaxanthin along with other ocular-active nutrients are highly
likely to be substantially more effective, in treating a wide
variety of eye disorders, than comparable formulations that do not
contain zeaxanthin; and,
[0141] (2) Any well-planned, useful, and publicly and socially
helpful research project that is intended to help create or
evaluate a useful and beneficial ocular-active nutrient formulation
must be designed to evaluate candidate agents, not in isolation,
but in combination with zeaxanthin, since zeaxanthin will be an
essential ingredient in any optimal or near-optimal nutrient
formulation that will truly benefit and protect the vision of as
many people as possible.
Animal Models for Initial Testing
[0142] As mentioned above, at least five different and distinct
animal models are known, for testing candidate ocular-active
nutrients. These models include the following:
1. Mice and Rats, Including "Knockout" Mice
[0143] Mice and rats are very widely used in research on small
animals, and a huge foundation of information, species-specific
biomolecules (including gene promoter sequences, gene coding
sequences, monoclonal antibodies, etc.) and specialized strains
have been developed for genetic work with mice. Gateways that can
be used to access mouse genetic information are freely available on
websites such as www.informatics.jax.org and
www.ncbi.nlm.gov/genome/seq/MmHome.html. Although the corresponding
genetic information on rats is somewhat smaller, it is still
enormous and quite useful, and can be accessed through websites
such as http://rgd.mcw.edu, http://ratmap.gen.gu.se, and
www.hgsc.bcm.tmc.edu/projects/rat.
[0144] This genetic information can be put to good use, because a
growing number of gene defects have been and are being correlated
with known eye disorders. These genes can be discovered by any of
several procedures. For example, research revealed that many people
who suffer from Stargardt's disease, which causes severe vision
impairment, have a defective protein known as the Rim protein,
which normally functions as an ATP-binding cassette (ABC)
transporter gene, in rod outer segment discs, in mammalian retinas.
Additional research on that protein (and the gene which encodes
that protein) led to identification of a gene called the ABCR gene,
as the specific defect that leads to the defective Rim protein in
people who suffer from Stargardt's disease.
[0145] After the human ABCR gene was identified as a causative
factor in Stargardt's disease, a "homologous" ABCR gene in mice was
located, which encodes the mouse version of the Rim protein. The
exact DNA sequence of the mouse ABCR gene was determined, and
researchers then used genetic engineering techniques to create
mutant mice with "knockout" ABCR genes that are no longer properly
functional. These mutant mice, with "knockout" ABCR genes and the
mouse equivalent of Stargardt's disease, are described in articles
such as Weng et al 1999 and Mata et al 2000. Their descendants
suffer from severe visual impairment, which grows gradually worse
as certain waste metabolites gradually accumulate within the
retinas. Therefore, the descendants of these knockout mice offer
useful animal models, for testing candidate nutrients that may be
able to help slow down the gradual loss of vision in such mice.
[0146] This example, focusing on the ABCR gene that was rendered
nonfunctional in a colony of "knockout" mice, is just one of
numerous examples of how rapid progress is being made, by using and
comparing gene sequence information that has already been gathered
as part of the human genome project, the mouse genome project, and
the rat genome project. Dozens or even hundreds of genes that
express specific proteins involved in eye structures and/or vision
processing have been identified, and the only things that limit how
quickly and effectively that genetic information can be used are
money, and resources.
[0147] Four presumptions apply to such research: (1) every
structural protein that is present in any eye structure, and every
enzymatic protein that is involved in any step in vision processing
in the eyes, is present within the eyes for a good reason, and
plays some useful and necessary role in vision; (2) a gene defect
that renders any such protein nonfunctional will very likely lead
to some type of identifiable and potentially important eye
disorder; (3) once any such genetic defect has been identified,
either in humans or in mice or rats, colonies of lab animals which
will carry that genetic defect can be created and/or raised; and,
(4) any such colony can provide an animal model, which can help
researchers evaluate and rank the ability of various candidate
nutrients or other treatments to overcome the problem that is
caused or aggravated by that particular defective protein, in that
particular animal model.
[0148] Accordingly, genetic analysis and research, including
research involving mice or rat colonies having "knockout" genes
that are correlated with specific vision disorders, offer extremely
powerful tools, and can provide an effectively unlimited number and
range of specific targeted "models" that can help researchers test
candidate nutrients, to evaluate whether any nutrient or nutrient
combination can act synergistically with zeaxanthin, to help
prevent or treat one or more specific types of ocular
disorders.
