U.S. patent application number 16/638834 was filed with the patent office on 2020-06-18 for reduction of advanced glycation endproducts from bodily fluids.
The applicant listed for this patent is CYTOSORBENTS CORPORATION. Invention is credited to Vincent CAPPONI, Phillip P. CHAN, Jorg SCHEIER, Andreas Viktor SIMM, Christian STEINER.
Application Number | 20200188427 16/638834 |
Document ID | / |
Family ID | 65527854 |
Filed Date | 2020-06-18 |
United States Patent
Application |
20200188427 |
Kind Code |
A1 |
SIMM; Andreas Viktor ; et
al. |
June 18, 2020 |
REDUCTION OF ADVANCED GLYCATION ENDPRODUCTS FROM BODILY FLUIDS
Abstract
The invention concerns removing advanced glycation end products
from a bodily fluid by contacting the bodily fluid with a
sorbent.
Inventors: |
SIMM; Andreas Viktor;
(Salzatal OT Lieskau, DE) ; SCHEIER; Jorg;
(Monmouth Junction, NJ) ; STEINER; Christian;
(Monmouth Junction, NJ) ; CAPPONI; Vincent;
(Monmouth Junction, NJ) ; CHAN; Phillip P.;
(Cherry Hill, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CYTOSORBENTS CORPORATION |
Monmouth Junction |
NJ |
US |
|
|
Family ID: |
65527854 |
Appl. No.: |
16/638834 |
Filed: |
August 30, 2018 |
PCT Filed: |
August 30, 2018 |
PCT NO: |
PCT/US2018/048678 |
371 Date: |
February 13, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62552424 |
Aug 31, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 20/3208 20130101;
A61K 31/79 20130101; B01J 20/28078 20130101; B01J 20/262 20130101;
B01J 20/28069 20130101; B01D 17/00 20130101; A61K 31/717 20130101;
A61K 2121/00 20130101; B01J 20/267 20130101; B01J 20/261 20130101;
A61K 31/78 20130101; B01J 20/3278 20130101 |
International
Class: |
A61K 31/79 20060101
A61K031/79; A61K 31/78 20060101 A61K031/78; A61K 31/717 20060101
A61K031/717 |
Claims
1. A method of removing advanced glycation end products from a
bodily fluid comprising contacting said bodily fluid with a
sorbent.
2. The method of claim 1, wherein the sorbent comprises a plurality
of pores ranging from 50 .ANG. to 40,000 .ANG. with a pore volume
of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm.
3. The method of claim 1 or claim 2, wherein the sorbent is
biocompatible.
4. The method of any one of claims 1-3, wherein the bodily fluid
comprises saliva, nasopharyngeal fluid, blood, plasma, serum,
saliva, gastrointestinal fluid, bile, cerebrospinal fluid,
pericardial, vaginal fluid, seminal fluid, prostatic fluid,
peritoneal fluid, pleural fluid, urine, synovial fluid,
interstitial fluid, intracellular fluid, extracellular fluid,
lymph, mucus, or vitreous humor.
5. The method of any one of claims 1-4, wherein the sorbent has a
pore structure such that the total pore volume of pore size in the
range of 50 .ANG. to 40,000 .ANG. is greater than 0.5 cc/g to 5.0
cc/g dry sorbent; wherein the ratio of pore volume between 50 .ANG.
to 40,000 .ANG. (pore diameter) to pore volume between 1,000 .ANG.
to 10,000 .ANG. (pore diameter) of the sorbent is smaller than
2:1.
6. The method of any one of claims 1-5, wherein the sorbent
comprises at least one crosslinking agent and at least one
monomer.
7. The method of any one of claims 1-5, wherein the sorbent
comprises at least one crosslinking agent, at least one monomer, at
least one dispersing agent and at least one porogen.
8. The method of claim 7, wherein the dispersing agent is one or
more of hydroxyethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),
poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),
poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethyl
acrylate), poly(diethylaminoethyl methacrylate),
poly(diethylaminoethyl acrylate), poly(vinyl alcohol),
poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), or
salts of poly(acrylic acid).
