U.S. patent application number 15/824842 was filed with the patent office on 2018-03-22 for synergistic glycocalyx treatment compositions and methods.
The applicant listed for this patent is Microvascular Health Solutions, LLC. Invention is credited to Robert Maxfield Long, Hans Vink.
Application Number | 20180078618 15/824842 |
Document ID | / |
Family ID | 57072731 |
Filed Date | 2018-03-22 |
United States Patent
Application |
20180078618 |
Kind Code |
A1 |
Long; Robert Maxfield ; et
al. |
March 22, 2018 |
SYNERGISTIC GLYCOCALYX TREATMENT COMPOSITIONS AND METHODS
Abstract
Compositions and methods for treating endothelial glycocalyx
include glucosamine, hyaluronan and/or fucoidan, and one or more
antioxidants, such as superoxide dismutase, catalase, and/or
polyphenol. The compositions improve vascular health by exhibiting
beneficial synergistic effects on endothelial glycocalyx over the
benefits of taking any single component alone or the sum of
reported effects of the individual components. Specifically,
components of the composition (1) enhance synthesis of new
glycocalyx by (a) providing and (b) increasing production of
glycocalyx precursors, (2) protecting existing glycocalyx against
damage, such as by oxidation degradation, by (a) providing and (b)
increasing production of antioxidants, some of which associate with
endothelial glycocalyx, and (3) enhance repair of damaged
glycocalyx by (a) providing glycocalyx mimetics and (b) increasing
the prevalence of glycocalyx scaffold for association and
incorporation thereof.
Inventors: |
Long; Robert Maxfield;
(Alpine, UT) ; Vink; Hans; (Schimmert,
NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Microvascular Health Solutions, LLC |
Alpine |
UT |
US |
|
|
Family ID: |
57072731 |
Appl. No.: |
15/824842 |
Filed: |
November 28, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15094757 |
Apr 8, 2016 |
|
|
|
15824842 |
|
|
|
|
62144484 |
Apr 8, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/737 20130101;
A61P 43/00 20180101; A61K 31/728 20130101; A61K 45/06 20130101;
A61P 9/00 20180101; A61K 35/744 20130101; A61K 38/446 20130101;
C12Y 111/01006 20130101; A61K 36/03 20130101; C12Y 115/01001
20130101; A61K 31/7008 20130101; A61K 31/05 20130101; A61K 38/446
20130101; A61K 2300/00 20130101; A61K 36/03 20130101; A61K 2300/00
20130101; A61K 35/744 20130101; A61K 2300/00 20130101; A61K 31/7008
20130101; A61K 2300/00 20130101; A61K 31/728 20130101; A61K 2300/00
20130101; A61K 31/737 20130101; A61K 2300/00 20130101; A61K 31/05
20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 38/44 20060101
A61K038/44; A61K 31/7008 20060101 A61K031/7008; A61K 31/728
20060101 A61K031/728; A61K 31/737 20060101 A61K031/737; A61K 31/05
20060101 A61K031/05; A61K 36/03 20060101 A61K036/03; A61K 35/744
20060101 A61K035/744 |
Claims
1. A composition, comprising: one or more molecular precursor of
endothelial glycocalyx in an amount of effective to increase
production of endothelial glycocalyx in a mammal to which the
composition is administered, the one or more molecular precursor of
endothelial glycocalyx comprising glucosamine, or a suitable salt
or derivative thereof; one or more antioxidant that associates with
endothelial glycocalyx in an amount of effective to at least
partially protect existing endothelial glycocalyx against damage
caused by enzyme and/or oxidant in a mammal to which the
composition is administered, the one or more antioxidant that
associates with endothelial glycocalyx comprising superoxide
dismutase, or a suitable transition metal conjugate or derivative
thereof; and one or more glycocalyx mimetic in an amount of
effective to increase the density of endothelial glycocalyx at a
site of endothelial glycocalyx damage in a mammal to which the
composition is administered, the one or more glycocalyx mimetic
selected from the group consisting of: a nonsulfated
glycosaminoglycan; hyaluronan, or a suitable salt or derivative
thereof; a sulfated polysaccharide; and fucoidan, or a suitable
salt or derivative thereof.
2. The composition of claim 1, wherein the composition is
configured to exhibit a synergistic therapeutic effect on the
endothelial glycocalyx of the mammal when administered thereto, the
composition comprising: the one or more molecular precursor of
endothelial glycocalyx in an amount of effective to enhance
synthesis of new glycocalyx, enhance repair of damaged glycocalyx,
and protect existing glycocalyx against damage, in the mammal to
which the composition is administered; the one or more antioxidant
that associates with endothelial glycocalyx in an amount of
effective to protect existing glycocalyx against damage, enhance
synthesis of new glycocalyx, and enhance repair of damaged
glycocalyx, and the one or more glycocalyx mimetic in an amount of
effective to enhance repair of damaged glycocalyx, enhance
synthesis of new glycocalyx, and protect existing glycocalyx
against damage.
3. The composition of claim 1, wherein: the glucosamine, or
suitable salt or derivative thereof, is include as glucosamine
sulfate in an amount of at least about 375 mg; the fucoidan, or
suitable salt or derivative thereof, is included as fucoidan
sulfate in an amount of at least about 106.25 mg; the hyaluronan,
or suitable salt or derivative thereof, is include as sodium
hyaluronate in an amount of at least about 17.5 mg; and total
antioxidants, including the superoxide dismutase, or suitable
transition metal conjugate or derivative thereof, are included in
an amount of at least about 120 mg.
4. A composition, comprising: one or more molecular precursor of
endothelial glycocalyx, comprising glucosamine, or a suitable salt
or derivative thereof; one or more antioxidant that associates with
endothelial glycocalyx, comprising superoxide dismutase, or a
suitable transition metal conjugate or derivative thereof; and one
or more glycocalyx mimetic selected from the group consisting of: a
nonsulfated glycosaminoglycan; hyaluronan, or a suitable salt or
derivative thereof; a sulfated polysaccharide; and fucoidan, or a
suitable salt or derivative thereof.
5. The composition of claim 4, further comprising one or more
additional antioxidants selected from the group consisting of:
catalase, or a suitable transition metal conjugate or derivative
thereof; and one or more polyphenols.
6. The composition of claim 4, wherein the composition comprises:
the hyaluronan, or suitable salt or derivative thereof; and the
fucoidan, or suitable salt or derivative thereof.
7. The composition of claim 6, wherein at least one of: the
glucosamine, or suitable salt or derivative thereof, is included as
glucosamine sulfate, the hyaluronan, or suitable salt or derivative
thereof, is included as sodium hyaluronate; and the fucoidan, or
suitable salt or derivative thereof, is included as fucoidan
sulfate.
8. The composition of claim 6, wherein at least one of: the
glucosamine, or suitable salt or derivative thereof, is selected
from the group consisting of glucosamine sulfate, non-GMO vegetable
glucosamine sulfate, non-GMO corn glucosamine sulfate, and
D-glucosamine, or suitable salt or derivative thereof; the
superoxide dismutase, or suitable transition metal conjugate or
derivative thereof, is selected from the group consisting of
non-GMO plant, olive, artichoke, red grape, white grape, and melon
superoxide dismutase, or suitable transition metal conjugate or
derivative thereof; and the hyaluronan, or suitable salt or
derivative thereof, is selected from the group consisting of sodium
hyaluronate, non-GMO microbial sodium hyaluronate, non-GMO
Streptoccoccus sodium hyaluronate, non-GMO Streptoccoccus equi
subsp. Zooepidemicus sodium hyaluronate, sodium hyaluronate having
a purity of at least about 90% w/w, non-GMO microbial sodium
hyaluronate having a purity of at least about 90% w/w, non-GMO
Streptoccoccus sodium hyaluronate having a purity of at least about
90% w/w, and non-GMO Streptoccoccus equi subsp. Zooepidemicus
sodium hyaluronate having a purity of at least about 90% w/w; and
the fucoidan, or suitable salt or derivative thereof, is selected
from the group consisting of fucoidan sulfate, non-GMO plant,
seaweed, or algae fucoidan sulfate, non-GMO Laminaria fucoidan
sulfate, non-GMO Laminaria japonica fucoidan sulfate, fucoidan
sulfate having a purity of at least about 85% w/w, non-GMO plant,
seaweed, or algae fucoidan sulfate having a purity of at least
about 85% w/w, non-GMO Laminaria fucoidan sulfate having a purity
of at least about 85% w/w, and non-GMO Laminaria japonica fucoidan
sulfate having a purity of at least about 85% w/w.
9. The composition of claim 6, wherein: the glucosamine, or
suitable salt or derivative thereof, is include as glucosamine
sulfate in an amount of at least about 375 mg; the fucoidan, or
suitable salt or derivative thereof, is included as fucoidan
sulfate in an amount of at least about 106.25 mg; the hyaluronan,
or suitable salt or derivative thereof, is include as sodium
hyaluronate in an amount of at least about 17.5 mg; and total
antioxidants, including superoxide dismutase, or suitable
transition metal conjugate or derivative thereof, are included in
an amount of at least about 120 mg.
10. The composition of claim 6, wherein: the glucosamine, or
suitable salt or derivative thereof, is include as glucosamine
sulfate in an amount of at least about 1500 mg; the fucoidan, or
suitable salt or derivative thereof, is included as fucoidan
sulfate in an amount of at least about 425 mg; the hyaluronan, or
suitable salt or derivative thereof, is include as sodium
hyaluronate in an amount of at least about 70 mg; and total
antioxidants, including the superoxide dismutase, or suitable
transition metal conjugate or derivative thereof, are included in
an amount of at least about 480 mg.
11. The composition of claim 9, wherein the total antioxidants
include: the superoxide dismutase, or a suitable transition metal
conjugate or derivative thereof; catalase, or a suitable transition
metal conjugate or derivative thereof; and one or more
polyphenols.
