U.S. patent application number 17/198157 was filed with the patent office on 2022-03-24 for combination therapies with disulfiram.
The applicant listed for this patent is Spring Discovery, Inc.. Invention is credited to Daniel CHEN, Wendy COUSIN, Christian ELABD, Jarred HEINRICH, Rachel JACOBSON, Ben KOMALO, An NGUYEN, Dat NGUYEN, Lauren NICOLAISEN, Tempest PLOTT, William VAN TRUMP.
Application Number | 20220087955 17/198157 |
Document ID | / |
Family ID | 1000005567821 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220087955 |
Kind Code |
A1 |
JACOBSON; Rachel ; et
al. |
March 24, 2022 |
COMBINATION THERAPIES WITH DISULFIRAM
Abstract
Disclosed herein are compositions and methods for increasing
lifespan, for preventing or treating a disease including an
aging-related disorder, for reducing a symptom of aging, and/or
boosting an immune system in a mammal. Also disclosed herein are
compositions and methods for improving effectiveness of a vaccine
in a mammal. The compositions comprise, at least, a therapeutically
effective amount of disulfiram and one or more additional
ingredients.
Inventors: |
JACOBSON; Rachel; (Belmont,
CA) ; COUSIN; Wendy; (Belmont, CA) ; NGUYEN;
An; (Seattle, WA) ; PLOTT; Tempest; (San
Mateo, CA) ; VAN TRUMP; William; (San Francisco,
CA) ; NGUYEN; Dat; (Redwood City, CA) ; CHEN;
Daniel; (San Mateo, CA) ; HEINRICH; Jarred;
(Menlo Park, CA) ; KOMALO; Ben; (San Francisco,
CA) ; NICOLAISEN; Lauren; (Redwood City, CA) ;
ELABD; Christian; (Belmont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Spring Discovery, Inc. |
San Carlos |
CA |
US |
|
|
Family ID: |
1000005567821 |
Appl. No.: |
17/198157 |
Filed: |
March 10, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17149575 |
Jan 14, 2021 |
11033516 |
|
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17198157 |
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63080639 |
Sep 18, 2020 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/06 20180101;
A61K 31/145 20130101; A61K 39/39 20130101; A61K 31/11 20130101 |
International
Class: |
A61K 31/145 20060101
A61K031/145; A61P 37/06 20060101 A61P037/06; A61K 39/39 20060101
A61K039/39; A61K 31/11 20060101 A61K031/11 |
Claims
1.-20. (canceled)
21. A method for inhibiting and/or reducing pyroptotic cell death
in a cell, the method comprising contacting the cell with an active
agent that is disulfiram and a potentiating ingredient that is
cinnamaldehyde, thereby inhibiting and/or reducing pyroptotic cell
death.
22. The method of claim 21, wherein disulfiram and cinnamaldehyde
are included in one composition and the composition comprises
disulfiram and cinnamaldehyde.
23. The method of claim 21, wherein the method comprises contacting
the cell with a first composition comprises disulfiram and
contacting the cell with a second composition comprising
cinnamaldehyde.
24. The method of claim 21, wherein inhibiting and/or reducing
pyroptotic cell death in the cell increases the lifespan of the
cell.
25. The method of claim 21, wherein the amount of disulfiram is
from about 5 mg to about 500 mg and the amount of cinnamaldehyde is
from about 0.01% to about 45% by weight of disulfiram.
26. The method of claim 21, wherein the cinnamaldehyde further
potentiates disulfiram's ability to treat acute lung injury (ALI),
acute respiratory distress syndrome (ARDS), idiopathic pulmonary
fibrosis, chronic obstructive pulmonary disease, dry eye, actinic
keratosis, alopecia, and/or skin cancer.
27. The method of claim 21, wherein the cinnamaldehyde further
potentiates disulfiram's ability to inhibit and/or reduce a
pathological inflammatory response, alter a T-cell's age, and/or
alter mitochondrial function in the cell.
28. A method for boosting activity of an immune cell, the method
comprising contacting the immune cell with an active agent that is
disulfiram and a potentiating ingredient that is cinnamaldehyde,
thereby boosting activity of the immune cell.
29. The method of claim 28, wherein disulfiram and cinnamaldehyde
are included in one composition.
30. The method of claim 28, wherein the method comprises contacting
the immune cell with a first composition comprising disulfiram and
contacting the cell with an at least second composition comprising
cinnamaldehyde.
31. The method of claim 28, wherein boosting activity of the immune
cell increases an effective immune response against an infectious
agent and/or an atypical cell.