2. Use of Agents to Increase Carotenoid Uptake in Rodents
[0149] When carrying out vision-related research on mice or rats,
it must be noted that most rodents are prey rather than predators,
and almost never go out into direct sunlight in the middle of the
day, since that would make them highly vulnerable to predators.
Accordingly, rodents did not evolve with any need for carotenoids
to help protect them against UV radiation. Therefore, rodents
generally do not metabolize carotenoids in ways comparable to
humans, and they tend to make relatively poor models for studying
the uptake or effects of carotenoids.
[0150] However, various manipulations can be used to increase
carotenoid uptake in rats and other rodents. As one example, if
relatively high concentrations of bile salts or other compounds
that help solubilize fatty compounds are added to the diets of mice
or rats, the animals will transport higher quantities of
carotenoids through the intestinal walls and into circulating
blood, which will lead to greater rates and concentrations of
tissue deposition. Therefore, by feeding special diets to mice or
rats, various types of research involving zeaxanthin (or other
carotenoids) can be carried out in these animals.
[0151] It should also be recognized that research which directly
uses and includes zeaxanthin will not always be necessary, to do
research on mice or rats that can help evaluate and rank candidate
nutrients that may be able to work synergistically with zeaxanthin.
Instead, the benefits of working with mice or rats usually are
limited to initial research, which hopefully will lead to expanded
and more expensive research on larger animals and/or humans.
Accordingly, mice and rats may be well-suited for evaluating
candidate nutrients such as lipoid acid, isoflavonoids, plant
polyphenols, omega-3 fatty acids, taurine, carnitine, etc., to
evaluate their effects on ocular or vision defects, in tests that
will not use or include any zeaxanthin or other carotenoids.
Subsequently, after initial evaluations and rankings have been
determined by means of initial testing in mice or rats, the most
promising candidates can then be tested in more expensive tests
that will involve zeaxanthin, using animals that metabolize
carotenoids in a manner comparable to humans (such as Japanese
quails or other suitable birds, or primates), or in human clinical
trials.
[0152] It should also be recognized that mice, rats, and other
rodents do not have pigmented maculas; instead, in general, the
only animals that use UV-absorbing carotenoids to protect their
retinas are primates, and some species of birds. However, if rats
are induced (by bile salts in their diets) to begin taking up
substantial quantities of carotenoids into circulating blood, at
least some of those carotenoids will be deposited into
photoreceptors in the retina, and into the lens of the eye. thereby
allowing at least some types of research on those structures.
3. Agents and Methods to Create and Emulate Disorders
[0153] Additional options that can be used to evaluate candidate
ocular-active nutrients involves the use of certain drugs or diets,
to induce certain types of damage that can emulate known ocular
disorders. As one example, cataracts can be induced by a drug
called buthionin sulfoximine (e.g., Maitra et al 1996), or by
feeding lab animals certain types of high-starch diets Borenshtein
et al 2001). As another example, diabetes can be induced by drugs
such as streptozotocin (e.g., Kowluru et al 2003) or allosan.
[0154] If the goal of a research project is to study a disorder
that involves abnormally high levels of cell growth (such as wet
macular degeneration, with excessive blood vessel growth, or
certain types of "proliferative retinopathies"), pellets contain
cell-stimulating hormones can be implanted into an eye. Such
research, using "vascular endothelial growth factor" (VEGF) or
"basic fibroblast growth factor" (bFGF), is described in articles
such as Yoon et al 2000 and oussen et al 2000.
[0155] Various types of surgical or mechanical interventions can
also be used to emulate certain ocular disorders. As one example,
clamping off an artery for a fixed period of time is used to create
ischemia, then the clamp can be suddenly released, to create a
"reperfusion" injury involving oxygen free radicals. In addition,
external methods can be used to accelerate certain types of visual
impairment. Such methods include, for example, increasing the
intensity of ultraviolet and blue light, and increasing the
atmospheric oxygen concentrations, in the pens or rooms where lab
animals are being kept.