9. The method of claim 6 or 7, wherein the crosslinking agent is
one or more of divinylbenzene, trivinylbenzene, divinylnaphthalene,
trivinylcyclohexane, divinylsulfone, trimethylolpropane
trimethacrylate, trimethylolpropane dimethacrylate,
trimethylolpropane triacrylate, trimethylolpropane diacrylate,
pentaerythrital dimethacrylates, pentaerythrital trimethacrylates,
pentaerythrital, tetramethacrylates, pentaerythritol diacrylates,
pentaerythritol triiacrylates, pentaerythritol tetraacrylates,
dipentaerythritol dimethacrylates, dipentaerythritol
trimethacrylates, dipentaerythritol tetramethacrylates,
dipentaerythritol diacrylates, dipentaerythritol triacrylates,
dipentaerythritol tetraacrylates, or divinylformamide.
10. The method of claim 6 or 7, wherein the monomer is one or more
of divinylbenzene and ethylvinylbezene, styrene, ethylstyrene,
acrylonitrile, butyl methacrylate, octyl methacrylate, butyl
acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl
methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene,
vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl
acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane,
divinylsulfone, trimethylolpropane trimethacrylate,
trimethylolpropane dimethacrylate, trimethylolpropane triacrylate,
trimethylolpropane diacrylate, pentaerythritol dimethacrylate,
pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate,
pentaerythritol diacrylate, pentaerythritol triiacrylate,
pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate,
dipentaerythritol trimethacrylate, dipentaerythritol
tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol
triacrylate, dipentaerythritol tetraacrylate, divinylformamide and
mixtures thereof.
11. The method of claim 7, wherein the porogen is one or more of
benzyl alcohol, cyclohexane, cyclohexanol, cyclohexanol/toluene
mixtures, cyclohexanone, decane, decane/toluene mixtures,
di-2-ethylhexylphosphoric acid, di-2-ethylhexyl phthalate,
2-ethyl-1-hexanoic acid, 2-ethyl-1-hexanol,
2-ethyl-1-hexanol/n-heptane mixtures, 2-ethyl-1-hexanol/toluene
mixtures, isoamyl alcohol, n-heptane, n-heptane/ethylacetate,
n-heptane/isoamyl acetate, n-heptane/tetraline mixtures,
n-heptane/toluene mixtures, n-hexane/toluene mixtures, pentanol,
poly(styrene-co-methyl methacrylate)/dibutyl phthalate,
polystyrene/2-ethyl-1-hexanol mixtures, polystyrene/dibutyl
phthalate, polystyrene/n-hexane mixtures, polystyrene/toluene
mixtures, toluene, tri-n-butylphosphate,
1,2,3-trichloropropane/2-ethyl-1-hexanol mixtures, 2,2,4-trimethyl
pentane (isooctane), trimethyl pentane/toluene mixtures,
poly(propylene glycol)/toluene mixtures poly(propylene
glycol)/cyclohexanol mixtures, and poly(propylene
glycol)/2-ethyl-1-hexanol mixtures.
12. The method of any one of claims 1-11 wherein the contacting
occurs ex vivo.
13. The method of any one of claims 1-11 wherein the contacting
occurs in vivo.
14. The treatment of a degenerative disease comprising the method
of any one of claims 1-13.
15. The treatment of claim 14 wherein the degenerative disease is
Alzheimer's disease.
16. The treatment of claim 14, wherein the degenerative disease is
a macular degeneration.
17. The treatment of claim 14, wherein the degenerative disease is
osteoarthritis.
18. The treatment of claim 14, wherein the degenerative disease is
atherosclerosis.
19. The treatment of claim 14, wherein the degenerative disease is
heart disease or kidney failure.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit of U.S. Patent
Application No. 62/552,424 filed on Aug. 31, 2017, the disclosure
of which is incorporated herein in its entirety.
TECHNICAL FIELD
[0002] The invention concerns reduction of advanced glycation end
products from bodily fluids.
BACKGROUND
[0003] Degenerative diseases as well as aging are mainly based on a
life-long accumulation of molecular damages within molecules, cells
and tissues. Important examples of damaging structures are the
advanced glycation end products (AGEs).