12. The composition of claim 11, wherein the superoxide dismutase,
or suitable transition metal conjugate or derivative thereof,
catalase, or suitable transition metal conjugate or derivative
thereof, and one or more polyphenols are independently selected
from the group consisting of non-GMO plant, olive, artichoke, red
grape, white grape, and melon superoxide dismutase, catalase, and
polyphenols.
13. The composition of claim 11, wherein the catalase, or suitable
transition metal conjugate or derivative thereof, is selected from
the group consisting of iron(III)-conjugated catalase and
iron(IV)-conjugated catalase.
14. The composition of claim 4, wherein the superoxide dismutase,
or suitable transition metal conjugate or derivative thereof, is
selected from the group consisting of copper-conjugated superoxide
dismutase, zinc-conjugated superoxide dismutase, extracellular
superoxide dismutase, copper-conjugated extracellular superoxide
dismutase, and zinc-conjugated extracellular superoxide
dismutase.
15. A method of manufacturing a composition that exhibits a
synergistic therapeutic effect on the endothelial glycocalyx of a
mammal when administered thereto, the method comprising preparing a
mixture comprised of: one or more molecular precursor of
endothelial glycocalyx in an amount of effective to increase
production of endothelial glycocalyx in a mammal to which the
composition is administered, the one or more molecular precursor of
endothelial glycocalyx comprising glucosamine, or a suitable salt
or derivative thereof one or more antioxidant that associates with
endothelial glycocalyx in an amount of effective to at least
partially protect existing endothelial glycocalyx against damage
caused by enzyme and/or oxidant in a mammal to which the
composition is administered, the one or more antioxidant that
associates with endothelial glycocalyx comprising superoxide
dismutase, or a suitable transition metal conjugate or derivative
thereof; and one or more glycocalyx mimetic in an amount of
effective to increase the density of endothelial glycocalyx at a
site of endothelial glycocalyx damage in a mammal to which the
composition is administered, the one or more glycocalyx mimetic
selected from the group consisting of a nonsulfated
glycosaminoglycan, preferably hyaluronan, or a suitable salt or
derivative thereof, and a sulfated polysaccharide, preferably
fucoidan, or a suitable salt or derivative thereof.
16. The method of claim 15, wherein at least one of: the
glucosamine, or suitable salt or derivative thereof, is selected
from the group consisting of glucosamine sulfate, non-GMO vegetable
glucosamine sulfate, non-GMO corn glucosamine sulfate,
D-glucosamine; the superoxide dismutase, or a suitable transition
metal conjugate or derivative thereof, is selected from the group
consisting of non-GMO plant, olive, artichoke, red grape, white
grape, and melon superoxide dismutase; and the hyaluronan, or
suitable salt or derivative thereof, is selected from the group
consisting of sodium hyaluronate, non-GMO microbial sodium
hyaluronate, non-GMO Streptoccoccus sodium hyaluronate, non-GMO
Streptoccoccus equi subsp. Zooepidemicus sodium hyaluronate, sodium
hyaluronate having a purity of at least about 90% w/w, non-GMO
microbial sodium hyaluronate having a purity of at least about 90%
w/w, non-GMO Streptoccoccus sodium hyaluronate having a purity of
at least about 90% w/w, and non-GMO Streptoccoccus equi subsp.
Zooepidemicus sodium hyaluronate having a purity of at least about
90% w/w; and the fucoidan, or suitable salt or derivative thereof,
is selected from the group consisting of fucoidan sulfate, non-GMO
plant, seaweed, or algae fucoidan sulfate, non-GMO Laminaria
fucoidan sulfate, non-GMO Laminaria japonica fucoidan sulfate,
fucoidan sulfate having a purity of at least about 85% w/w, non-GMO
plant, seaweed, or algae fucoidan sulfate having a purity of at
least about 85% w/w, non-GMO Laminaria fucoidan sulfate having a
purity of at least about 85% w/w, and non-GMO Laminaria japonica
fucoidan sulfate having a purity of at least about 85% w/w.
17. The method of claim 15, wherein the mixture further comprises
one or more additional antioxidants selected from the group
consisting of: catalase, or a suitable transition metal conjugate
or derivative thereof; and one or more polyphenols.
18. The method of claim 17, wherein the mixture comprises:
glucosamine, or suitable salt or derivative thereof; hyaluronan, or
suitable salt or derivative thereof; fucoidan, or suitable salt or
derivative thereof; superoxide dismutase, or suitable transition
metal conjugate or derivative thereof; catalase, or a suitable
transition metal conjugate or derivative thereof; and one or more
polyphenols.
19. The method of claim 18, wherein: the glucosamine, or suitable
salt or derivative thereof, is in an amount of at least about 375
mg; the fucoidan, or suitable salt or derivative thereof, is in an
amount of at least about 106.25 mg; the hyaluronan, or suitable
salt or derivative thereof, is in an amount of at least about 17.5
mg; and the superoxide dismutase, or suitable transition metal
conjugate or derivative thereof, catalase, or suitable transition
metal conjugate or derivative thereof, and one or more polyphenols
are included in an amount of at least about 120 mg.
20. The method of claim 18, wherein the glucosamine, or suitable
salt or derivative thereof, is in an amount of at least about 1500
mg; the fucoidan, or suitable salt or derivative thereof, is in an
amount of at least about 425 mg; the hyaluronan, or suitable salt
or derivative thereof, is in an amount of at least about 70 mg; and
the superoxide dismutase, or suitable transition metal conjugate or
derivative thereof, catalase, or suitable transition metal
conjugate or derivative thereof, and one or more polyphenols are
included in an amount of at least about 480 mg.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Divisional of U.S. application
Ser. No. 15/094,757, filed on Apr. 8, 2016, entitled "SYNERGISTIC
GLYCOCALYX TREATMENT COMPOSITIONS AND METHODS," which claims the
benefit of and priority to U.S. Provisional Application No.
62/144,484, filed on Apr. 8, 2015, entitled "SYNERGISTIC
GLUCOSAMINE COMPOSITIONS AND USES," the entire contents of each of
which being incorporated herein by specific reference.
BACKGROUND
1. Technical Field
[0002] The present disclosure relates to compositions and methods
for improving vascular health. Specifically, the present disclosure
relates to synergistic compositions and methods of treating
endothelial glycocalyx.
2. Relevant Technology
[0003] The glycocalyx is a polysaccharide-rich layer found on the
luminal surface of epithelial cells lining mammalian organs and
tissues. In the case of the vascular system, the glycocalyx coats
the luminal surface of the endothelium--the vascular endothelial
cells lining the inside of all blood vessels. As depicted in FIG.
1, for example, in vivo imaging of a capillary blood vessel
illustrates that red blood cells (RBC) flowing through the lumen of
the blood vessel do not contact the vessel wall endothelium. FIG. 2
illustrates a detailed view of an electron micrograph image
capturing a cross-section of a capillary. As depicted, the dense
glycocalyx extends from the endothelial cells into the lumen of the
blood vessel, forming a micro-thin, gel-like layer.
[0004] Until recently, the role of the endothelial glycocalyx had
not been well understood. In theory, however, the glycocalyx may
act as a protective barrier for the vascular wall or may provide a
micro-environment for certain vascular processes. Molecules that
associate with the glycocalyx may dynamically interact with the
endothelial cells to play a role in orchestrating a variety of
functions in the circulatory system. The circulatory system, in
turn, plays a role in regulating adequate organ perfusion and in
the distribution and exchange of oxygen, nutrients, and hormones
within tissues. Furthermore, microcirculation controls tissue
hydration and organizes the defense against pathogens.
[0005] As illustrated in FIGS. 2A-2D, endothelial glycocalyx can be
observed in varying degrees of thickness and/or density;
indications of the "health" of the endothelial glycocalyx. FIG. 2A,
for example, depicts an electron micrograph image of a "healthy"
endothelial glycocalyx, while FIG. 2D depicts a severely damaged or
perturbed "unhealthy" endothelial glycocalyx. FIG. 2B and FIG. 2C
illustrate, respectively, intermediate states of endothelial
glycocalyx health (e.g., as indicated visually by the thickness
and/or density thereof). The cause(s) of such structural damage
and/or depletion of the endothelial glycocalyx remain largely
unknown.
[0006] Impairment of the glycocalyx barrier through structural
damage or depletion, functional deficiency, or other mechanism may
be a contributing cause of microvascular endothelial dysfunction,
including inflammatory and coagulatory endothelial activation,
vascular leakage of fluid, proteins, and other substances (e.g.,
cholesterol), failure to properly modulate perfused blood vessel
density, and other deleterious conditions, leading to general and
specific negative vascular health indicators. As depicted in FIG.
3B, for example, an unhealthy endothelial glycocalyx is associated
with a "leaky" endothelium, as evidenced by (1) the presence (or
"leakage") of cholesterol (or other substances, such as fluids,
proteins, etc.) in (or into) the subendothelial space, and (2) a
constricted lumen, which may reduce blood flow or perfusion into
distal capillaries, muscles, organs, etc., increase blood pressure,
and so forth. As illustrated in FIG. 3A, however, a healthy (thick
and/or dense) endothelial glycocalyx is associated with a
well-formed endothelium and healthy blood vessel structural
configuration.
[0007] Accordingly, there is a need for products and processes for
treating (e.g., supporting and/or maintaining) endothelial
glycocalyx.
BRIEF SUMMARY
[0008] Embodiments of the present disclosure address one or more of
the foregoing or other problems in the art with compositions and
methods for treating endothelial glycocalyx. The compositions can
include nutritional building blocks required to support and
maintain a healthy endothelial glycocalyx, antioxidants to help
prevent damage to the glycocalyx, and/or glycocalyx mimetics for
acute repair of damaged endothelial glycocalyx. In at least one
embodiment, the building blocks comprise glucosamine, the
antioxidants comprise superoxide dismutase, catalase, and/or one or
more polyphenols, and the glycocalyx mimetics comprise hyaluronan
and/or fucoidan. The components can be combined in an orally
administrable form.