[0156] Any of these methods can impose additional levels of ocular
stress an lab animals, thereby substantially accelerating the rates
at which they will develop ocular disorders. Accordingly, various
candidate ocular-active nutrients can be evaluated for potency and
efficacy, by measuring how effectively they can delay, prevent, or
reduce the disorders that will arise from the stresses that were
imposed on the animals.
4. Japanese Quail and Other Birds
[0157] As mentioned above, some types of birds use carotenoid
pigments to help protect their retinas against damage by UV light.
In most bird species, these pigments are deposited throughout the
entire retina, rather than just in a small central area comparable
to the maculas of primates. A review of the use of birds, in
retinal research, is contained in Fite et al 1991. Japanese quail
have become a. widely used and accepted bird model for retinal
testing, as described in articles such as Fite et al 1993, Fite
1994. Detailed methods for testing this species, to evaluate the
ability of zeaxanthin or lutein to protect against retinal damage
caused by high-intensity lights, were described in Thomson et al
2002.
[0158] In addition, an albino strain of Japanese quail has been
developed, which suffers from rapid lens degeneration and cataract
formation.
5. Testing of Dogs and Livestock
[0159] Among the types of lab animals larger than rodents that are
used in vision testing, dogs and livestock tend to be used most
commonly, for various reasons.
[0160] With respect to dogs, their irises (which are circular) are
more similar to human and primate irises, than the vertical-slit
irises of cats; in addition, dogs also suffer fairly commonly from
cataraas. They can also be induced to incur various types of
retinopathies, and there are certain aspects of their vision
processing that are of interest to neurology researchers (including
limitations in the ability of dogs to generate nerve impulses that
will help them recognize and identify things, unless some type of
motion is involved that will trigger a set of nerve cell firings).
For all of these reasons, dogs are used fairly commonly for ocular
and vision research. While they are more expensive than mice or
rats, they are less expensive than primate studies or human
clinical trials. Accordingly, if dogs are being considered as a
potential animal model for studies as disclosed herein, a network
of experts who are already familiar with that type of research in
dogs can he located, quickly and easily, by a database search for
published articles describing vision research in dogs.
[0161] Research on eye components or other tissues from various
livestock species (including pigs, cows, and sheep) is enabled by
an important factor: these animals are killed, in large numbers, at
known locations and under controlled conditions (i.e., at
slaughterhouses). Therefore, specialized treatment procedures can
be carried out on livestock animals shortly before they are killed,
and the affected tissues can be harvested at a controlled time,
soon thereafter. Alternately, other types of specialized procedures
can be carried out on tissue that was harvested immediately after
an animal is killed; these types of tissue samples are usually
perfused (i.e., placed in specialized equipment that will pump
fluids with oxygen and nutrients through or around the tissue), to
sustain the tissue in a condition where its cells remain viable and
metabolically active for a span of hours or days after the animal
was killed. Compared to ocular tissue samples from mice or rats,
ocular tissues from animals such as cows or pigs are much easier to
handle and work with, and they also provide more relevant results,
if dimensional factors are important (such as, for example, when
the permeation of a drug or nutrient into or through lens tissue is
important).
6. Primate Tests
[0162] Primates include lemurs, monkeys, and apes. While they are
expensive to raise, keep, and test, they nevertheless provide
animal models that, in some situations, will provide better and
more applicable and relevant data than any other type of animal
test, short of a human clinical trial. Therefore, they must be kept
in mind as one option. In many situations, to keep costs under
control, it may be possible to "piggyback" a vision-related test on
top of some other type of ongoing test (such as a cancer-related
test), using the same animals that are being tested for other
purposes.
Human Clinical Trials and Meta-trials
[0163] Based on the results of animal tests, as described above and
as otherwise known to those skilled in the art, candidate
formulations that have performed well in such animal tests can be
further evaluated, in clinical trials. As used herein and in common
practice, the term "clinical" implies that the subjects will be
humans, rather than laboratory animals.
[0164] Proper and lawful general procedures for carrying out human
clinical trials are described in numerous published articles and
books, and are known to thousands of researchers, consultants, and
other experts. Those general procedures and requirements will not
be discussed or analyzed herein.
[0165] However, two aspects of such testing on humans deserve
special note and consideration herein.