32. The method of claim 28, wherein boosting activity of the immune
cell improves the immune cell's response against a component
contained in a vaccine, wherein the component contained in the
vaccine is an antigen obtained from, related to, homologous to, or
expressed by an infectious agent.
33. The method of claim 28, wherein boosting activity of the immune
cell comprises inhibiting a pathological immune response.
34. The method of claim 33, wherein boosting activity of the immune
cell minimizes overactive immune cell activity.
35. The method of claim 28, wherein the amount of disulfiram is
from about 5 mg to about 500 mg and the amount of cinnamaldehyde is
from about 0.01% to about 45% of the weight of the disulfiram.
36. A composition comprising an active agent that is disulfiram and
a potentiating ingredient that is cinnamaldehyde, wherein the
amount of disulfiram is from about 5 mg to about 500 mg and the
amount of cinnamaldehyde is from about 0.01% to about 45% of the of
the disulfiram.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 17/149,575 filed Jan. 14, 2021, which claims priority to U.S.
Provisional Application No. 63/080,639 filed Sep. 18, 2020, the
contents of which is incorporated by reference herein in its
entirety.
BACKGROUND
[0002] Of the approximately 150,000 human deaths per day,
approximately two-thirds are due to age-related causes. Aging leads
to functional deterioration and progressive decline across multiple
tissues, organs, and systems, including the immune system, that
arise from the progressive accumulation of cellular and tissue
damage. This damage may be attributed, in part, to dysfunction or
disruption in one or more signaling pathways. Accordingly, there
remains an unmet need for compositions and methods that stop, slow,
or reverse these dysfunctions or disruptions and are capable of
thereby treating aging-related disorders and/or reducing symptoms
of aging.
SUMMARY
[0003] The present invention addresses this need. Accordingly, the
present disclosure relates to compositions and methods for
increasing lifespan, for preventing or treating a disease including
an aging-related disorder, for reducing a symptom of aging, and/or
boosting an immune system in a mammal. The present disclosure
additionally relates to compositions and methods for improving
effectiveness of a vaccine in a mammal.
[0004] An aspect of the present disclosure is a method for
inhibiting and/or reducing pyroptotic cell death in a cell. The
method comprises contacting the cell with an active agent that is
disulfiram and a potentiating ingredient that is cinnamaldehyde,
thereby inhibiting and/or reducing pyroptotic cell death.
[0005] In some embodiments, the disulfiram and cinnamaldehyde are
included in one composition and the composition consists
essentially of disulfiram and cinnamaldehyde. In some cases, the
composition further comprises one or more additional ingredients
from Table 1.
[0006] In various embodiments, the method comprises contacting the
cell with a first composition consisting essentially of disulfiram
and contacting the cell with a second composition consisting
essentially cinnamaldehyde. In some cases, the either or both of
the first composition and the second composition further comprises
one or more additional ingredients from Table 1.
[0007] In embodiments, inhibiting and/or reducing pyroptotic cell
death in the cell increases the lifespan of the cell.
[0008] In some embodiments, the amount of disulfiram is from about
5 mg to about 500 mg and the amount of cinnamaldehyde is from about
0.01% to about 45% by weight of disulfiram.
[0009] In various embodiments, the cinnamaldehyde further
potentiates disulfiram's ability to treat acute lung injury (ALI),
acute respiratory distress syndrome (ARDS), idiopathic pulmonary
fibrosis, chronic obstructive pulmonary disease, dry eye, actinic
keratosis, alopecia, and/or skin cancer.
[0010] In embodiments, the cinnamaldehyde further potentiates
disulfiram's ability to inhibit and/or reduce a pathological
inflammatory response, alter a T-cell's age, and/or alter
mitochondrial function in the cell.
[0011] Another aspect of the present disclosure is a method for
boosting activity of an immune cell. The method comprises
contacting the immune cell with an active agent that is disulfiram
and a potentiating ingredient that is cinnamaldehyde, thereby
boosting activity of an immune cell.
[0012] In some embodiments, the disulfiram and cinnamaldehyde are
included in one composition and the composition consists
essentially of disulfiram and cinnamaldehyde. In some cases, the
composition further comprises one or more additional ingredients
from Table 1. The method may comprise contacting the cell with a
first composition consisting essentially of disulfiram and
contacting the cell with an at least second composition consisting
essentially cinnamaldehyde. Either or both of the first composition
and the second composition further comprises one or more additional
ingredients from Table 1.
[0013] In various embodiments, boosting activity of an immune cell
increases an effective immune response against an infectious agent
and/or an atypical cell.