[0004] Advanced glycation end products (AGEs), pathophysiological
important posttranslational modifications, are formed in vivo by a
non-enzymatic reaction of proteins with reactive carbohydrates and
accumulate during aging. They are discussed to be responsible for
degenerative diseases. Glycation modifies the structure and
function of proteins and induces tissue stiffening via
crosslinking. Soluble AGEs can bind to receptors like the receptor
for advanced glycation end products (RAGE). Binding to RAGE induces
on the one hand the expression of RAGE itself and on the other
hand, the expression of proinflammatory cytokines leading to a
long-lasting inflammatory response. This may have an impact on
aging, as aging is mostly connected to inflammation (Inflammaging).
RAGE-knock out mice are protected in models of sepsis (increased
survival). In the cardiovascular system, AGEs are a major cause of
cardiac and vascular dysfunction.
[0005] High levels of AGEs have been linked with the development of
a variety of diseases including diabetes, heart disease, kidney
failure, Alzheimer's and macular degeneration. There is a need in
the art for methods that treat, prevent or low the progression of
diseases associated with AGEs.
SUMMARY
[0006] In some embodiments, the invention concerns method of
removing advanced glycation end products from a bodily fluid
comprising contacting the bodily fluid with a sorbent.
[0007] In certain embodiments, the invention concerns treatment of
a degenerative disease by removing advanced glycation end products
from a bodily fluid comprising contacting the bodily fluid with a
sorbent
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1a shows that Cytosorbents Adsorber do not bind
Acetyllysine efficiently.
[0009] FIG. 1b shows that Cytosorbents Adsorber bind AGEs (CIVIL)
efficiently.
[0010] FIG. 2 shows concentration of 1 protein (25 kD): by staining
CIVIL green and Acetyllysine red (Odyssee system), it can be
clearly seen that after a passage through an Cytosorbents adsorber,
the green (GFP) modified proteins disappeared whereas red
(Acetyllysine) modified proteins are still detectable.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0011] The present invention may be understood more readily by
reference to the following detailed description taken in connection
with the accompanying figures and examples, which form a part of
this disclosure. It is to be understood that this invention is not
limited to the specific materials, devices, methods, applications,
conditions or parameters described and/or shown herein, and that
the terminology used herein is for the purpose of describing
particular embodiments by way of example only and is not intended
to be limiting of the claimed invention. The term "plurality", as
used herein, means more than one. When a range of values is
expressed, another embodiment includes from the one particular
value and/or to the other particular value. Similarly, when values
are expressed as approximations, by use of the antecedent "about,"
it will be understood that the particular value forms another
embodiment. All ranges are inclusive and combinable.
[0012] It is to be appreciated that certain features of the
invention which are, for clarity, described herein in the context
of separate embodiments, may also be provided in combination in a
single embodiment. Conversely, various features of the invention
that are, for brevity, described in the context of a single
embodiment, may also be provided separately or in any
subcombination. Further reference to values stated in ranges
include each and every value within that range.
[0013] The term "biocompatible" is defined to mean the sorbent is
capable of coming in contact with physiologic fluids, living
tissues, or organisms without producing unacceptable clinical
changes during the time that the sorbent is in contact with the
physiologic fluids, living tissues, or organisms. In some
embodiments, it is intended that the sorbent is tolerated by the
gut and alimentary canal of the organism. The sorbents of the
present invention are preferably non-toxic. A biocompatible sorbent
may be a biodegradable polymer, a resorbable polymer, or both.
[0014] As used herein, the term "sorbent" includes adsorbents and
absorbents.
[0015] As used herein, the term "physiologic fluids" are liquids
that originate from the body and can include, but are not limited
to, nasopharyngeal, oral, esophageal, gastric, pancreatic, hepatic,
pleural, pericardial, peritoneal, intestinal, prostatic, seminal,
vaginal secretions, as well as tears, saliva, lung or bronchial
secretions, mucus, bile, blood, lymph, plasma, serum, synovial
fluid, cerebrospinal fluid, urine, and interstitial, intracellular,
and extracellular fluid, such as fluid that exudes from burns or
wounds.
[0016] As used herein, the singular forms "a," "an," and "the"
include the plural, and reference to a particular numerical value
includes at least that particular value, unless the context clearly
dictates otherwise. When a range of values is expressed, another
embodiment includes from the one particular value and/or to the
other particular value. Similarly, when values are expressed as
approximations, by use of the antecedent "about," it will be
understood that the particular value forms another embodiment. All
ranges are inclusive and combinable.