[0009] The components of the compositions can act synergistically
to improve vascular health by supporting a healthy endothelial
glycocalyx. In other words, the combination of components included
in the compositions can provide an effect on glycocalyx maintenance
that is greater than taking any single component alone or the sum
of reported effects of the individual components. For instance, the
nutritional building blocks can aid not only in the synthesis of
new glycocalyx, but also in acute repair of damaged glycocalyx
and/or protecting the glycocalyx against structural damage.
Similarly, the antioxidants can not only help to prevent damage to
the glycocalyx, but also aid in acute repair of damaged glycocalyx
and/or synthesis of new glycocalyx Likewise, the glycocalyx
mimetics can not only induce acute repair of damaged glycocalyx,
but also aid in the synthesis of new glycocalyx and/or help to
prevent damage to the glycocalyx.
[0010] An embodiment of the present disclosure can include a
composition for treating endothelial glycocalyx, the composition
comprising glucosamine, hyaluronan and/or fucoidan, and one or more
antioxidants, such as superoxide dismutase, catalase, and/or
polyphenol. The composition can exhibit a synergistic, therapeutic
effect on the endothelial glycocalyx when administered to a
mammal.
[0011] Another aspect of the present disclosure includes repairing
damaged endothelial glycocalyx by providing and/or administering
exogenous (nonsulfated) glycosaminoglycan and/or (sulfated)
polysaccharides, such as hyaluronan and/or fucoidan, that associate
with existing glycocalyx structures at sites of glycocalyx
perturbation.
[0012] A further aspect of the present disclosure includes
stimulating endothelial glycocalyx synthesis by providing and/or
administering glycocalyx precursor and/or substrate, such as
glucosamine, for local production and incorporation of glycocalyx
constituents.
[0013] Yet another aspect of the present disclosure includes
reducing damage (e.g., (oxidative) degradation) of endothelial
glycocalyx and/or constituents thereof by providing antioxidant
enzymes, such as superoxide dismutase and/or catalase, and/or
antioxidant compounds, such as polyphenols, that reduce (excessive,
local) levels or concentrations of reactive oxygen species.
[0014] Additional features, aspects, and advantages of exemplary
embodiments of the present disclosure will be set forth in the
description which follows and, in part, will be apparent from the
description or may be learned by the practice of such exemplary
embodiments. The features and advantages of such embodiments may be
realized and obtained by means of the instruments and combinations
particularly pointed out in the appended claims. These and other
features, aspects, and advantages will become more fully apparent
to those of skill in the art from the following description and
appended claims, or may be learned by the practice of such
exemplary embodiments as set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] In order to describe the manner in which the above-recited
and other advantages and features of the present disclosure can be
obtained, a more particular description of various embodiments of
the present disclosure will now be rendered with reference to the
appended drawings, in which the exemplary embodiments are
illustrated. It is appreciated that these drawings depict only
typical embodiments of the present disclosure and are not,
therefore, to be considered limiting of its scope.
[0016] FIG. 1A is an in vivo image of a capillary blood vessel;
[0017] FIG. 1B is a detailed view of an electron micrograph image
capturing a cross-section of a capillary blood vessel;
[0018] FIGS. 2A-2D illustrate diminishing health of endothelial
glycocalyx;
[0019] FIG. 3A illustrates an electron micrograph image capturing a
cross-section of a blood vessel having a generally healthy
glycocalyx;
[0020] FIG. 3B illustrates an electron micrograph image capturing a
cross-section of a blood vessel having a generally unhealthy
glycocalyx;
[0021] FIG. 4 illustrates a flowchart depicting synergistic
interactions and effects of components of a synergistic glycocalyx
treatment composition administered to a subject in need thereof in
according to an embodiment of the present disclosure; and
[0022] FIG. 5 illustrates the change in various endothelial
glycocalyx health indicators in subject humans treated with a
synergistic glycocalyx treatment composition according to an
embodiment of the present disclosure.
DETAILED DESCRIPTION
[0023] Before describing the present disclosure in further detail,
it is to be understood that this disclosure is not limited to the
description of the particularly exemplified methods and/or products
that may vary from one embodiment to the next. Thus, while certain
embodiments of the present disclosure will be described in detail,
with reference to specific configurations, parameters, features
(e.g., components, members, elements, parts, and/or portions),
etc., the descriptions are illustrative and are not to be construed
as limiting the scope of the claimed invention. In addition, the
terminology used herein is for the purpose of describing the
embodiments, and is not necessarily intended to limit the scope of
the claimed invention.
[0024] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the present disclosure
pertains.
[0025] Various aspects of the present disclosure, including
systems, processes, and/or products may be illustrated with
reference to one or more implementations or embodiments, which are
exemplary in nature. As used herein, the terms "embodiment" and
"implementation" mean serving as an example, instance, or
illustration, and should not necessarily be construed as preferred
or advantageous over other aspects disclosed herein. In addition,
reference to an "implementation" of the present disclosure or
invention includes a specific reference to one or more embodiments
thereof, and vice versa, and is intended to provide illustrative
examples without limiting the scope of the invention, which is
indicated by the appended claims rather than by the following
description.
[0026] As used throughout this application the words "can" and
"may" are used in a permissive sense (i.e., meaning having the
potential to), rather than the mandatory sense (i.e., meaning
must). Additionally, the terms "including," "having," "involving,"
"containing," "characterized by," as well as variants thereof
(e.g., "includes," "has," and "involves," "contains," etc.), and
similar terms as used herein, including the claims, shall be
inclusive and/or open-ended, shall have the same meaning as the
word "comprising" and variants thereof (e.g., "comprise" and
"comprises"), and do not exclude additional, un-recited elements or
method steps, illustratively.
[0027] It will be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to a "polyphenol" includes one, two,
or more polyphenols. Similarly, plural referents, such as
"polyphenols," should be interpreted as comprising a single
referent and/or a plurality of referents unless the content and/or
context clearly dictate otherwise. Thus, reference to "polyphenols"
does not necessarily require a plurality of such polyphenols.
Instead, it will be appreciated that independent of conjugation;
one or more polyphenols are contemplated herein.
[0028] To facilitate understanding, like references (i.e., like
naming of components and/or elements) have been used, where
possible, to designate like elements common to the description
and/or figures. Specifically, in the exemplary embodiments
described herein and/or illustrated in the figures, like
structures, or structures with like functions, may be provided with
similar names and/or reference designations, where possible.
Specific language will be used herein to describe the exemplary
embodiments. Nevertheless, it will be understood that no limitation
of the scope of the disclosure is thereby intended. Rather, it is
to be understood that the language used to describe the exemplary
embodiments is illustrative only and is not to be construed as
limiting the scope of the disclosure (unless such language is
expressly described herein as essential).
[0029] It will also be appreciated that where multiple
possibilities of values or a range of values (e.g., less than,
greater than, at least, and/or up to a certain value, and/or
between two recited values) is disclosed or recited, any specific
value or range of values falling within the disclosed range of
values is likewise disclosed and contemplated herein. Thus,
disclosure of an illustrative measurement or amount less than or
equal to about 10 units or between 0 and 10 units includes,
illustratively, a specific disclosure of: (i) a measurement or
amount of 9 units, 5 units, 1 units, or any other value between 0
and 10 units, including 0 units and/or 10 units; and/or (ii) a
measurement or amount between 9 units and 1 units, between 8 units
and 2 units, between 6 units and 4 units, and/or any other range of
values between 0 and 10 units.
[0030] Weight- or mass-based measurements provided herein (e.g.,
milligrams (mg)) are given on a dry weight or dry mass basis.
[0031] The headings used herein are for organizational purposes
only and are not meant to be used to limit the scope of the
description or the claims.
[0032] Embodiments of the present disclosure address and/or provide
solutions to the problem of glycocalyx deficiency, dysfunction,
degradation, vascular health-related problems resulting therefrom,
and/or one or more of the foregoing or other problems in the art
with novel, effective, and/or synergistic compositions and methods
for treating endothelial glycocalyx. As used herein the term
"synergistic" refers to the phenomenon where the combination of two
or more components (e.g., therapeutic agents, ingredients, etc.)
provides an effect that is greater than the effect of the
individual components or the sum of the components acting alone.
Thus, embodiments of the present disclosure can include a
combination or mixture of components in an amount effective to
produce or exhibit a (physiological) effect (when administered to a
subject or patient in need thereof) that is greater than the effect
of any single component or the sum of the effects of each component
acting alone.
[0033] Some embodiments can include one or more nutritional
building blocks (e.g., glycocalyx precursor or substrate molecule)
adapted to support and maintain a healthy endothelial glycocalyx
(e.g., by increasing (natural) production thereof). Such glycocalyx
building blocks, precursors, and/or substrate molecules can
include, for example, glucosamine (e.g., glucosamine sulfate). Some
embodiments can include one or more antioxidant (e.g., enzyme or
compound) to help prevent damage to the glycocalyx. Such
antioxidant can include, for example, superoxide dismutase (SOD)
(e.g., extracellular SOD, SOD3, copper- or zinc-conjugated SOD,
etc.), catalase (e.g., iron(III)- or iron(IV)-conjugated catalase),
and/or one or more polyphenols). Some embodiments can include one
or more glycocalyx mimetics, glycocalyx-binding compound, or
glycocalyx-associating compounds for acute repair of damaged
glycocalyx or sites of glycocalyx damage (e.g., degradation,
alteration, thinning, etc.). Such glycocalyx mimetics,
glycocalyx-binding compound, or glycocalyx-associating compounds
can include, for example, hyaluronan (e.g., sodium hyaluronate)
and/or fucoidan (e.g., fucoidan sulfate). The components of the
compositions can act synergistically to improve vascular health by
supporting a healthy endothelial glycocalyx, such that the
combination of components can provide an effect on glycocalyx
maintenance that is greater than taking any single component alone
or the sum of reported effects of the individual components. In at
least one embodiment, a composition for use in treating endothelial
glycocalyx is provided.