[0166] The first special point worth noting is this: at least some
types of ocular or vision-related tests can be designed to speed up
the gathering of useful data, when testing patients who are
suffering from diseases that gradually manifest or grow worse over
a long span of time, such as multiple years. This type of
accelerated data gathering can be enabled by various approaches,
such as by focusing on selected patients who, at the point in time
when they will be tested, are entering or progressing through
certain stages that involve accelerated and rapid degeneration and
loss of vision acuity.
[0167] As one example, among most patients who suffer from the dry
form of macular degeneration (which includes roughly 90% of all
cases of macular degeneration), their retinas will pass, at sonic
point during the disease, through an intermediate stage called
"geographic atrophy". During this stage, distinct patches and areas
of degeneration in or around the macula become visible (as
indicated by certain types of cellular debris, such as abnormally
large pieces of drusen and lipofuscin), in certain types of
photographs that can be taken of the retina.
[0168] When retinas suffering from dry macular degeneration reach
this stage, and begin to suffer from "geographic atrophy" showing
clear and distinct patches of degeneration, they have begun (or
will soon begin) to suffer from accelerated and rapid retinal
degeneration. Briefly, this process can be depicted, in a schematic
manner, by using the "S-curve" shown in FIG. 5B. A person suffering
from the dry form of macular degeneration typically will spend
several years, passing through slow, gradual, and incremental
losses of visual acuity, sometimes without even noticing that his
or her vision is slowly growing worse (or sometimes choosing to
remain silent about it, when they do notice it, for fear of being
ordered to stop driving). This long slow stage is represented by
the flat slope of the plateau to the left side of the sharper
slope.
[0169] At some point in time, most victims of macular degeneration
will reach a stage when the gradually accumulating stresses seem to
begin piling on top of each other, and the person begins to lose
visual acuity at an accelerated rate that can no longer be ignored
or hidden. When this occurs, if the patient visits an
ophthalmologist and has his or her eyes checked, he or she usually
will be found to be in the stage called "geographic atrophy." If
effective steps are not taken to halt the spread of the damage, it
usually will begin accelerating even faster, and will lead to a
rapid and severe loss of visual acuity.
[0170] When it comes to clinical testing of candidate ocular-active
nutrients, patients who are approaching or who have already entered
a "rapid acceleration" stage of degeneration can be highly useful
and helpful, for carrying out tests that are specially designed to
provide relatively rapid data, to help reveal which particular
nutrients (out of the various candidates that are being tested) can
be the most effective in preventing further degeneration, when
combined with zeaxanthin in orally-ingestible formulations and
foodstuffs. Accordingly, anyone who is contemplating or designing
tests on various candidate ocular-active nutrients, should be alert
to the possibility of placing patients who are at the "geographic
atrophy" stage of macular degeneration (or at a comparable stage of
any other ocular disorder) into a special testing or control
population, which can then be analyzed carefully over a shorter
period of time than would otherwise be required.
[0171] Another important approach that should be carefully
considered, by anyone who is contemplating or designing tests on
candidate ocular-active nutrients, involves tests that are usually
referred to as "meta-trials". In general, these types of tests
involve numerous discrete and relatively small data-gathering
centers, which are grouped or tied together in ways that allow the
data from all of the multiple small centers to be compiled into a
larger pool of consistent shared data.
[0172] As an example, one of the most promising approaches to human
testing of various candidate ocular-active formulations as
disclosed herein can use a network of cooperating optometrists
and/or ophthalmologists, who are already skilled in examining eyes.
Any optometrist or ophthalmologist who wishes to become involved in
a meta-trial will need to be instructed (with video, written, or
in-person instruction or training, as necessary) in the exact
procedures that will need to be followed by all patients enrolled
in a test, and by any clerical or healthcare workers who will
monitor and review the data gathered at that site.
[0173] The procedures that will be used can involve either
double-blinded trials, or open-label trials, depending on the
desires and goals of the people, companies, or agencies who are
organizing and running the study. Monitoring of results can involve
any appropriate data-gathering methods, such as visual acuity tests
by optometrists (which usually measure "lines of resolution" on
standardized eye charts), or more complicated tests by
ophthalmologists (such as measurements of pigment densities in
lenses or maculas).
[0174] Each participating optometrist or ophthalmologist will be
responsible for gathering data at his or her site, and one or more
workers at the coordinating office will be responsible for (i)
creating reporting forms that will help ensure that the data from
different sites are uniform and consistent, and (ii) monitoring the
quality of the data coming from numerous sites. Participating
optometrists or ophthalmologists will be supplied with consistent
and exact formulations by a single coordinating office, and if a
trial is double-blinded, these products can be in the form of
number-coded bottles, containing capsules or tablets that do not
indicate whether the contents are test compounds, or controls.