[0017] Unless defined otherwise, all other technical and scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art pertinent to the methods and
compositions described. As used herein, the following terms and
phrases have the meanings ascribed to them unless specified
otherwise.
[0018] The phrase "advanced glycation end products" represents
proteins or lipids that become glycated. AGEs are harmful compounds
that can be formed when protein or fat combine with sugar in the
bloodstream in a process called glycation. AGEs can also be formed
in foods, particularly foods exposed to high temperatures that can
occur with grilling, frying or toasting,
[0019] RAGE (receptor for advanced glycation end products) is a
receptor that is able to bind advanced glycation end products.
While not wanting to be bound by theory, it is believed that RAGE
comprises a 35 kilodalton transmembrane receptor of the
immunoglobulin super family.
Sorbents
[0020] In some embodiments, the sorbent comprises at least one
crosslinking agent and at least one monomer. In other embodiments,
the sorbent comprises at least one crosslinking agent, at least one
monomer, at least one dispersing agent and at least one
porogen.
[0021] Preferred sorbents comprise polymers derived from one or
more monomers selected from divinylbenzene and ethylvinylbezene,
styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl
methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate,
cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene,
vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl
methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene,
trivinylcyclohexane, divinylsulfone, trimethylolpropane
trimethacrylate, trimethylolpropane dimethacrylate,
trimethylolpropane triacrylate, trimethylolpropane diacrylate,
pentaerythritol dimethacrylate, pentaerythritol trimethacrylate,
pentaerythritol tetramethacrylate, pentaerythritol diacrylate,
pentaerythritol triiacrylate, pentaerythritol tetraacrylate,
dipentaerythritol dimethacrylate, dipentaerythritol
trimethacrylate, dipentaerythritol tetramethacrylate,
dipentaerythritol diacrylate, dipentaerythritol triacrylate,
dipentaerythritol tetraacrylate, divinylformamide and mixtures
thereof.
[0022] In certain embodiments, the sorbent is a biocompatible
macroporous polymeric sorbent comprising residues of one or more
monomers from the group comprising divinylbenzene and
ethylvinylbezene, styrene, and ethylstyrene.
[0023] Some preferred polymers comprise ion exchange polymers.
[0024] Some preferred polymers comprise cellulosic polymers.
Suitable polymers include cross-linked dextran gels such as
Sephadex.TM..
[0025] Certain preferred polymers comprise porous highly
crosslinked styrene or divinylbenzene copolymers. Some of these
copolymers comprise a macroporous or mesoporous
styrene-divinylbenzene-ethylstyrene copolymer subjected to a
partial chloromethylation to a chlorine content of up to 7%
molecular weight. Other of these polymers are a hypercrosslinked
polystyrene produced from crosslinked styrene copolymers by an
extensive chloromethylation and a subsequent post-crosslinking by
treating with a Friedel-Crafts catalyst in a swollen state. Yet
other of these polymers are a hypercrosslinked polystyrene produced
from crosslinked styrene copolymers by an extensive additional
post-crosslinking in a swollen state with bifunctional crosslinking
agents selected from the group comprising of monochlorodimethyl
ether and p-xylilene dichloride.
[0026] One preferred sorbent is Cytosorb.TM. marketed by
Cytosorbents.
[0027] Some polymers useful in the practice of the invention are
hydrophilic self-wetting polymers that can be administered as dry
powder containing hydrophilic functional groups such as, amines,
hydroxyl, sulfonate, and carboxyl groups.
[0028] Certain polymers useful in the invention are macroporous
polymers prepared from the polymerizable monomers of styrene,
divinylbenzene, ethylvinylbenzene, and the acrylate and
methacrylate monomers such as those listed below by manufacturer.
Rohm and Haas Company, (now part of Dow Chemical Company): (i)
macroporous polymeric sorbents such as Amberlite.TM. XAD-1,
Amberlite.TM. XAD-2, Amberlite.TM. XAD-4, Amberlite.TM. XAD-7,
Amberlite.TM. XAD-7HP, Amberlite.TM. XAD-8, Amberlite.TM. XAD-16,
Amberlite.TM. XAD-16 HP, Amberlite.TM. XAD-18, Amberlite.TM.