[0014] In embodiments, boosting activity of an immune cell improves
the immune cell's response against a component contained in a
vaccine, wherein the component contained in the vaccine is an
antigen obtained from, related to, homologous to, or expressed by
an infectious agent.
[0015] In some embodiments, boosting activity of an immune cell
comprises inhibiting a pathological immune response. In some cases,
boosting activity of an immune cell minimizes overactive immune
cell activity.
[0016] In various embodiments, the amount of disulfiram is from
about 5 mg to about 500 mg and the amount of cinnamaldehyde is from
about 0.01% to about 45% of the weight of the disulfiram.
[0017] Yet another aspect of the present disclosure is a
composition consisting essentially of an active agent that is
disulfiram and a potentiating ingredient that is cinnamaldehyde.
The amount of disulfiram is from about 5 mg to about 500 mg and the
amount of cinnamaldehyde is from about 0.01% to about 45% of the of
the disulfiram.
[0018] It shall be understood that different aspects and/or
embodiments of the invention can be appreciated individually,
collectively, or in combination with each other. Various aspects
and/or embodiments of the invention describe herein may be applied
to any of the uses set forth below and in other methods for
increasing lifespan in a mammal. Any description herein concerning
a specific composition and/or method apply to and may be used for
any other specific composition and/or method as disclosed herein.
Additionally, any composition disclosed herein is applicable to any
herein-disclosed method.
[0019] In other words, any aspect or embodiment described herein
can be combined with any other aspect or embodiment as disclosed
herein.
BRIEF DESCRIPTION OF DRAWINGS
[0020] FIG. 1A to FIG. 1D show data obtained when virally infected
cells were treated with a disulfiram. FIG. 1A shows cytokine levels
from the supernatant of vesicular stomatitis virus encoding a red
fluorescent protein (rVSV-.DELTA.G-mCherry)-infected cells
(infected at 10.times. MOI); asterisks indicate statistical
significance relative to untreated control cells. Data is
normalized by total cell count. In FIG. 1B and FIG. 1C,
respectively, show reticularity measurements of mitochondria and
aging scores in T cells. In FIG. 1B and FIG. 1C, horizontal bars
represent the distribution of untreated controls from younger and
older donors; the solid line represents the median and the lower
and upper dashed lines represent the 25.sup.th and 75.sup.th
quartiles, respectively. The line graph represents the median and
95% CI for treated cells, with statistical significance relative to
untreated control cells indicated by asterisks. In FIG. 1D,
"on-age" and "off-age" scores for T cells treated with either
disulfiram or dimethyl fumarate. Distributions for younger and
older control (untreated) cells are plotted using a Gaussian kernel
density estimation. Statistical significance relative to untreated
control cells is indicated by the following: *, P<0.5; **,
P<0.001; ***, P<0.0001. IL, interleukin; MCP1, monocyte
chemoattractant protein 1; MOI, multiplicity of infection; PBMC,
peripheral blood mononuclear cell; TNF, tumor necrosis factor.
[0021] FIG. 2 shows the effect of cells treated with disulfiram
alone, cinnamaldehyde alone, or disulfiram and cinnamaldehyde in
combination at different concentrations.
[0022] FIG. 3 shows the effect of cells treated with cinnamaldehyde
and different concentrations of disulfiram.
[0023] FIG. 4A to 4C show synergistic effects of cinnamaldehyde on
disulfiram activity. FIG. 4A is a table of synergy ratio of
actual/expected effect at each concentration of cinnamaldehyde and
disulfiram; cells in grey indicate positive synergy. FIG. 4B and
FIG. 4C are graphs showing average synergy at different
concentrations of cinnamaldehyde and disulfiram.
[0024] FIG. 5 is a table showing the percent difference in IC50
between disulfiram alone vs. disulfiram and cinnamaldehyde at
various concentrations or constant ratio (last column).
Cinnamaldehyde combined with disulfiram shifts the IC50 to the left
relative to disulfiram alone in a dose-dependent manner.
cinnamaldehyde has no effect on pyroptosis inhibition or a clear
IC50, indicating effects on early inhibition and shifted IC50 is
synergistic.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present disclosure relates to compositions and methods
for increasing lifespan, for preventing or treating a disease
including an aging-related disorder, for reducing a symptom of
aging, and/or boosting an immune system in a mammal. The present
disclosure additionally relates to compositions and methods for
improving effectiveness of a vaccine in a mammal.
[0026] 1. Compounds and Compositions
[0027] The methods of the present disclosure comprise administering
to a mammal a therapeutically effective amount of an active
ingredient that is disulfiram and a potentiating ingredient that is
cinnamaldehyde or comprise contacting a cell (in vivo, in vitro, or
ex vivo) with an active ingredient that is disulfiram and a
potentiating ingredient that is cinnamaldehyde.