[0034] Some embodiments of the present disclosure include one or
more methods of (synergistically) treating (e.g., supporting,
maintaining, protecting, repairing, patching, and/or enhancing
production of) endothelial glycocalyx, methods of improving
vascular health, methods of restoring healthy endothelial
glycocalyx, etc. Embodiments can also achieve a desired result
(e.g., physiological reaction, biological response, etc.), such as
increased endothelial glycocalyx density or thickness, reduced
endothelial glycocalyx damage or degradation, improved vascular
shear stress signaling, reduced blood pressure, increased blood
nitric oxide levels and/or production, increased oxygen exchange,
decreased endothelial permeability (e.g., to large plasma
molecules, thereby decreasing leakage thereof into or across the
endothelium), reduced accumulation of cholesterol in
sub-endothelial space, increased size or volume of perfused
boundary region, improved blood perfusion or distribution (e.g., to
capillaries, organs, muscles, etc.), microvascular blood volume,
and so forth.
[0035] Embodiments can include providing or administering to a
subject or patient (e.g., mammal, human, etc.) an effective amount
of a composition, or a composition in an amount effective, to
(synergistically) treat endothelial glycocalyx, improve vascular
health, restore healthy endothelial glycocalyx, etc. The
composition can include an effective amount of one or more
nutritional building blocks that can aid not only in the synthesis
of new glycocalyx, but also in acute repair of damaged glycocalyx
and/or protecting the glycocalyx against structural damage. The
composition can also include an effective amount of one or more
antioxidants that can not only help to prevent damage to the
glycocalyx, but also aid in acute repair of damaged glycocalyx
and/or synthesis of new glycocalyx. The composition can also
include an effective amount of one or more glycocalyx mimetics that
can not only induce acute repair of damaged glycocalyx, but also
aid in the synthesis of new glycocalyx and/or help to prevent
damage to the glycocalyx.
[0036] By repairing, protecting, and enhancing synthesis of
endothelial glycocalyx, embodiments of the present disclosure can
treat (e.g., bolster, maintain, support, etc.) the glycocalyx,
(e.g., ensuring structural and functional integrity thereof). Such
structural and functional integrity can be associated with overall
vascular (e.g., microvascular) health and function, including
proper regulation and/or modulation of perfused blood vessel
density, blood pressure, vascular barrier properties, blood flow or
perfusion into distal capillaries, muscles, organs, etc.,
inflammatory and/or coagulatory response, and so forth.
[0037] Illustrative components (and combinations thereof) useful in
the formation, production, and/or manufacture of certain
embodiments of the present disclosure, and illustrative methods
(and steps thereof) involving the same, will be discussed in
further detail below. For organizational purposes only, such
components have been grouped into three categories based on their
direct and/or primary function or mode of action in treating (e.g.,
supporting or maintaining) a (healthy) endothelial glycocalyx. Such
modes of actions include (1) synthesizing (or producing new)
endothelial glycocalyx (e.g., through supporting natural pathways
and/or processes with glycocalyx precursors or building blocks),
(2) repairing (or patching) damaged or perturbed glycocalyx
(structural features) (e.g., with glycocalyx-mimetics), and (3)
protecting (or defending) existing endothelial glycocalyx (e.g.,
with antioxidants).
1. Synthesizing Endothelial Glycocalyx--Glycocalyx Precursors
Glucosamine
[0038] Glucosamine is an amino sugar and a precursor in the
biochemical synthesis of glycosylated proteins and lipids. Although
there is a substantial amount of data about the health benefits of
glucosamine, its exact role in glycocalyx synthesis has not been
previously recognized or documented. For example, it has not been
reported or recognized that (soluble and/or exogenous) glucosamine
(e.g., glucosamine sulfate) can be introduced (orally,
intravenously, etc.) to stimulate synthesis of endothelial
glycocalyx (through natural biochemical pathways), as contemplated
by the present disclosure.
[0039] Indeed, glucosamine can increase synthesis of two main
constituents of the endothelial glycocalyx, namely heparan sulfate
and hyaluronan. Moreover, labeled glucosamine administered to
cultured endothelial cells is incorporated in the glycocalyx. Thus,
the addition and/or administration of glucosamine can support
endothelial glycocalyx production by providing a (necessary and/or
rate-limiting) component in the synthesis thereof. Accordingly,
glucosamine can be or comprise a molecular precursor of endothelial
glycocalyx.
[0040] One or more embodiments of the present disclosure can
include glucosamine (e.g., in an amount effective to increase
vascular production of endothelial glycocalyx). In some embodiments
the glucosamine can be included (or provided) as glucosamine
sulfate and/or other form of (D-)glucosamine. The glucosamine can
be natural or synthetic. In a preferred embodiment, the glucosamine
can be or comprise glucosamine (sulfate) extracted and/or purified
from a (non-GMO) plant source, such as vegetable(s), (e.g., corn).
In at least one embodiment, the glucosamine (sulfate) (extract) can
have a purity greater than or equal to about 80%, 85%, 90%, 95%,
96%, 97%, 98%, or 99%.
[0041] The glucosamine can be included in compositions of the
present disclosure in an amount of at least about 50 mg, 100 mg,
200 mg, 250 mg, 300 mg, 350 mg, 375 mg, 400 mg, 500 mg, 600 mg, 700
mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1500 mg, 2000 mg,
2500 mg, 3000 mg, or more. In a preferred embodiment, glucosamine
can be provided in an amount sufficient to result in the
administration of about 1500 mg of glucosamine (or glucosamine
extract) per day. Accordingly, certain embodiments (e.g., a daily
dose) can include about 1500 mg of (corn) glucosamine (sulfate)
(extract).
2. Repairing Endothelial Glycocalyx--Glycocalyx-Mimetics
Hyaluronan
[0042] Hyaluronan, or hyaluronic acid, is a polysaccharide with a
structure similar to heparan sulfate and heparin; that is, it
includes repeats of the monosaccharides glucosamine and glucuronic
acid. Unlike heparan sulfate, however, hyaluronan is a nonsulfated
glycosaminoglycan (that lacks sulfation) and is not linked to a
core protein. Endogenous hyaluronan also associates with the
glycocalyx, becoming incorporated into the endothelial membrane by
its synthesizing enzyme hyaluronan synthase ("HAS") or via binding
to CD44 or other hyaluronan binding proteins.
[0043] Although reports of some of the benefits of hyaluronan are
known, especially in patients with fibromyalgia, it has not been
previously recognized that hyaluronan is a part of glycocalyx
repair. In particular, although hyaluronan is a building block of
the glycocalyx, it has not been previously known or recognized that
hyaluronan can be introduced to repair damaged glycocalyx (at sites
of glycocalyx damage or perturbation), as contemplated by the
present disclosure. Furthermore, due to its high molecular weight
(e.g., reaching long lengths of up to several microns), it is also
unclear to what degree (orally) administered (exogenous) hyaluronan
can or does enter the circulatory system (e.g., by means of the
lymphatic system) intact. For instance, without being bound to any
theory, the half-life of hyaluronan in the circulatory system may
be very short (e.g., 5 minutes or less). While existing theory
and/or accepted wisdom attributes the short half-life of hyaluronan
to enzymatic or other degradation (e.g., by oxidants, such as free
radicals), the present disclosure reports the (direct) association
of hyaluronan with and/or binding of hyaluronan to existing
endothelial glycocalyx (e.g., resulting in the rapid decrease of
free, circulating hyaluronan after administration.
[0044] Indeed, hyaluronan can be, act as, and/or provide a
glycocalyx-mimetic (or patch) that associates with existing
glycocalyx structures at sites of glycocalyx perturbation.
Introduction and/or administration of (exogenous) hyaluronan causes
thickening of endothelial glycocalyx at sites of damage and/or
thinning of the glycocalyx. Thus, in addition to (naturally)
produced hyaluronan, which is synthesized and incorporated into the
endothelium, exogenous or administered hyaluronan can (directly)
associate with existing glycocalyx and/or glycocalyx-sparse regions
of the endothelium.
[0045] One or more embodiments of the present disclosure can
include hyaluronan (e.g., in an amount effective to increase the
density of endothelial glycocalyx). In some embodiments the
hyaluronan can be included (or provided) as sodium hyaluronate. The
hyaluronan can be natural or synthetic. In a preferred embodiment,
the hyaluronan can be or comprise hyaluronan (sodium salt)
extracted and/or purified from a (non-GMO) microbial (e.g.,
bacterial) source, such as Streptoccoccus, (e.g., Streptoccoccus
equi subsp. Zooepidemicus). In at least one embodiment, the
hyaluronan (sodium salt) (extract) can have a purity greater than
or equal to about 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or
99%.
[0046] The hyaluronan can be included in compositions of the
present disclosure in an amount of at least about 5 mg, 10 mg, 12
mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60
mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, or more. In
a preferred embodiment, hyaluronan can be provided in an amount
sufficient to result in the administration of about 70 mg of
hyaluronan (or hyaluronan extract) per day. Accordingly, certain
embodiments (e.g., a daily dose) can include about 425 mg of
(Streptoccoccus (equi subsp. Zooepidemicus)) hyaluronan (or sodium
hyaluronate) (extract).
[0047] Hyaluronan can also be found in a wide variety of
polymerization states and/or molecular weight (MW) sizes.
Embodiments of the present disclosure can include so-called high
molecular weight (HMW) hyaluronan, having a MW of greater than
about 100 kDa, 200 kDa, 300 kDa, 400 kDa, 500 kDa, 600 kDa, 700
kDa, 800 kDa, 900 kDa, 1000 kDa, 1200 kDa, 1500 kDa, 1800 kDa, or
more and/or less than about 3000 kDa, 3200 kDa, 3500 kDa, 3800 kDa,
4000 kDa, 4200 kDa, 4500 kDa, 4800 kDa, or 5000 kD. At least one
embodiment can include hyaluronan having a MW of between about
100-5000 kDa, between about 500-4500 kDa, between about 1000-4000
kDa, between about 1200-3800 kDa, between about 1500-3500 kDa, or
between about 1800-3000 kDa.