XAD-200, Amberlite.TM. XAD-1180, Amberlite.TM. XAD-2000,
Amberlite.TM. XAD-2005, Amberlite.TM. XAD-2010, Amberlite.TM.
XAD-761, and Amberlite.TM. XE-305, and chromatographic grade
sorbents such as Amberchrom.TM. CG 71,s,m,c, Amberchrom.TM. CG
161,s,m,c, Amberchrom.TM. CG 300,s,m,c, and Amberchrom.TM. CG
1000,s,m,c. Dow Chemical Company: Dowex.TM. Optipore.TM. L-493,
Dowex.TM. Optipore.TM. V-493, Dowex.TM. Optipore.TM. V-502,
Dowex.TM. Optipore.TM. L-285, Dowex.TM. Optipore.TM. L-323, and
Dowex.TM. Optipore.TM. V-503. Lanxess (formerly Bayer and Sybron):
Lewatit.TM. VPOC 1064 MD PH, Lewatit.TM. VPOC 1163, Lewatit.TM. OC
EP 63, Lewatit.TM. S 6328A, Lewatit.TM. OC 1066, and Lewatit.TM.
60/150 MIBK. Mitsubishi Chemical Corporation: Diaion.TM. HP 10,
Diaion.TM. HP 20, Diaion.TM. HP 21, Diaion.TM. HP 30, Diaion.TM. HP
40, Diaion.TM. HP 50, Diaion.TM. SP70, Diaion.TM. SP 205,
Diaion.TM. SP 206, Diaion.TM. SP 207, Diaion.TM. SP 700, Diaion.TM.
SP 800, Diaion.TM. SP 825, Diaion.TM. SP 850, Diaion.TM. SP 875,
Diaion.TM. HP 1MG, Diaion.TM. HP 2MG, Diaion.TM. CHP 55A,
Diaion.TM. CHP 55Y, Diaion.TM. CHP 20A, Diaion.TM. CHP 20Y,
Diaion.TM. CHP 2MGY, Diaion.TM. CHP 20P, Diaion.TM. HP 20SS,
Diaion.TM. SP 20SS, and Diaion.TM. SP 207SS. Purolite Company:
Purosorb.TM. AP 250 and Purosorb.TM. AP 400.
[0029] The present invention does not rely on charge or a
ligand-receptor complex binding reaction to inhibit or reduce
pathogen toxicity. A polymer using acid functional group(s)
attached to the polymer backbone to bind Clostridium difficile
Toxin A and Toxin B is described by Bacon Kurtz et al. (U.S. Pat.
No. 6,890,523). The interaction in Kurtz is ionic where a
hydrophobic or hydrophilic group attached to the polymer binds the
toxin. Chamot et al. (US Patent Application 2006/009169) describe
using inorganic polymer particles linked to a toxin binding moiety
comprised of oligosaccharide sequences that bind C. difficile Toxin
A and Toxin B. Also described is a toxin binding surface pore size
2.times. larger than toxin diameter. Chamot described
oligosaccharide moieties that bind toxins to form a
ligand/receptor-like complex.
[0030] The polymer materials used as the sorbent are generally not
metabolizable by human and animal, but may be synthesized from
materials characterized as being a biodegradable polymer, a
resorbable polymer, or both. Certain polymers may be irregular or
regular shaped particulates such as powders, beads, or other forms
with a diameter in the range of 0.1 micron meters to 2
centimeters.
[0031] The polymers used in the instant invention preferably have a
biocompatible and hemocompatible exterior surface coatings but are
not absolutely necessary, especially in certain circumstances, such
as oral or rectal administration. Certain of these coatings are
covalently bound to the polymer particle (beads, for example) by
free-radical grafting. The free-radical grafting may occur, for
example, during the transformation of the monomer droplets into
polymer beads. The dispersant coating and stabilizing the monomer
droplets becomes covalently bound to the droplet surface as the
monomers within the droplets polymerize and are converted into
polymer. Biocompatible and hemocompatible exterior surface coatings
can be covalently grafted onto the preformed polymer beads if the
dispersant used in the suspension polymerization is not one that
imparts biocompatibility or hemocompatibility. Grafting of
biocompatible and hemocompatible coatings onto preformed polymer
beads is carried out by activating free-radical initiators in the
presence of either the monomers or low molecular weight oligomers
of the polymers that impart biocompatibility or hemocompatibility
to the surface coating.