[0028] Disulfiram is a specific inhibitor of an
aldehyde-dehydrogenase (ALDH1). Disulfiram was approved by the US
Food and Drug Administration in 1951 for alcohol aversion therapy
after researchers observed that it induced the effects of a
hangover after alcohol consumption. Disulfiram blocks the major
metabolic reaction that converts alcohol into acetaldehyde.
Disulfiram inhibits pyroptosis of a cell by inhibition of gasdermin
D.
[0029] As used herein, the term disulfiram includes disulfiram
itself and any of its metabolites and/or derivatives. Examples of
metabolites include diethyldithiocarbamate, diethyl-amine, and
carbon disulfide.
[0030] In each aspect and embodiment of the present disclosure, the
active agent is disulfiram and the potentiating ingredient is
cinnamaldehyde. Cinnamaldehyde has the following chemical
identifiers: CAS: 14371-10-9, 104-55-2; DrugBank: DB14184; MedChem:
HY-N0609; and SelleckChem: S3763. Cinnamaldehyde is the aldehyde
that gives cinnamon its flavor and odor. Cinnamaldehyde occurs
naturally in the bark of cinnamon trees and other species of the
genus Cinnamomum like camphor and cassia. These trees are the
natural source of cinnamon, and the essential oil of cinnamon bark
is about 90% cinnamaldehyde. Cinnamaldehyde is also used as a
fungicide. Proven effective on over 40 different crops,
cinnamaldehyde is typically applied to the root systems of plants.
Its low toxicity and well-known properties make it ideal for
agriculture. To a lesser extent, cinnamaldehyde is an effective
insecticide, and its scent is also known to repel animals like cats
and dogs. Cinnamaldehyde is also known as a corrosion inhibitor for
steel and other ferrous alloys in corrosive fluids. It can be used
in combination with additional components such as dispersing
agents, solvents and other surfactants. Concentrated cinnamaldehyde
is a skin irritant, and the chemical is toxic in large doses, but
no agencies suspect the compound is a carcinogen or poses a
long-term health hazard. Most cinnamaldehyde is excreted in urine
as cinnamic acid, an oxidized form of cinnamaldehyde.
[0031] Additional names for cinnamaldehyde include
(2E)-3-Phenyl-2-propenal, (2E)-3-Phenylacrylaldehyde,
(e)-3-Phenyl-2-propenal, (e)-3-Phenylpropenal,
(e)-3-Phenyl-propenal, (e)-Cinnamaldehyde, (e)-Cinnamic aldehyde,
(e)-Phenylvinyl aldehyde, 3-Fenylpropenal, 3-Phenyl-2-propen-1-al,
3-Phenyl-2-propenaldehyde, 3-Phenylacrolein, 3-Phenylacrylaldehyde,
3-Phenylprop-2-enal, 3-Phenylprop-2-enaldehyde, 3-Phenylpropenal,
Benzylideneacetaldehyde, beta-Phenylacrolein, beta-Phenylcrolein,
Cinnamal, Cinnamic aldehyde, Cinnamic aldehyde, (e)-isomer,
Cinnamyl aldehyde, Cinnamylaldehyde, fv-Cinnemaldehyde,
Supercinnamaldehyde, trans-3-Phenyl-2-propenal,
trans-3-Phenylprop-2-enaldehyde, trans-Cinnamaldehyde,
trans-Cinnamic aldehyde, and trans-Cinnamylaldehyde.
[0032] Cinnamaldehyde is generally recognized as safe (GRAS; e.g.,
by the FDA), is listed in the FDA inactive ingredient database (IID
(see, the World Wide Web at
accessdata.fda.gov/scripts/cder/iig/index.cfm), and/or is included
in the FDA's Substances Added to Food list (see, the World Wide Web
at cfsanappsexternal.fda.gov/scripts/fdcc/?set=FoodSubstances and
the regulations set forth in 21 CFR 73, 74, 172, 173, 181, 182, and
184, the contents of each of which is incorporated by reference in
its entirety).
[0033] As used herein, the term cinnamaldehyde includes
cinnamaldehyde itself and any of its metabolites, derivatives,
relatives. and/or precursors. An example of a cinnamaldehyde
metabolite includes cinnamic acid. An example of a cinnamaldehyde
precursor includes cinnamyl alcohol. Examples of other
cinnamaldehyde relatives include benzyl cinnamate (which is an
ester of cinnamaldehyde), methyl cinnamate (which is an ester of
cinnamic acid), and hydrocinnamic acid (which results from
hydrogenation of cinnamic acid).