Fucoidan
[0048] Fucoidans are sulfated fucosylated (polysaccharide) polymers
that exhibit some heparin/heparan sulfate-like properties, which
are components of the glycocalyx matrix structure. Fucoidans have
been isolated and studied for various biological activities, but
have not been shown or recognized as contributing to glycocalyx
repair (at sites of glycocalyx damage or perturbation), as
contemplated by the present disclosure. Thus, although some
benefits of fucoidan are known, it has not been previously known or
contemplated that fucoidan can be introduced (exogenously) to
repair damaged glycocalyx. Moreover, similar to hyaluronan, it is
also unclear to what degree (orally) administered (exogenous)
fucoidan can or does enter the circulatory system intact.
[0049] Indeed, fucoidan can be, act as, and/or provide a glycocalyx
mimetic (or patch) that helps repair and maintain the backbone of
the glycocalyx by (directly) associating with existing glycocalyx
and/or glycocalyx-sparse regions of the endothelium. Thus, in
addition to (naturally) produced heparin/heparan sulfate, which are
synthesized and incorporated into the endothelium, exogenous or
administered fucoidan can (directly) associate with existing
glycocalyx and/or glycocalyx-sparse regions thereof. Introduction
and/or administration of (exogenous) fucoidan causes thickening of
endothelial glycocalyx at sites of damage and/or thinning of the
glycocalyx. Certain fucoidans can also have antioxidant properties.
Accordingly, introduction and/or administration of fucoidan can
provide site-directed antioxidant activity at the endothelial
glycocalyx and/or regions of the glycocalyx being repaired.
[0050] One or more embodiments of the present disclosure can
include fucoidan (e.g., in an amount effective to increase the
density of endothelial glycocalyx). In some embodiments the
fucoidan can be included (or provided) as fucoidan sulfate. The
fucoidan can be natural or synthetic. In a preferred embodiment,
the fucoidan can be or comprise fucoidan (sulfate) extracted and/or
purified from a (non-GMO) plant, preferably (brown, green, or red)
seaweed or algae, more preferably Laminaria, such as Laminaria
japonica. In at least one embodiment, the fucoidan (sulfate)
(extract) can have a purity greater than or equal to about 75%,
80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99%. Other genus and/or
species of seaweed, including but not limited to Monostroma, such
as Monostroma nitidum, are also contemplated herein.
[0051] The fucoidan can be included in compositions of the present
disclosure in an amount of at least about 50 mg, 60 mg, 70 mg, 75
mg, 80 mg, 90 mg, 100 mg, 106.25 mg, 125 mg, 150 mg, 200 mg, 212.5
mg, 250 mg, 300 mg, 350 mg, 400 mg, 425 mg, 450 mg, 500 mg, 600 mg,
700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or more. In a preferred
embodiment, fucoidan can be provided in an amount sufficient to
result in the administration of about 425 mg of fucoidan (or
fucoidan extract) per day. Accordingly, certain embodiments (e.g.,
a daily dose) can include about 425 mg of (Laminaria japonica )
fucoidan (sulfate) (extract).
3. Protecting Endothelial Glycocalyx--Antioxidants
Superoxide Dismutase and Catalase
[0052] Superoxide dismutase (SOD) (e.g., extracellular superoxide
dismutase (ecSOD), or SOD3) and catalase are enzymes found in most
living organisms exposed to oxygen, including animals, (green)
plants, and most bacteria. SOD "dismutases" superoxide anions
(O.sub.2.sup.-) to oxygen (O.sub.2), or hydrogen peroxide
(H.sub.2O.sub.2), which can be further decomposed (e.g., partially
reduced) to hydroxyl radical (HO.sup.-), or (fully reduced) to
water (H.sub.2O) and O.sub.2 by catalase. Thus, SOD and catalase
enzymes act as antioxidants capable of helping to prevent cellular
and molecular damage caused by free radicals, such as reactive
oxygen species/oxygen radicals, through "scavenging" the
oxidants.
[0053] Glycocalyx can become damaged, perturbed, and/or destroyed
by the action of oxidants, such as reactive oxygen species/oxygen
radicals (e.g., O.sub.2.sup.-). Although supplemental forms of SOD
and catalase have been reported to provide health benefits, there
are no reports of either SOD or catalase having a potential impact
on glycocalyx protection or defense, as contemplated by the present
disclosure. Thus, although some benefits of SOD and catalase are
known, it has not been previously recognized or contemplated that
SOD and/or catalase can be introduced orally to protect or defend
endothelial glycocalyx against (oxidative) damage (by free
radicals). Moreover, it is also unclear to what degree (orally)
administered (exogenous) SOD and catalase can or does enter the
circulatory system intact.
[0054] Indeed, SOD and catalase can help protect and maintain the
backbone of the endothelial glycocalyx. Reducing the degradation of
glycocalyx constituents caused by excessive local levels of oxygen
radicals can be one benefit of providing the anti-oxidant enzymes
SOD and catalase, which bind to the glycocalyx and/or lower local
concentrations of oxygen species, which in turn reduce oxidative
damage to the glycocalyx and, thereby, preserve endothelial
function.
[0055] For instance, exogenous, labeled SOD administered (orally
and/or intravenously) to mice co-localizes (binds (directly) to)
the endothelial glycocalyx. By so doing, the local concentration of
SOD at the endothelial glycocalyx is increased, providing added or
enhanced (site-directed) protection against oxygen radicals at the
endothelial glycocalyx. Thus, in addition to (naturally) produced
SOD, which may be synthesized and bound to the endothelium,
exogenous or administered SOD can (directly) associate with (bind
to) endothelial glycocalyx. Accordingly, introduction and/or
administration of SOD can provide site-directed antioxidant
activity at the endothelial glycocalyx.
[0056] Moreover, (oral and/or intravenous) administration of
catalase to mice increases catalase concentrations in blood
vessels. Thus, in addition to (naturally) produced SOD, which may
be produced and secreted into the blood stream, exogenous or
administered catalase can be absorbed into the blood stream and be
available for oxidant scavenging at or adjacent to the endothelial
glycocalyx (and SOD bound thereto). Accordingly, introduction
and/or administration of catalase can also provide antioxidant
activity in blood vessels and/or at the endothelial glycocalyx.
[0057] One or more embodiments of the present disclosure can
include SOD (e.g., in an amount effective to increase scavenging of
oxidants, such as free radicals, particularly reactive oxygen
species/oxygen radicals (e.g., O.sub.2.sup.-) at or adjacent to the
endothelial glycocalyx). In some embodiments the SOD can be
included (or provided) as ecSOD, or SOD3, preferably bound to
copper or zinc and/or as copper- or zinc-conjugated SOD. The SOD
can be natural or synthetic. In a preferred embodiment, the SOD can
be or comprise (ec)SOD(3) extracted and/or purified from (or be
included as an extract of or from) a (non-GMO) plant (part),
preferably one or more fruit or vegetable plant parts, more
preferably Momordica charantia (a.k.a. bitter melon) (fruit). Other
plant parts, including, for example, olive (fruit), artichoke
(leaf), white grape (fruit), and/or red grape (fruit), are also
contemplated herein.
[0058] One or more embodiments of the present disclosure can
include catalase (e.g., in an amount effective to increase
scavenging of oxidants, such as reactive oxygen species-/oxygen
radical-precursors (e.g., H.sub.2O.sub.2), illustratively at or
adjacent to the endothelial glycocalyx). In some embodiments the
catalase can be included (or provided) bound to iron, such as
iron(III) or iron(IV) and/or as iron(III)- or iron(IV)-conjugated
catalase. The catalase can be natural or synthetic. In a preferred
embodiment, the catalase can be extracted and/or purified from (or
be included as an extract of or from) a (non-GMO) plant (part),
preferably one or more fruit or vegetable plant parts, more
preferably Momordica charantia (a.k.a. bitter melon) (fruit). Other
plant parts, including, for example, olive (fruit), artichoke
(leaf), white grape (fruit), and/or red grape (fruit), are also
contemplated herein.
[0059] Antioxidants, such as SOD and/or catalase, can be included
in compositions of the present disclosure (e.g., as Momordica
charantia (a.k.a. bitter melon) (fruit) extract) in an amount of at
least about 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg,
50 mg, 100 mg, 150 mg, 200 mg, or more. In a preferred embodiment,
SOD and/or catalase can be provided in an amount sufficient to
result in the administration of about 30 mg of SOD and/or catalase
(or SOD and/or catalase extract) per day. Accordingly, certain
embodiments (e.g., a daily dose) can include about 30 mg of
((bitter) melon (fruit)) antioxidant (e.g., SOD and/or catalase)
(extract).
Other Naturally Occurring Antioxidants--Polyphenols
[0060] Antioxidants are potent scavengers of free radicals and
other oxidants and serve as inhibitors of neoplastic processes and
other cellular and/or molecular degrading, damaging, or destroying
activities thereof. Naturally occurring antioxidants, widely
available in fruits, vegetables, nuts, flowers and bark, possess a
broad spectrum of biological and therapeutic properties against
free radicals and oxidative stress. It has not, however, been shown
that particular antioxidant compounds, such as polyphenols, can
lower the concentration of oxygen radicals or other oxidants at or
adjacent to the endothelial glycocalyx and/or and reduce oxidative
damage thereto, as contemplated by the present disclosure. Thus,
although some benefits of antioxidant compounds, such as
polyphenols, are known, it has not been previously known or
contemplated that such antioxidants can be introduced (exogenously)
to protect and defend endothelial glycocalyx. Moreover, it is also
unclear to what degree (orally) administered (exogenous)
antioxidants, such as polyphenols, can or do enter the circulatory
system intact.
[0061] Indeed, polyphenols can help protect and maintain the
backbone of the endothelial glycocalyx by reducing the prevalence
of oxidants in the blood stream. For instance, polyphenols
extracted from olive, artichoke, and (white and/or red) grapes
extracts can lower the concentration of oxygen radicals (e.g., in
blood vessels) and thereby reduce damage of the glycocalyx.