Presumably, any such controls likely will contain an anti-oxidant
formulation that already has been shown to work at some level of
efficacy, such as the AREDS-1 formulation, which contains fairly
high dosages of vitamins C and E, beta-carotene, and zinc.
[0175] If fifty optometrists or ophthalmologists (each continuing
to work out of his or her normal office) are involved, and if each
participating optometrist or ophthalmologist enrolls twenty
patients in a control group, and twenty patients in a test group,
that will generate combined totals of 1000 patients in the control
group, and 1000 patients in the test group.
[0176] This approach can be used to generate relatively rapid yet
statistically powerful data, without placing a huge burden on any
one particular person or location. Accordingly, meta-trials deserve
careful attention, since they offer highly promising and relatively
rapid yet relatively inexpensive methods for carrying out human
clinical trials, involving large numbers of test and control
subjects, on candidate ocular-active combinations as described
herein.
Candidate: Ocular Active Nutrients
[0177] As mentioned in the Summary of the Invention, eight
categories of ocular-active nutrients are identified herein, which
are believed to offer good and promising candidates for early
evaluation, to determine whether they can provide synergistic
benefits when orally ingested along with zeaxanthin. These eight
categories are summarized and described below.
[0178] Most of the compounds mentioned below have one or more
"chiral" carbon atoms, and therefore have different stereoisomers.
As a general rule, if any one particular stereoisomer is
predominant, in plant sources or in animals, then a strong
presumption arises that steps should be taken to provide the
natural stereoisomer in a purified or semi-purified form, in any
ocular-active nutrient that is being sold or administered to people
who wish to protect their eye health. Various known factors suggest
that the eye is one of the most "stereo-specific" organs anywhere
in the body, and is highly sensitive to differences in
stereoisomers. In many cases, this goal can be accomplished by
using plant extracts, or by using compounds that have been
synthesized by chemically modifying plant-derived stereospecifi c
precursors.
[0179] 1. Lipoic Acid
[0180] This is a fatty acid having 8 carbon atoms in a straight
chain, with the carboxy group at the #8 carbon atom, and with the
#1 and #3 carbon atoms both coupled to mercaptan groups (--SH, also
called sulfhydrl or sulfide groups). In the reduced form, the two
mercaptan groups stay separated from each other, with hydrogen
protons attached to the sulfur atoms in both pendant groups. In the
oxidized form, the hydrogen protons are removed, and the two sulfur
atoms bond to each other, to form a five-member ring with the #1,
#2, and #3 carbon atoms forming the remainder of the ring.
[0181] Because it can convert back and forth between a reduced form
and an oxidized form, lipoic acid can help reduce and prevent
unwanted oxidation of cells and tissues, and under some
circumstances, it can also help regenerate vitamin E (Stoyanovsky
et al 1995). Other articles that describe lipoic acid's ability to
protect ocular tissues in various tests include Packer 1994,
Obrosova et al 1998, Borenshtein et al 2001, Chidlow 2002, and
Goralska et al 2003.
[0182] Maitra et al 1996 reported that the naturally-occurring "W`
(dextrorotatory) stereoisomer has better anti-oxidant activity than
the S (levorotatory) isomers that are found in synthetic racemic
mixtures. Accordingly, lipoic acid preparations having pure or
enriched R stereoisomers are preferred for testing and evaluation
as disclosed herein.
2. Omega-3 Fatty Acids
[0183] Certain types of compounds that animals must eat in their
diets are called "essential fatty acids", because (i) animals need
them, mainly for cell membrane formation, but animals cannot
synthesize them; (ii) they contain a chain of carbon atoms with a
length (usually ranging from about 10 to about 24 carbon atoms)
that will form a fatty substance that is solid or semi-solid at
room temperature; and (iii) the last carbon atom in the carbon
chain is part of a carboxylic acid group (--COOH).