[0034] A composition of the present disclosure comprises an active
agent that is disulfiram and a potentiating ingredient that is
cinnamaldehyde. A plurality of compositions of the present
disclosure may comprise a first composition comprising an active
agent that is disulfiram and a second composition comprising a
potentiating ingredient that is cinnamaldehyde.
[0035] The present disclosure provides methods that comprise
administering a therapeutically effective amount of an active agent
that is disulfiram and a potentiating ingredient that is
cinnamaldehyde, contacting a cell or immune cell with an active
agent that is disulfiram and a potentiating ingredient that is
cinnamaldehyde, a composition comprising an active agent that is
disulfiram and a potentiating ingredient that is cinnamaldehyde,
and a plurality of compositions comprising a first composition
comprising an active agent that is disulfiram and a second
composition comprising a potentiating ingredient that is
cinnamaldehyde.
[0036] A potentiating ingredient, i.e., cinnamaldehyde, enhances,
increases, and/or improves the desirable activity of the active
ingredient, i.e., disulfiram. As a non-limiting example, the
potentiating ingredient enhances pyroptosis activity of
disulfiram.
[0037] The potentiating ingredient, i.e., cinnamaldehyde, used in
the present disclosure enhances, increases, and/or improves the
effectiveness and/or desirable activity of the active ingredient,
i.e., disulfiram. Thus, a composition comprising disulfiram alone
will be less effective, for example, than a composition comprising
disulfiram and its potentiating ingredient cinnamaldehyde.
Similarly, a method in which disulfiram is administered alone is
less effective than a method in which disulfiram is administered
with cinnamaldehyde (either as a single composition or as distinct
compositions that are administered contemporaneously or
sequentially). In various embodiments, the potentiating ingredient,
as disclosed herein, enhances disulfiram's ability to inhibit
pyroptosis. In some embodiments, the enhanced, increased, and/or
improved effectiveness and/or activity of the active agent, i.e.,
disulfiram, may be any amount between about 1.1-fold and about
3-fold, e.g., about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2,
2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3-fold, and any
fold therebetween. In embodiments, the enhanced, increased, and/or
improved effectiveness and/or activity of the active agent, i.e.,
disulfiram, may be any amount between about 3-fold and about
5-fold, e.g., about 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,
4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5-fold, and any
fold therebetween. The enhanced, increased, and/or improved
effectiveness and/or activity of the active agent, i.e.,
disulfiram, may be any amount between about 5-fold and about
15-fold. As examples, the effectiveness may be increased about 5,
5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5,
13, 13.5, 14, 14.5, or 15-fold, and any fold therebetween. In some
embodiments, the enhanced, increased and/or improved effectiveness
and/or activity of the active agent, i.e., disulfiram, is greater
than about 15-fold. The increased and/or improved effectiveness may
be greater than about 1%, e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%,
8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, 95%, or about 100%, and any percentage
therebetween.
[0038] An enhanced, increased, and/or improved effectiveness and/or
activity of the active agent, i.e., disulfiram, may be determined
by any assay, phenotype, marker, or indicator demonstrating a
desired outcome from a treatment or administration of a
composition. As examples, effectiveness and/or activity may be
shown as a reduction in markers/indicators of an aging cell, an
increase in markers/indicators of a healthy cell, an extension of
the active life of a cell, a reduction in apoptosis, increased
longevity of a mammal, a reduction in the predicted biological age
of a cell, increased titer of antibodies in response to a vaccine,
inhibition of pyroptosis in an in vitro assay, an immune profile,
and phenotypic changes in a cell that report health and/or
activity. Increased and/or improved effectiveness may be objective
(e.g., quantifiable) or subjective (e.g., qualifiable).
[0039] Because the potentiating ingredient, i.e., cinnamaldehyde,
enhances, increases, and/or improve disulfiram's effectiveness
and/or activity (e.g., in pyroptosis inhibition), lower doses of
disulfiram may be administered to a mammal while still providing a
desired outcome. This lower dose may minimize adverse effects
resulting from disulfiram administration.