[0062] In a preferred embodiment, antioxidants, such as
polyphenols, can be extracted and/or purified from (or be included
as an extract of or from) (non-GMO) plant(s), preferably (fruits
and vegetables, including olive (fruit), artichoke (leaf), and
white grape (fruit), and/or red grape (fruit). Antioxidants, such
as polyphenols, can be included in compositions of the present
disclosure in an amount of at least about 50 mg, 60 mg, 70 mg, 75
mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 240 mg, 300 mg,
350 mg, 400 mg, 450 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900
mg, 1000 mg, or more. In a preferred embodiment, polyphenols (e.g.,
derived and/or extracted from olive (fruit), artichoke (leaf), and
white grape (fruit), and/or red grape (fruit)) can be provided in
an amount sufficient to result in the administration of about 450
mg of (olive (fruit), artichoke (leaf), and white grape (fruit),
and/or red grape (fruit)) polyphenol (extract) per day.
Accordingly, certain embodiments (e.g., a daily dose) can include
about 450 mg of (olive (fruit), artichoke (leaf), and white grape
(fruit), and/or red grape (fruit)) polyphenol (extract).
[0063] In certain embodiments, (a mixture of (enzymatic and/or
molecular)) antioxidants can be obtained as a (non-GMO) plant or
plant-based extract. For instance, one or more fruit(s),
vegetable(s), and/or other plant(s) or plant part(s) can be
processed so as to extract, isolate, purify, and/or concentrate
antioxidant(s), such as SOD, catalase, and/or polyphenol(s)
therefrom. Extract(s) from a plurality of such plants or plant
parts can be mixed together and/or included as an antioxidant
component of (compositions of) the present disclosure. In at least
one embodiment, for instance, the antioxidant mixture can comprise
extracts, isolates, and/or concentrates of or from olive (fruit),
artichoke (leaf), and white grape (fruit), red grape (fruit),
and/or melon (fruit).
[0064] A mixture of (enzymatic and/or molecular) antioxidants,
including, for example, SOD, catalase, and/or polyphenol(s) can be
included in compositions of the present disclosure in an amount of
at least about 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg,
120 mg, 150 mg, 200 mg, 240 mg, 300 mg, 350 mg, 400 mg, 450 mg, 480
mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or more. In a
preferred embodiment, the antioxidant mixture can be provided in an
amount sufficient to result in the administration of about 480 mg
of the antioxidant (extract) mixture per day. Accordingly, certain
embodiments (e.g., a daily dose) can include about 480 mg of (olive
(fruit), artichoke (leaf), and white grape (fruit), red grape
(fruit), and/or (bitter) melon (fruit)) polyphenol (extract).
[0065] Excipients and Non-Active Components
[0066] Various components (e.g., therapeutic agents or (active)
ingredients) of the composition (as described above) may be
combined with one or more excipients, such as microcrystalline
cellulose and/or silicon dioxide, and then encapsulated using
techniques known in the art. For example, the therapeutic agents
may be combined with the excipients and dry blended. The resulting
dry blend may then be encapsulated by hand or by machine. The
microcrystalline cellulose and silicon dioxide act as excipients to
allow the dry blend to flow smoothly into the capsules. Other known
excipients may be added or substituted as necessary as determined
by those having skill in the art. In addition, such excipients may
be added in varying amounts without necessarily departing from the
scope of this disclosure. The capsules may be any known in the art
such as softgels, gelatin, and/or vegetarian capsules. The
composition can also be provided as a tablet, pill, powder, dry
blend, tincture, solution, suspension, (flavored or unflavored)
drinks or drink mixes, aerosols, or other suitable form of
matter.
[0067] In at least one embodiment, components of the present
disclosure (e.g., therapeutic agents or (active) ingredients of the
composition) can be coated and/or encapsulated to protect the
therapeutic agents or (active) ingredients from degradation in the
acidic conditions of the mammalian gut. For instance, in some
embodiments, a protective coating can be formed around a dry blend
of the components and the coated dry blended components optionally
encapsulated (in a protective capsule) for oral administration.
Alternatively, the coated dry blended components can be provide for
and/or prepared as an oral slurry, solution, and/or suspension,
such as a drink or tincture.
EXAMPLE 1
[0068] An illustrative embodiment of (an encapsulated) composition
of the present disclosure is provided in the table below:
TABLE-US-00001 Composition of a 750.75 mg capsule Ingredient Amount
(mg/capsule) Fucoidan (85%) 106.25 mg Antioxidants (SOD, catalase,
polyphenols) 120.00 mg Glucosamine Sulfate 375.00 mg Hyaluronic
Acid (1800-3000 kDa) 17.50 mg Microcrystalline Cellulose 130.00 mg
Silicon Dioxide 2.00 mg Total mg per capsule 750.75 mg
[0069] The composition provided in Example 1 can be obtained
commercially from MicroVascular Health Solutions, L.L.C., a
Delaware limited-liability company, under the trademark
ENDOCALYX.TM..
[0070] Embodiments of the present disclosure (e.g., one or more
capsules having a composition of components according to Example 1)
can be administered one or more times per day, and preferably up to
four times per day. For example, four capsules can be administered
once per day, two capsules can be administered two times per day,
or one capsule can be administered four times per day.
Alternatively, double-dose capsules comprising twice the above
amounts can be provided. Such double-dose capsules can be provided,
for example, as two capsules that can be administered one time per
day or one capsule that can be administered two times per day.
Other dosages, regimen, treatment (schedules), and/or formulations
are also contemplated herein.
[0071] A preferred embodiment of the present disclosure comprises a
daily dosage form of a composition comprising up to, at least,
and/or about 1500 mg of glucosamine (e.g., glucosamine sulfate),
480 mg of a mixture of antioxidants (e.g., superoxide dismutase,
catalase, and/or polyphenols), 425 mg of fucoidan (e.g., fucoidan
sulfate), and 70 mg of hyaluronan (e.g., sodium hyaluronate). Such
a daily dosage form can comprise a single dose, two one-half doses,
three one-third doses, four one-fourth doses, and so forth. In
addition, the dosage form can be provided as one, two, three, four,
or more capsules, tablets, pills, or other dosage forms, such as a
volume of liquid dose (e.g., drink), weight of a powdered or other
dry dose (e.g., powdered drink mix), etc.
[0072] The embodiment described in Example 1 can represent a
one-fourth daily dosage for a human or other (large) mammal. It
will be appreciated, that dosage amounts of one or more (e.g.,
each) of the components (e.g., active ingredients and/or
therapeutic agents) can be adjusted and/or modified, preferably
while maintaining a similar ratio between such components.
Accordingly, in at least one embodiment, a mammalian dosage form of
the present disclosure can comprise a composition having a ratio of
components according to the formula 375:120:106.25:17.50
(glucosamine (e.g., glucosamine sulfate):mixture of antioxidants
(e.g., superoxide dismutase, catalase, and/or polyphenols):fucoidan
(e.g., fucoidan sulfate):hyaluronan (e.g., sodium hyaluronate)), by
weight, volume, or molar. Other ratios, for example, alternative
ratios of up to about +/-1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, or 50% of one or more of the foregoing components (or
ratios thereof) are also contemplated herein.
[0073] Synergistic Effects of Active Ingredients
[0074] As indicated herein, embodiments (e.g., compositions and/or
methods) of the present disclosure can improve (micro)vascular
health, not only through direct modes of action (as described
above), but by exhibiting beneficial synergistic effects on
endothelial glycocalyx (e.g., over the benefits of taking any
single component (of the composition) alone or the sum of reported
effects of the individual components. Complimentary or synergistic
benefits of such components (or compositions (e.g., nutritional
supplements) including the same) on the endothelial glycocalyx (and
overall vascular health) include further enhancing the repair of
glycocalyx damage, further stimulating synthesis of new glycocalyx
(e.g., by enhancing production of glycocalyx precursors or building
blocks), and/or further protecting glycocalyx (and
constituents/components thereof) from (oxidative and/or other forms
of degradation (e.g., enzymatic)).
[0075] FIG. 4 is an illustrative synergistic flowchart illustrating
one or more complimentary, synergistic, and/or overlapping modes of
activity, leading to further enhanced or improved health of
endothelial glycocalyx. As depicted in FIG. 4, a healthy and/or
improved glycocalyx (GX) 1 can be achieved by three general,
separate, distinct, overlapping, intersecting, and/or interrelated
modes of action and/or activity, indicated as: A. repairing damaged
GX; B. protecting against damage to GX; and C. synthesizing new
GX.
[0076] As described herein, the addition and/or administration of
one or more glycocalyx-mimetics 10, such as hyaluronan (HA) and/or
fucoidan(s) (FS), can result in the (direct) incorporation 12 of
such compounds (polysaccharides and/or glycosaminoglycans) at sites
of GX damage and/or perturbation. Incorporation 12 can, therefore,
repair (or patch) sites where the GX has been damaged, degraded,
and/or destroyed, leading to healthy and/or improved GX 1. One
consequence of healthy and/or improved GX 1 (e.g., from
incorporation 12) can be an increase in the ability of the
endothelium to function in shear stress (SS) signaling pathways 14.
In particular, a healthy GX is associated with proper levels and/or
modulation of SS signaling.
[0077] Proper and/or increased SS signaling 14 can result in a
corresponding increase in the expression and/or activity of
hyaluronan synthase (HAS) 18 and/or one or more (other) SS
sensitive genes 16. The addition and/or administration of one or
more GX precursors and/or building blocks 20, such as glucosamine,
can feed one or more of activities 16 and/or 18, resulting,
respectively, in an increase in the production of one or more GX
polysaccharides 22, such as heparin sulfates, and/or increase
production of one or more (nonsulfated) glycosaminoglycans 24,
hyaluronic acid (HA). Increased production 22 and/or 24 can result
in, correspond with, and/or be accompanied by incorporation 12 of
such polysaccharides and/or glycosaminoglycans as new endothelial
GX, further and/or synergistically improving, enhancing, and/or
supporting healthy GX 1.