[0032] Porogens that may be used in the invention may be one or
more of benzyl alcohol, cyclohexane, cyclohexanol,
cyclohexanol/toluene mixtures, cyclohexanone, decane,
decane/toluene mixtures, di-2-ethylhexylphosphoric acid,
di-2-ethylhexyl phthalate, 2-ethyl-1-hexanoic acid,
2-ethyl-1-hexanol, 2-ethyl-1-hexanol/n-heptane mixtures,
2-ethyl-1-hexanol/toluene mixtures, isoamyl alcohol, n-heptane,
n-heptane/ethylacetate, n-heptane/isoamyl acetate,
n-heptane/tetraline mixtures, n-heptane/toluene mixtures,
n-hexane/toluene mixtures, pentanol, poly(styrene-co-methyl
methacrylate)/dibutyl phthalate, polystyrene/2-ethyl-1-hexanol
mixtures, polystyrene/dibutyl phthalate, polystyrene/n-hexane
mixtures, polystyrene/toluene mixtures, toluene,
tri-n-butylphosphate, 1,2,3-trichloropropane/2-ethyl-1-hexanol
mixtures, 2,2,4-trimethyl pentane (isooctane), trimethyl
pentane/toluene mixtures, poly(propylene glycol)/toluene mixtures
poly(propylene glycol)/cyclohexanol mixtures, and poly(propylene
glycol)/2-ethyl-1-hexanol mixtures.
[0033] The present biocompatible sorbent compositions are comprised
of a plurality of pores. The biocompatible sorbents are designed to
adsorb a broad range of toxins from less than 1 kDa to 1,000 kDa.
While not intending to be bound by theory, it is believed the
sorbent acts by sequestering molecules of a predetermined molecular
weight within the pores. The size of a molecule that can be
adsorbed by the polymer will increase as the pore size of the
polymer increases. Conversely, as the pore size is increased beyond
the optimum pore size for adsorption of a given molecule,
adsorption of the protein may or will decrease.
[0034] In one embodiment a porous polymer that absorbs small to
midsize protein molecules equal to or less than 50,000 Daltons (50
kDa) and excludes absorption of large blood proteins comprises the
pore structure such that the total pore volume of pore size in the
range of 50 .ANG. to 40,000 .ANG. are in the range of 0.5 cc/g to
5.0 cc/g dry sorbent. The sorbent has a pore structure such that
the total pore volume of pore size in the range of 50 .ANG. to
40,000 .ANG. is greater than 0.5 cc/g to 5.0 cc/g dry sorbent;
wherein the ratio of pore volume between 50 .ANG. to 40,000 .ANG.
(pore diameter) to pore volume between 100 .ANG. to 1,000 .ANG.
(pore diameter) of the sorbent is smaller than 3:1.
[0035] In another embodiment a porous polymer that optimally
absorbs midsize to large size protein molecules of approximately
300,000 Daltons and excludes or minimizes absorption of very large
blood proteins comprises the pore structure such that the total
pore volume of pore size in the range of 50 .ANG. to 40,000 .ANG.
are in the range of 0.5 cc/g to 5.0 cc/g dry sorbent. The sorbent
has a pore structure such that the total pore volume of pore size
in the range of 50 A to 40,000 .ANG. is greater than 0.5 cc/g to
5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50
.ANG. to 40,000 .ANG. (pore diameter) to pore volume between 1,000
.ANG. to 10,000 .ANG. (pore diameter) of the sorbent is smaller
than 2:1.
[0036] In another embodiment a porous polymer that optimally
absorbs very large size protein molecules equal to or less than
1,000,000 Daltons and excludes or minimizes absorption of very
large blood proteins comprises the pore structure such that the
total pore volume of pore size in the range of 50 .ANG. to 40,000
.ANG. are in the range of 0.5 cc/g to 5.0 cc/g dry sorbent. The
sorbent has a pore structure such that the total pore volume of
pore size in the range of 50 .ANG. to 40,000 .ANG. is greater than
0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume
between 50 .ANG. to 40,000 .ANG. (pore diameter) to pore volume
between 10,000 .ANG. to 40,000 .ANG. (pore diameter) of the sorbent
is smaller than 3:1.