[0184] In humans, the three most important essential fatty acids
are docosa-hexaenoic acid (abbreviated as DHA), eicosa-pentaenoic
acid (EPA), and alpha-linolenic acid (ALA). All three of these
compound are called omega-3 fatty acids, since the #3 carbon atom
(counting from the non-acid end of the chain) is the first carbon
atom that is involved in an unsaturated bond. All three of those
omega-3 fatty acids are present in relatively high concentrations
in certain types of fish oils, and they can also be obtained from
other natural sources, such as certain types of marine algae. They
are associated with a number of health benefits, including
cardiovascular benefits, anti-cancer activity, etc., so they are of
substantial interest throughout the entire field of dietary
supplements, as described in articles such as Connor 2000.
[0185] Omega-6 fatty acids (with the first double-bond positioned
between the #6 and #7 carbon atoms in the carbon chain) are more
abundant in nature; however, their health benefits are not as great
as for omega-3 fatty acids, and most people already get too many
omega-6 fatty acids and not enough omega-3 fatty acids in their
diets. Therefore, if a dietary supplement contains a mixture of
omega-3 and omega-6 fatty acids, it preferably should contain at
least about 30%, and preferably 50% or more, of the omega-3
compounds.
[0186] Among the omega-3 fatty acids, DHA has a more important role
in mammalian metabolism than EPA, and ALA is generally regarded as
merely a precursor to DHA and EPA. Therefore, in purified or
semi-purified preparations, DHA is generally the preferred
compound, and it has received the most study. Its activities and
effects in eyes are described in articles such as Jeffrey et al
2001, Polit et al 2001, Murayama et al 2002, and Rutstein et al
2003.
3. Plant-Derived Active Agents (Flavonoids, Anthocyanins, Plant
Polyphenolics, and Phytonutrients)
[0187] A third category of candidate ocular-active nutrients that
is of interest herein includes a number of plant-derived compounds,
which can be referred to by terms that include flavonoids (or
bioflavonoids), anthocyanins, plant polyphenolics, or
phytonutrients. These labels overlap heavily with each other, and
compounds that fall within labels are described in various articles
such as Beecher 1999 and Beecher 2003. The molecular structures for
each of the named compounds listed below are publicly known, and
can be located in various public sources (e.g, the chemical
structures of numerous flavonoids, both common and rare, are nicely
illustrated and organized at
http://www.friedli.com/herbs/phytochem/flavonoids.html).
[0188] Compounds that fall within the categories of flavonoids,
anthocyanins, plant polyphenolics, or phytonutrients can include
either or both of the following: (i) non-purified or semi-purified
multi-component mixtures that have been extracted from the fruits,
leaves, seeds, nuts, or other parts of various known plants, such
as bilberry, grapeseed, green tea, or soybeans; or, (ii) specific
known and purified compounds (or limited mixtures of a small number
of similar and related compounds) from such plants, such as
quercetin, genestein, diazedem, fisetin, luteolin, resveretrol, and
pycogenol.
[0189] These and various other similar known agents have different
specific activities and roles, and each one needs to be considered
separately. For example, most flavonoid compounds reduce the
activity of an enzyme called aldose reductase. This enzyme converts
certain types of beneficial sugars (such as glucose) into
sugar-alcohols (such as sorbitol) that will cause problems if they
accumulate in excessive quantities. Sorbitol is an important
causative factor in cataract formation, especially among diabetics.
Therefore, flavonoids that inhibit aldose reductase enzymes can
help prevent or slow down cataract formation (Jung et al 2002,
Matsuda et al 2002).
[0190] The specific activities, in animal eyes, of any known plant
polyphenol (or flavonoid, anthocyanin, phytonutrient, etc.) that
has been studied in animals can be identified fairly easily, by
searching the free database that is maintained by the National
Library of Medicine.
[0191] As examples, resveretrol reportedly can suppress
vascularization (e.g., Brakenhielm et al 2001), and is a good
antioxidant and free radical scavenger (Lorenz et al 2003), while
genistein reportedly inhibits certain protein kinase enzymes, and
can help suppress unwanted types of cell-signaling pathways (e.g.,
Yoon 2000).
4. Taurine
[0192] Taurine is the common name for 2-amino-ethane-sulfonic acid,
a "conditionally essential nutrient" that is present in milk and
elsewhere. Taurine's ability to protect various ocular tissues in
various types of tests (especially involving diabetic pathologies)
is described in articles such as Devamanoharan et al 1998, Obrosova
et al 1999 and 2001, Chen et al 2000, Militante et al 2002,
Pasantes-Morales et al 2002, and DiLeo et al 2003.