[0040] In certain embodiments, disulfiram is administered at a
daily dosage of about 5 mg to about 500 mg per day. For example,
disulfiram is administered at a total daily dosage of about 5, 6,
7, 8, 9, 10, 15, 20, 25, 30, 45, 40, 45, 50, 55, 60, 65, 70, 75,
80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,
350, 375, 400, 425, 450, 475, or 500 mg per day, and any total
dosage therebetween. As examples, the daily dosage may be 5-10 mg,
10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45
mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg,
75-80 mg, 80-85 mg, 85-90 mg, 90-95 mg, 95-100 mg, 100-125 mg,
125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 250-275
mg, 275-300 mg, 300-325 mg, 325-350 mg, 350-375 mg, 375-400 mg,
400-425 mg, 425-450 mg, 450-475 mg, or 475-500 mg. The disulfiram
may be administered 1.times., 2.times., or 3.times. per day to
achieve the daily dosage. Thus, for a daily dose of 5 mg with a
once per day administration, only a single administration of 5 mg
will be given; for a daily dose of 5 mg with a twice per day
administration, two administrations of about 2.5 mg will be given;
and for a daily dose of 5 mg with a thrice per day administration,
three administrations of about 1.7 mg will be given. Similarly, for
a daily dose of 500 mg with a once per day administration, only a
single administration of 500 mg will be given; for a daily dose of
500 mg with a twice per day administration, two administrations of
about 250 mg will be given; and for a daily dose of 500 mg with a
thrice per day administration, three administrations of about 170
mg will be given. The potentiating ingredient, i.e.,
cinnamaldehyde, may be administered 1.times., 2.times., or 3.times.
per day.
[0041] In certain embodiments, the potentiating ingredient, i.e.,
cinnamaldehyde, and the disulfiram are administered in two separate
formulations. In certain embodiments, the cinnamaldehyde and the
disulfiram are administered in a single formulation.
[0042] In certain embodiments, the potentiating ingredient, i.e.,
cinnamaldehyde, is administered at a ratio of about 1:1 to about
1:3000 moles of cinnamaldehyde to disulfiram. The cinnamaldehyde
may be administered at a ratio of about 1:1, 1:1.01, 1:1.02,
1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1,
1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18,
1:1.19, 1:1.2, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26,
1:1.27, 1:1.28, 1:1.29, or 1:1.3 moles cinnamaldehyde per mole of
disulfiram. The cinnamaldehyde may be administered at a ratio of
about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11,
1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20 moles
cinnamaldehyde per mole of disulfiram. The cinnamaldehyde may be
administered at a ratio of about 1:10, 1:20, 1:30, 1:40, 1:50,
1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150,
1:160, 1:170, 1:180, 1:190, or 1:200 moles cinnamaldehyde per mole
of disulfiram, and any ratio therebetween. As examples, the ratio
may be about 1:10-1:15, 1:15-1:20, 1:20-1:25, 1:25-1:30, 1:30-1:35,
1:35-1:40, 1:40-1:45, 1:45-1:50, 1:50-1:55, 1:55-1:60, 1:60-1:65,
1:65-1:70, 1:70-1:75, 1:75-1:80, 1:80-1:85, 1:85-1:90, 1:90-1:95,
1:95-1:100, 1:100-1:125, 1:125-1:150, 1:150-1:175, 1:175-1:200
moles cinnamaldehyde per mole of disulfiram. The cinnamaldehyde may
be administered at a ratio of about 1:100, 1:200, 1:300, 1:400,
1:500, 1:600, 1:700, 1:800, 1:900, or 1:1000 moles cinnamaldehyde
per mole of disulfiram, and any ratio therebetween. As examples,
the ratio may be about 1:100-1:125, 1:125-1:150, 1:150-1:175,
1:175-1:200, 1:200-1:225, 1:225-1:250, 1:250-1:275, 1:275-1:300,
1:300-1:325, 1:325-1:350, 1:350-1:375, 1:375-1:400, 1:400-1:425,
1:425-1:450, 1:450-1:475, 1:475-1:500, 1:500-1:525, 1:525-1:550,
1:550-1:575, 1:575-1:600, 1:600-1:625, 1:625-1:650, 1:650-1:675,
1:675-1:700, 1:700-1:725, 1:725-1:750, 1:750-1:775, 1:775-1:800,
1:800-1:825, 1:825-1:850, 1:850-1:875, 1:875-1:900, 1:900-1:925,
1:925-1:950, 1:950-1:975, or 1:975-1:1000 moles cinnamaldehyde per
mole of disulfiram. The cinnamaldehyde may be administered at a
ratio of about 1:1000, 1:1100, 1:1200, 1:1300, 1:1400, 1:1500,
1:1600, 1:1700, 1:1800, 1:1900, 1:2000, 1:2100, 1:2200, 1:2300,
1:2400, 1:2500, 1:2600, 1:2700, 1:2800, 1:2900, or 1:3000 moles
cinnamaldehyde per mole of disulfiram, and any ratio therebetween.