[0078] Proper and/or increased SS signaling 14 can also result in
increased nitric oxide production 26. Increased nitric oxide
production 26 can lead to decreased expression of one or more
GX-degrading enzymes 28, such as heparinase, which can
enzymatically digested and/or degrade heparin and/or heparin-like
compounds (heparinoids), such as those described herein. Such
degradation can cause (substantial and/or significant) damage to
endothelial GX. Accordingly, decreased expression of GX degrading
enzymes 28, such as heparinase, can cause and/or result in an
(overall) decrease in endothelial GX damage 30, further and/or
synergistically improving, enhancing, and/or supporting healthy GX
1.
[0079] Increased nitric oxide production 26 can also lead to
improved and/or increased oxygen radical scavenging 32, which can
further decrease endothelial GX damage 30, resulting in further
and/or synergistically improved, enhanced, and/or healthy GX 1.
Healthy and/or improved GX 1 also provides an increase in
antioxidant (e.g., enzyme), such as superoxide dismutase (SOD),
specifically, extracellular superoxide dismutase (ecSOD), or SOD3,
binding sites 34. The addition and/or administration of one or more
antioxidants 38, such as SOD, catalase, and/or polyphenols, can
result in a corresponding increase in SOD at the GX 36, a
corresponding increase in catalase at the GX 40 and/or a
corresponding increase in polyphenols at the GX 42. One or more of
increased antioxidants 36, 40, 42, can also result in improved
and/or increased oxygen radical scavenging 32, which can further
decrease endothelial GX damage 30, resulting in further and/or
synergistically improved, enhanced, and/or healthy GX 1.
[0080] The increase in SOD at the GX 36 from the addition and/or
administration of SOD at 38, in particular, coupled with the
increase in antioxidant-binding sites 34 (e.g., for enzymes, such
as SOD) provided by healthy and/or improved GX resulting from the
addition and/or administration of one or more glycocalyx-mimetics
10, such as hyaluronan (HA) and/or fucoidan(s) (FS) and/or one or
more GX precursors and/or building blocks 20, such as glucosamine,
as described above, can enhance and/or increase oxygen radical
scavenging 32, which can further decrease endothelial GX damage 30,
resulting in further and/or synergistically improved, enhanced,
and/or healthy GX 1. This healthy and/or improved GX 1 further
enhances SS signaling 14, thereby enhancing nitric oxide production
26 and expression of relevant genes 16 and downstream products 18
and, coupled with the addition and/or administration of glucosamine
20 results in further production of GX constituents 22 and 24,
which incorporate as GX 12, even further and/or synergistically
improving, enhancing, and/or supporting healthy GX 1, which further
protects against damage thereto, as described above.
[0081] Accordingly, embodiments of the present disclosure,
including compositions comprising one or more components described
herein, can produce synergistic (beneficial) outcomes, effects,
and/or results on the structural and/or functional state and/or
health of endothelial glycocalyx. Such components, while
individually and/or directly impacting the health of endothelial
glycocalyx through one of (A.) repairing damaged glycocalyx, (B.)
protecting against damage to glycocalyx, or (C.) synthesizing new
glycocalyx, can also synergistically enhance the health of
endothelial glycocalyx by feeding, enhancing, or otherwise
affecting one or more additional pathways and/or modes of
action.
[0082] Specifically, inducing and/or effectuating repair (or
patching) of damaged glycocalyx (e.g., through the addition and/or
administration of one or more glycocalyx-mimetics, such as
hyaluronan (HA) and/or fucoidan(s) (FS)), can also protect and/or
defend against damage, degradation, and/or perturbation to the
glycocalyx and/or increase (natural) synthesis of new glycocalyx.
Similarly, protecting and/or defending against damage, degradation,
and/or perturbation to the glycocalyx (e.g., through the addition
and/or administration of one or more antioxidants, such as
superoxide dismutase, catalase, and/or one or more polyphenols),
can also enhance repair (or patching) of damaged glycocalyx and/or
increase (natural) synthesis of new glycocalyx. Likewise,
increasing (natural) synthesis of new glycocalyx (e.g., through the
addition and/or administration of one or more glycocalyx precursors
and/or building blocks, such as glucosamine), can also protect
and/or defend against damage, degradation, and/or perturbation to
the glycocalyx and/or enhance repair (or patching) of damaged
glycocalyx.
[0083] Based on the foregoing description, the combined effect of
certain, individual therapeutic agents or ingredients can be
greater than the literature reported effects of each therapeutic
agent or ingredient alone on glycocalyx repair, synthesis, and/or
protection. Thus, although available literature shows an impact of
the foregoing individual therapeutic agents on vascular and/or
overall health, there is no report or suggestion of any one of them
demonstrating an impact as an (exogenous and/or oral) supplement
having an effect on glycocalyx repair and/or synthesis, let alone a
synergistic effect.
[0084] Methods
[0085] A preferred method of administration comprises administering
(to a patient or subject (e.g., a mammal, such as a human), in need
thereof) an effective amount of one or more compositions described
herein (e.g., in an acceptable pharmaceutical dose and/or dosage
form, such as one, two, three, four, or more capsules, tablets,
pills, etc., or a corresponding amount (e.g., by weight, volume, or
molar) of powder, gel, granules, solution, suspension, tincture,
etc.). Preferably, the compositions are administered orally, but
the compositions may also be formulated for sublingual, rectal,
vaginal, intravenous, subcutaneous, intramuscular, and transdermal
administration as well. Thus, the compositions may be administered
by various methods of delivery, such as but not limited to,
conventional oral dosage forms, prepared drinks, (flavored or
unflavored) drink mixes, aerosols, and intravenous drips. The
compositions may be made using conventional techniques, such as by
mixing the active agents with suitable excipients, such as but not
limited to, binders, fillers, preservatives, disintegrators, flow
regulators, plasticizers, dispersants, emulsifiers, etc. Suitable
food-grade additives, such as but not limited to, sweeteners,
colors, and flavoring agents may also be incorporated to encourage
consumption.
[0086] Embodiments of the present disclosure are not limited to
administration to humans, and may be administered to any animal,
but are preferably administered to mammals. For example, one use
aspect of the present disclosure comprises the administration of
the compositions of the present disclosure to humans. While another
use aspect of the present disclosure comprises the administration
of the compositions of the present disclosure to mammals in the
form of a veterinary composition that may be administered to
bovines, equines, ovines, caprines, canines, felines, and other
domestic animal species.
[0087] Thus, an embodiment of the present disclosure comprises
administering a composition to a mammal comprising a
(therapeutically-) effective amount of one or more of the
components (e.g., active ingredients and/or therapeutic agents)
described herein. For example, an oral dosage form of the
compositions may be administered one or more times a day to achieve
the desired physiological reaction or biological response.
[0088] As described in greater detail herein, each therapeutic
agent is independently helpful for supporting and maintaining a
healthy endothelial glycocalyx, thereby preserving or improving
vascular health. For example, components such as glucosamine can be
limiting reagents (precursor and/or building blocks) in a pathway
for the synthesis of two main constituents of the endothelial
glycocalyx--heparan sulfate and hyaluronan. Accordingly, the
addition of available components such as glucosamine can enhance
and support production of new glycocalyx, and can also support
activities that protect and/or defend the glycocalyx against
structural and/or functional damage, degradation, destruction,
perturbation, etc. and/or repair (e.g., patch) endothelial
glycocalyx at sites of glycocalyx damage, perturbation, etc.
[0089] Components such as hyaluronan and fucoidan can be and/or
function as glycocalyx-mimetics that can repair (e.g., patch)
endothelial glycocalyx at sites of glycocalyx damage, perturbation,
etc. Accordingly, the addition of available components such as
hyaluronan and fucoidan can repair damaged glycocalyx, and can also
support activities that protect and/or defend the glycocalyx
against structural and/or functional damage, degradation,
destruction, perturbation, etc. and/or synthesize and incorporate
new glycocalyx at the endothelium.
[0090] Component such as superoxide dismutase, catalase, and/or
polyphenols can protect and/or defend endothelial glycocalyx
against damage and/or degradation caused by enzymes and/or
oxidants. Accordingly, the addition of components such as
superoxide dismutase, catalase, and/or polyphenols can protect
and/or defend endothelial glycocalyx against damage and/or
degradation, and can also support activities that synthesize and
incorporate new glycocalyx at the endothelium and/or repair (e.g.,
patch) endothelial glycocalyx at sites of glycocalyx damage,
perturbation, etc.
[0091] Such components can be combined in any suitable manner or
fashion, including various amounts (by weight, volume, or molar)
and/or dosage forms to produce one or more compositions of the
present disclosure. The compositions disclosed herein can be made
into any dosage form and administered to a mammal, and more
preferably to a human being. Preferably, an effective amount of one
or more of the active agents can be mixed with appropriate
excipients into the compositions disclosed herein and administered
orally as an acceptable pharmaceutical dosage form, such as a
capsule or tablet, though any suitable dosage form can be used in
some embodiments. An oral dosage form of the compositions may be
administered one or more times a day to achieve the desired
physiological reaction or biological response. Optionally, the
amount of each therapeutic agent or ingredient may be adjusted in
each individual dosage form, and taken as needed to maintain the
desired level of effectiveness.
[0092] Vascular health, particularly health of the endothelial
glycocalyx, can be assessed via suitable detection or modulation of
the endothelial glycocalyx. Methods of such detection and suitable
biosensor devices are described in U.S. Pat. No. 8,759,095, the
entirety of which is incorporated by reference herein. One suitable
method of detection includes the use of the GLYCOCHECK.RTM.
Microvascular Health Monitor available from MicroVascular Health
Solutions, which is a complete imaging solution for screening a
subject's or patient's perfused boundary region ("PBR") by
accurately measuring and monitoring changes in the PBR in real
time. The PBR in microvessels is the cell-poor layer which results
from phase separation between the flowing red blood cells ("RBC")
and plasma, and represents the most luminal part of the endothelial
glycocalyx that allows cell penetration. Loss of endothelial
glycocalyx integrity allows for deeper penetration by the outer
edge of the RBC-perfused lumen, thereby increasing PBR, resulting
in increased vulnerability of the endothelium.