Treatments
[0037] Degenerative diseases as well as aging are believed to
mainly be based on a life-long accumulation of molecular damages
within molecules, cells and tissues. An important example of
damaging structures are the advanced glycation end products (AGEs).
It is believed that AGEs may be related to many degenerative
diseases. Illustrative degenerative disease are Alzheimer's
disease, macular degeneration, osteoarthritis, atherosclerosis,
heart disease and kidney failure. The instant methods and sorbents
may be useful in treatment of the disease or may be used
prophylactically.
[0038] The sorbent may be contained in a cartridge and the bodily
fluid treated ex vivo. For example, blood or other bodily fluid is
pumped out of the body, directly through a CytoSorb.TM.
hemoperfusion cartridge where the beads remove AGEs, and the
purified fluid is then pumped back into the body.
[0039] In some embodiments, the bodily fluid comprises saliva,
nasopharyngeal fluid, blood, plasma, serum, saliva,
gastrointestinal fluid, bile, cerebrospinal fluid, pericardial,
vaginal fluid, seminal fluid, prostatic fluid, peritoneal fluid,
pleural fluid, urine, synovial fluid, interstitial fluid,
intracellular fluid, extracellular fluid, lymph, mucus, or vitreous
humor.
[0040] In other embodiments, the treatment may be in vivo. For
example, the compositions may be given orally, rectally or via a
feeding tube. The sorbent can be supplied as a dry powder or other
dry particulate capable of being wetted externally or internally in
the alimentary canal, including in the gastric or enteric
environment, with or without the addition of wetting agents such as
ethyl or isopropyl alcohol, potable liquids such as water, or other
carrier fluid. Other possible routes of administration include
subcutaneous or transdermal delivery. In some embodiments,
administration is topical. Such methods include ophthalmic
administration, administration to skin or wounds, direct
administration into a body cavity or joint, and delivery to mucous
membranes such as nasal, oral, vaginal and rectal delivery or other
delivery to the alimentary canal. In some embodiments, the
treatment is extracorporeal. Extracorporeal administration would
include removal of inflammatory mediators from blood or physiologic
fluids by circulating the fluids through a device containing
sorbent and returning it back to the body. In some embodiments,
such methods include local or systemic administration through a
parenteral route. Parenteral administration includes intravenous,
intraarterial, subcutaneous, intraperitoneal or intramuscular
injection or infusion; or intracranial (including intrathecal or
intraventricular, administration).
[0041] The sorbent may be formulated as for example, a powder, a
tablet, a capsule, a solution, a slurry, an emulsion, a
suppository, or in a food substance. The sorbent may be packaged in
portable bottles, vials, blister packs, bags, pouches, or other
container that allows for either single or multiple dosages.
Depending on the use, the sorbent may be sterile or non-sterile.
The polymer may be sterilized by standard methods. Such methods are
well known to those skilled in the art. The therapeutically
effective amount can be administered in a series of doses separated
by appropriate time intervals, such as hours. The compositions of
the instant invention may be administered by methods well known to
those skilled in the art.
EXAMPLES
[0042] The following examples are intended to be illustrative and
non-limiting.
Example 1
[0043] Plasma samples were treated with Aspirin/Glucose or both to
induce posttranslational modifications. Samples were used directly
(-) or after passage through a CytoSorbents adsorber (+), separated
by gel electrophoresis, blotted and stained with antibodies against
Acetyllysine or Carboxymethyllysine (CML, advanced glycation end
product, AGE). FIG. 1a shows that Cytosorbents Adsorber does not
bind Acetyllysine efficiently (comparison pairwise lanes (-/). FIG.
1b shows that Cytosorbents Adsorber does bind AGEs (CML)
efficiently (comparison pairwise lanes (-/+)).
Example 2
[0044] This example utilizes a protein (25 kD) and stains CML green
and Acetyllysine red (Odyssee system). In FIG. 2, it can be clearly
seen that after a passage through an adsorber, the green (GFP)
modified proteins disappeared whereas red (Acetyllysine) modified
proteins are still detectable (comparison pairwise lanes
(-/+)).
Example 3
[0045] It is observed that sorption of AGE molecules having a
molecular weight of 80 or 100 or 120 kDa or more may be achieved by
contacting bodily fluid with the instant sorbents.
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