5. Carnitine
[0193] L-Carnitine is a sulfur-containing amino acid (not one of
the 20 primary amino acids used in protein synthesis) that is
formed in the liver and certain other tissues. It is believed to
facilitate the transport of fatty acids into mitochondria, for
certain types of oxidation. Certain esters of carnitine (mainly
acetyl-L-carnitine) are preferred for oral ingestion.
[0194] Carnitine's ability to help prevent or treat ocular
disorders is described in articles such as Pessotto et al 1997,
Peluso et al 2001, Alagoz et al 2002, and Feher et al 2003. The
acetyl-L-carnitine precursor is one of three ingredients (along
with omega-3 fatty acids, and coenzyme Q10) in an ocular
formulation called PHOTOTROP.TM., sold by the Sigma Tau
Company.
6. Coenzyme-Q10
[0195] An enzyme cofactor known as Coenzyme-Q10 (the Q stands for
quinone) is a known anti-oxidant that provides energy-related
support to mitochondria. Mitochondria are organelles, inside animal
cells, that are enclosed within their own membranes and that have
their own set of genes (these genes even use their own special
genetic code, which is slightly different from the standard genetic
code used in the nucleus of a cell). In a truly remarkable feat of
adaptive biology, mitochondria actually are the descendant; of tiny
anaerobic bacteria, which invaded larger cells billions of years
ago, and which then established a symbiotic relationship with their
host cells. In this symbiotic relationship, the
invaders-turned-guests carry out processes known as "oxidative
phosphorylation", which is a crucial part of energy metabolism in
the host cells. Because of this role, mitochondria are sometimes
referred to as the "furnaces" that handle the burning operations
that supply heat and power to the rest of the cell.
[0196] When mitochondria are under severe stress, they begin
releasing certain types of cytochrome compounds, which will then
begin acting as signalling compounds, which will activate a process
called "apoptosis", also referred to as "programmed cell death".
Apoptosis is a natural process that is beneficial in most
situations, since it gives tissues and organs a way to clean up and
get rid of dead and dying cells, and replace them with newly-formed
and healthy cells. However, in some situations (especially
involving neurons, which are extremely difficult and often
impossible to replace), apoptosis can lead to severe problems,
including (in eye tissues) the unprogrammed and unwanted death and
destruction of neurons in the retina. Therefore, by helping
stabilize mitochondria, Coenzyme-Q10 can help prevent the release
of mitochondrial cytochromes that would lead to unwanted cell
deaths, in ocular tissues that are struggling to cope with a
serious disorder.
[0197] As mentioned above, Coenzyme Q10 is one of the three
ingredients in an ocular formulation called PHOTOTROP.TM., sold by
the Sigma Tau Company.
7. Carnosine
[0198] Carnosine is a di-peptide, formed when alanine and histidine
bond to each other. It can bond to and quench aldehydes, which are
potentially dangerous reactive molecules that can otherwise cause
random and unwanted modifications (such as glycosylation or
crosslinking) to proteins. The most commonly used orally-ingestible
form of carnosine is an ester precursor, N-alpha-acetyl-carnosine.
Eyedrops containing carnosine also have been developed and are
being publicly sold in Europe.
[0199] The protective activities and effects of carnosine in ocular
tissues are described in articles such as Maichuk et al 1997,
Hipkiss et al 1998, and Babizhayev et al 2002.
8. Glutathione Boosters
[0200] Glutathione is a tri-peptide molecule, formed by three amino
adds linked together, with cysteine in the middle. Cysteine has a
highly reactive sulfur group (--SH) as its side chain. This allows
the glutathione tri-peptide to become bonded to other
compounds.
[0201] With the help of enzymes such as glutathione-S-transferase,
glutathione most commonly gets bonded to waste metabolites. This
makes the waste products more soluble in water, which in turn helps
cells and tissues eliminate those wastes, through pathways that
typically end up in urine.