As examples, the ratio may be about 1:1000-1:1100, 1:1100-1:1200,
1:1200-1:1300, 1:1300-1:1400, 1:1400-1:1500, 1:1500-1:1600,
1:1600-1:1700, 1:1700-1:1800, 1:1800-1:1900, 1:1900-1:2000,
1:2000-1:2100, 1:2100-1:2200, 1:2200-1:2300, 1:2300-1:2400,
1:2400-1:2500, 1:2500-1:2600, 1:2600-1:2700, 1:2700-1:2800,
1:2800-1:2900, or 1:2900-1:3000 moles cinnamaldehyde per mole of
disulfiram.
[0043] In embodiments where the potentiating ingredient, i.e.,
cinnamaldehyde, and the active agent, i.e., disulfiram, are
administered in a single formulation, the amount of cinnamaldehyde
is about 0.01% to about 45% of the amount of disulfiram (by
weight). The amount of cinnamaldehyde may be about 0.01%, 0.02%,
0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%,
0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.3%,
0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% of the weight of the
disulfiram. The amount of cinnamaldehyde may be about 1%, 1.2%,
1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%,
3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%,
6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%,
8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the
disulfiram, and any percentage therebetween. As examples, the
percentage may be about 1%-1.5%, 1.5%-2%, 2%-20.5%, 2.5%-3%,
3%-30.5%, 3.5%-4%, 4%-40.5%, 4.5%-5%, 5%-5.5%, 50.5%-6%, 6%-60.5%,
6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-80.5%, 8.5%-9%, 9%-9.5%, or 9.5%-10%
of the weight of the disulfiram. The amount of cinnamaldehyde may
be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%,
32%, 34%, 36%, 38%, 40%, 42%, 44%, or 45% of the weight of the
disulfiram, and any percentage therebetween. As examples, the
percentage may be about 10%-15%, 15%-20%, 20%-25%, 25%-30%,
30%-35%, 35%-40%, or 40%-45% of the weight of the disulfiram. In
embodiments where the potentiating ingredient, i.e.,
cinnamaldehyde, and the active agent, i.e., disulfiram, are
administered in two formulations, the amount of cinnamaldehyde is
about 0.01% to about 45% of the weight of the disulfiram. The
amount of cinnamaldehyde may be about 0.01%, 0.02%, 0.03%, 0.04%,
0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%,
0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.3%, 0.4%, 0.5%,
0.6%, 0.7%, 0.8%, 0.9%, or 1% of the weight of the disulfiram. The
amount of cinnamaldehyde may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%,
2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%,
4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%,
6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%,
9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the disulfiram, and
any percentage therebetween. As examples, the percentage may be
about 1%-1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%,
4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%,
7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5%-10% of the weight of
the disulfiram. The amount of cinnamaldehyde may be about 10%,
12%1, 4%1, 6%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%,
38%, 40%, 42%, 44%, or 45% of the weight of the disulfiram, and any
percentage therebetween. As examples, the percentage may be about
10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, or 40%-45% of
the weight of the disulfiram.
[0044] In some embodiments, cinnamaldehyde is administered at a
daily dosage from about 0.001 mg to about 223 mg. As examples,
cinnamaldehyde is administered at a total daily dosage of about
0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007
mg, 0.008 mg, 0.009 mg, or 0.01 mg, and any daily dosage
therebetween. As examples, the daily dosage of cinnamaldehyde may
be about 0.001-0.002 mg, 0.002-0.003 mg, 0.003-0.004 mg,
0.004-0.005 mg, 0.005-0.006 mg, 0.006-0.007 mg, 0.007-0.008 mg,
0.008-0.009 mg, or 0.009-0.01 mg. The cinnamaldehyde may be
administered at a total daily dosage of about 0.01 mg, 0.02 mg,
0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, or
0.1 mg, and any daily dosage therebetween. As examples, the daily
dosage of cinnamaldehyde may be about 0.01-0.02 mg, 0.02-0.03 mg,
0.03-0.04 mg, 0.04-0.05 mg, 0.05-0.06 mg, 0.06-0.07 mg, 0.07-0.08
mg, 0.08-0.09 mg, or 0.09-0.1 mg. The cinnamaldehyde may be
administered at a total daily dosage of about 0.1 mg, 0.2 mg, 0.3
mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg, and
any daily dosage therebetween. As examples, the daily dosage of
cinnamaldehyde may be about 0.1-0.2 mg, 0.2-0.3 mg, 0.3-0.4 mg,
0.4-0.5 mg, 0.5-0.6 mg, 0.6-0.7 mg, 0.7-0.8 mg, 0.8-0.9 mg, or
0.9-1 mg. The cinnamaldehyde may be administered at a total daily
dosage of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9
mg, or 10 mg, and any daily dosage therebetween. As examples, the
daily dosage of cinnamaldehyde may be about 1-2 mg, 2-3 mg, 3-4 mg,