[0093] PBR is thus a measure for the depth of penetration of red
blood cells in the glycocalyx (or into the region where healthy
glycocalyx should be found). Low values of PBR indicate a
mechanically stable glycocalyx that protects the vessel wall
against damage by circulating blood cells and other constituents,
molecules or reagents circulating in the blood. The PBR is the main
readout parameter calculated by the GLYCOCHECK.RTM. software.
Calculation of further qualitative and/or quantitative (e.g.,
scores or numeric) measurements or representations can be performed
manually or automatically (e.g., by the GLYCOCHECK.RTM. software).
One such parameter--the Micro-Vascular Health Score (MVHS)--is
discussed in further detail below.
[0094] The measurement may be performed non-invasively with a
digital camera placed under the patient's tongue, under-arm area,
vagina, rectum, or other (highly) vascular area. It is noted that
such measurements, while providing a local read of blood vessel
structural features is highly indicative of an overall and/or
systemic vascular landscape. For instance, measurements taken from
one of the aforementioned locations can be confirmed (as accurate
and representative of systemic vascular landscape) by measurement
at other locations.
[0095] Other measurable indicators include (blood) volume, width
and dimension of the glycocalyx, vessel density, the number of
perfused vessels per tissue surface versus total number of vessels,
RBC filling percentage, capillary volume reserve, enzyme activity,
and presence or absence of glycocalyx contributing constituents,
nitric oxide concentration in the blood, etc. Changes in any of the
foregoing parameters, alone or in combination, are useful
indicators for assessing vascular health.
[0096] Glycocalyx health may also be assessed via biological
samples. For example, the status, volume or dimension of the
glycocalyx and/or the activity of one or more enzymes of glycocalyx
metabolism, may be performed via in vitro assays on a biological
sample removed from a subject. Such in vitro assays are generally
easy to perform and amenable to high-throughput analysis via
techniques known in the art. Suitable samples include, but are not
limited to, samples of whole blood, plasma or serum obtained from a
subject. In vivo, such fluids directly contact the vascular
endothelial tissue and are responsive to glycocalyx perturbation.
Some glycocalyx indicators, for example glycocalyx associated
lectin-like proteins, may also be detectable in urine.
[0097] Thus, profiles of lectin-like proteins that normally
associate with the glycocalyx, as determined in the foregoing
samples can provide suitable information about glycocalyx volume or
dimension and/or molecular accessibility. Glycocalyx perturbation
may also be diagnosed by detecting the presence and/or
concentrations of glycocalyx derived molecules, such as but not
limited to: oligo- or poly-saccharides, glycosaminoglycans,
hyaluronan, heparan sulfate or proteoglycans; enzymes that catalyze
glycocalyx anabolism or catabolism, such as hyaluronidase; and/or
endogenous or exogenous substances that can become incorporated or
otherwise associated with the glycocalyx.
[0098] More invasive techniques for assessing vascular health
include invasive microscopic visualization techniques which
comprise the injection of fluorescent labels attached to
glycocalyx-bound proteins or glycocalyx permeating tracer
molecules, and are contemplated herein.
[0099] As described above, the GLYCOCHECK.RTM. system can be used
to measure PBR in subjects and/or patients. A PBR score can be
calculated therefrom, providing an indication of the structural
stability of the endothelial glycocalyx. In addition, (the in vivo
camera of) the GLYCOCHECK.RTM. system can be used to measure
capillary/blood vessel density in subjects and/or patients,
providing an indication of overall number of capillary blood
vessels that are visible (and red blood cell-perfused) in the
captured region. A capillary red blood cell filling percentage can
also be measured by the GLYCOCHECK.RTM. system in subjects and/or
patients, providing an indication of the amount of red blood cells
per blood vessel. Taken together, these indicators can be used to
calculate a microvascular health score (MVHS) of the subjects
and/or patients (e.g., population), which is directly proportional
to blood vessel density, directly proportional to the capillary red
blood cell filling percentage, and inversely proportional to PBR
score.
[0100] The following results were obtained in a population of
self-proclaimed "healthy" humans (with no known disease state or
underlying health concerns) using the via GLYCOCHECK.RTM. system. A
pretreatment baseline (BL) measurement was taken for each of the
following vascular/glycocalyx health indicators: PBR; blood vessel
density; and red blood cell filling percentage, and/or score(s) or
measurements calculated therefrom. MVHS was also calculated from
the foregoing indicators. The population averages of each indicator
were normalized to 100% and plotted in FIG. 5 as a pretreatment
baseline measurement of vascular/glycocalyx health (BL). The
population was then orally administered a daily (4.times.) oral
dosage of the composition described in Example 1 over a treatment
course of 4 months, with the foregoing indicators measured and/or
calculated after one, two, three, and four months, respectively.
The (4.times.) dosage included about 1500 mg of glucosamine sulfate
per day, about 425 mg of fucoidan sulfate per day, about 70 mg of
sodium hyaluronate per day, and about 480 mg of a mixture of
antioxidants (superoxide dismutase, catalase, and polyphenols), per
day.
[0101] As illustrated in FIG. 5, over the course of treatment, the
population (on average) demonstrated an overall decrease in the PBR
score (e.g., reflecting a more stable glycocalyx), an overall
increase in the RBC filling percentage, indicating a per capita
increase in the amount of red blood cells per blood vessel, and a
significant increase in the number of capillaries visible and red
blood cell-perfused. This blood vessel density increase can be seen
as early as one month into the course of treatment and continues to
improve month after month.
[0102] Accordingly, compositions of the present disclosure can
substantially improve blood vessel density (i.e., the number of
capillaries (e.g., perfused with red blood cells)), can increase
the red blood cell filling percentage of such blood vessels, and
can improve the stability of endothelial glycocalyx (as evidenced
by a decrease in perfused boundary region). The MVHS based on these
measurements and/or calculations improved substantially (e.g., by
about 50%) over the course of treatment, beginning at the first
month (e.g., about 5-10% improvement), to the second month (e.g.,
about 10-15% improvement), to the third month (e.g., about 30%
improvement), and so forth. Accordingly, embodiments of the present
disclosure can produce a substantial and/or significant (e.g.,
between about 5% -50%) improvement in microvascular health (over a
one-month, two-month, three-month, and/or four-month treatment
(comprising daily doses of the composition described in Example
1)).
[0103] These results indicate a surprising and unexpected
improvement in the overall (micro)vascular health and specific
indications described above following treatment with composition
according to embodiments of the present disclosure.
[0104] It will also be appreciated that, based on the results
presented in FIG. 10, further improvement in microvascular health
is also contemplated herein. Indeed, because the microvascular
health indicators have not plateaued by the fourth month of
treatment, one of ordinary skill in the art would expect the level
of such health indicators to continue improving over an additional
course of treatment (e.g., five-months, six-months, seven-months,
eight-months, nine-months, ten-months, eleven-months,
twelve-months, or more).
[0105] The foregoing embodiments and examples are illustrative in
nature and non-restrictive. The present disclosure may be embodied
in other specific compositions without departing from the spirit,
scope or attributes thereof. Thus, it will be readily apparent to
those skilled in the art that modifications, derivations and
improvements may be made without departing from the scope of the
disclosure, and such modifications, derivations and improvements
are intended to fall within the full scope and protection of the
appended claims. Other equivalents to the specific embodiments
disclosed herein may be recognizable to those skilled in the art
and are also intended to fall within the full scope and protection
of the appended claims.
[0106] In addition to the foregoing, patients or subjects treated
with compositions of the present disclosure show a decrease in
blood pressure and/or an increase in blood (plasma) nitric oxide
levels, consistent with the proposed role of endothelial
(micro(vascular)) glycocalyx and/or the flow chart depicted in FIG.
4.
[0107] Various alterations and/or modifications of the inventive
features illustrated herein, and additional applications of the
principles illustrated herein, which would occur to one skilled in
the relevant art and having possession of this disclosure, can be
made to the illustrated embodiments without departing from the
spirit and scope of the invention as defined by the claims, and are
to be considered within the scope of this disclosure. Thus, while
various aspects and embodiments have been disclosed herein, other
aspects and embodiments are contemplated. While a number of methods
and components similar or equivalent to those described herein can
be used to practice embodiments of the present disclosure, only
certain components and methods are described herein.
[0108] It will also be appreciated that systems, processes, and/or
products according to certain embodiments of the present disclosure
may include, incorporate, or otherwise comprise properties features
(e.g., components, members, elements, parts, and/or portions)
described in other embodiments disclosed and/or described herein.
Accordingly, the various features of certain embodiments can be
compatible with, combined with, included in, and/or incorporated
into other embodiments of the present disclosure. It will be
understood that changes may be made in the function and arrangement
of elements discussed without departing from the spirit and scope
of the disclosure, and various embodiments may omit, substitute, or
add other procedures or components as appropriate. For instance,
the methods described may be performed in an order different from
that described, and various steps may be added, omitted, or
combined.
[0109] Thus, disclosure of certain features relative to a specific
embodiment of the present disclosure should not be construed as
limiting application or inclusion of said features to the specific
embodiment. Rather, it will be appreciated that other embodiments
can also include said features without necessarily departing from
the scope of the present disclosure. Moreover, unless a feature is
described as requiring another feature in combination therewith,
any feature herein may be combined with any other feature of a same
or different embodiment disclosed herein. Furthermore, various
well-known aspects of illustrative systems, processes, products,
and the like are not described herein in particular detail in order
to avoid obscuring aspects of the example embodiments. Such aspects
are, however, also contemplated herein.
[0110] The present disclosure may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims
rather than by the foregoing description. Each of the appended
claims, as well as the recited elements thereof, is intended to be
combinable with any other claims and/or element(s) in any suitable
combination or dependency without regard to the dependency in which
said claims are presented. While certain embodiments and details
have been included herein and in the attached disclosure for
purposes of illustrating embodiments of the present disclosure, it
will be apparent to those skilled in the art that various changes
in the methods and apparatus disclosed herein may be made without
departing from the scope of the invention, which is defined in the
appended claims. All changes which come within the meaning and
range of equivalency of the claims are to be embraced within their
scope.
* * * * *