[0202] Since the glutathione system provides a useful pathway that
helps cells and tissues get rid of waste products, nutrients that
can stimulate the production or metabolism of glutathione can help
badly-stressed cells and tissues cope more successfully with their
waste-handling problems. One such nutrient is N-acetyl cysteine, an
ester that when ingested orally will release cysteine, the
sulfur-containing amino acid that sits at the center of the
glutathione tri-peptide. Other candidates agents that are believed
to boost glutathione production or metabolism include selenium,
pyridoxine, and riboflavin. These are disclosed, as agents that can
help treat macular degeneration, in U.S. Pat. No. 5,075,116 (LaHaye
1991).
The AREDS-1 Components
[0203] In addition to the eight categories of ocular-active
nutrients listed above (none of which were tested during the
AREDS-1 trial in the 1990's), three additional types of compounds
that were tested in the AREDS-1 trial also deserve attention. These
compounds are also discussed in U.S. Pat. No. 6,660,297 (Bartels et
al 2003).
[0204] Tocopherol compounds, such as alpha-tocopherol (vitamin E),
merit special attention, because of an important physiological
factor. Carotenoids tend to be most effective, as antioxidants, in
the presence of relatively low oxygen concentrations. By contrast,
tocopherols tend to become more and more effective, as
antioxidants, when oxygen concentrations grow higher. Therefore, a
combination of zeaxanthin with one or more tocopherols is likely to
provide a good "broad-spectrum" antioxidant, where each compound
can work most effectively under the conditions where the other
compound is weakest.
[0205] Vitamin C has its own well-known benefits, and it is one of
the few vitamins or anti-oxidants that is water-soluble. Therefore,
if a water-soluble anti-oxidant such as Vitamin C is coadministered
with zeaxanthin (a hydrophobic, oil-soluble anti-oxidant), the two
of them together are likely to be more effective than either one
can be by itself.
[0206] Zinc also has a crucially important and valuable role in
biology, because it is the only essential mineral (or transition
metal) that has no reduction-oxidation potential. Its electric
charge is completely neutral; it will not seek to take protons or
electrons away from proteins or DNA, and it will not seek to get
rid of protons or electrons by pushing them off onto proteins or
DNA. In addition, it can bond in a stable manner to one, two,
three, or even four other molecules. Therefore, it evolved into an
essential cofactor in hundreds of enzymes and thousands of
DNA-regulatory proteins, and it is very widely used by proteins to
stabilize a variety of three-dimensional conformations, ranging
from the protruding "finger domains" in zinc-finger proteins, to
the "deep cleft" domains in carbonic anhydrase enzymes. It also
helps stabilize cell membranes, promotes wound-healing, and even
has significant microbicidal and bacteriostatic activity.
[0207] Because it is a known beneficial, stabilizing,
membrane-protecting agent, oral dosages of zinc were tested, years
ago, to determine whether they could help people suffering from
macular degeneration and other ocular problems. The results were
good, although not especially strong, as described in articles such
as Newsome et al 1988, Yuzbasiyan et al 1989, Hawkins 1991, Tempe
1992, and Beaumont 1993. Therefore, it was included in the AREDS-1
trial, and the benefits it provided were: (i) strong enough to
roughly match the benefits provided by a. combination of vitamins
A, C, and E, and (ii) strong enough to push the benefits offered by
vitamins A, C, and E into a higher category of significance.
[0208] Accordingly, zinc is regarded as one of the more promising
candidate agents, for testing as described herein. However, it is
suspected that the benefits of zinc, for at least most patients,
likely can be completely achieved by dosages in the range of about
40 mg/day (which is only about half of the dosages used in the
AREDS-1 trial), or possibly even less. Accordingly, if substantial
synergistic benefits can be provided by 40 mg/day or lower dosages
of zinc, when combined with zeaxanthin, those lower dosages of zinc
can help avoid various concerns over zinc-induced anemia, and/or
the need for yet another additive (such as copper sulfate), that
were raised by the 80 mg dosages used in the AREDS-1 trial.
[0209] Thus, there has been shown and described a new and useful
means for identifying agents that can perform synergistically with
zeaxanthin, in pharmaceutical, dietary, or food preparations that
can help protect eye health and treat ocular disorders. Although
this invention has been exemplified for purposes of illustration
and description by reference to certain specific embodiments, it
will be apparent to those skilled in the art that various
modifications, alterations, and equivalents of the illustrated
examples are possible. Any such changes which derive directly from
the teachings herein, and which do not depart from the spirit and
scope of the invention, are deemed to be covered by this
invention.
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References