4-5 mg, 5-6 mg, 6-7 mg, 7-8 mg, 8-9 mg, or 9-10 mg. The
cinnamaldehyde may be administered at a total daily dosage of about
10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or
100 mg, and any daily dosage therebetween. As examples, the daily
dosage of cinnamaldehyde may be about 10-20 mg, 20-30 mg, 30-40 mg,
40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg. The
cinnamaldehyde may be administered at a total daily dosage of about
100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180
mg, 190 mg, 200 mg, 210 mg, 220 mg, or 223 mg and any daily dosage
therebetween. As examples, the daily dosage of cinnamaldehyde may
be about 100-110 mg, 110-120 mg, 120-130 mg, 130-140 mg, 140-150
mg, 150-160 mg, 160-170 mg, 170-180 mg, 180-190 mg, 190-200 mg,
200-210 mg, 210-220 mg, or 220-223 mg. The potentiating ingredient,
i.e., cinnamaldehyde, may be administered 1.times., 2.times., or
3.times. per day to achieve the daily dosage. Thus, for a daily
dose of 5 mg with a once per day administration, only a single
administration of 5 mg will be given; for a daily dose of 5 mg with
a twice per day administration, two administrations of about 2.5 mg
will be given; and for a daily dose of 5 mg with a thrice per day
administration, three administrations of about 1.7 mg will be
given. Similarly, for a daily dose of 223 mg with a once per day
administration, only a single administration of 223 mg will be
given; for a daily dose of 223 mg with a twice per day
administration, two administrations of about 112 mg will be given;
and for a daily dose of 223 mg with a thrice per day
administration, three administrations of about 74 mg will be
given.
[0045] Compositions and methods of the present disclosure may
further comprise one or more additional ingredients. The additional
ingredients may also potentiate the activity of the active agent,
i.e., disulfiram. As such, the additional ingredient may be
considered a second potentiating ingredient. The additional
ingredient may also assist in the potentiating activity of
cinnamaldehyde. The additional ingredient may be generally activity
inert and, instead, provide other favorable properties to a
composition, e.g., acting as a binder, a buffer, a solute, an
excipient, and so forth. For example, a composition of the present
disclosure may comprise disulfiram and cinnamaldehyde and one or
more additional ingredients. When a plurality of compositions is
useful in the present disclosure, a first composition may comprise
disulfiram, a second composition may comprise cinnamaldehyde, and
an at least third composition may comprise one or more additional
ingredients. For methods of the present disclosure, a subject may
be administered a composition comprising disulfiram,
cinnamaldehyde, and one or more additional potentiating
ingredients. For other methods of the present disclosure, a subject
may be administered a first composition comprising disulfiram, a
second composition comprising cinnamaldehyde, and an at least third
composition comprising one or more additional ingredients.
[0046] An additional ingredient, as used herein, is a compound that
is generally recognized as safe (GRAS; e.g., by the FDA), is listed
in the FDA inactive ingredient database (IID (see, the World Wide
Web at accessdata.fda.gov/scripts/cder/iig/index.cfm), and/or is
included in the FDA's Substances Added to Food list (see, the World
Wide Web at
cfsanappsexternal.fda.gov/scripts/fdcc/?set=FoodSubstances and the
regulations set forth in 21 CFR 73, 74, 172, 173, 181, 182, and
184, the contents of each of which is incorporated by reference in
its entirety). An additional ingredient may be found in a plurality
of the above-mentioned lists/databases. In some instances, an
additional ingredient is considered an "inactive ingredient". An
inactive ingredient is any component of a drug product other than
the active ingredient (see, the World Wide Web at
fda.gov/drugs/drug-approvals-and-databases/inactive-ingredients-approved--
drug-products-search-frequently-asked-questions, the contents of
which is incorporated by reference in its entirety). In the present
disclosure, the active ingredient is disulfiram. In various
embodiments of the present disclosure, an additional ingredient is
any substance that can intentionally be added to a food as a food
additive and which is generally recognized, among qualified
experts, as having been adequately shown to be safe under the
conditions of its intended use. In particular, additional
ingredients are exempted from the usual Federal Food, Drug, and
Cosmetic Act (FFDCA) food additive tolerance requirements. An
additional ingredient, as used herein, includes both the specific
additional ingredient and any of its metabolites and/or their
derivatives. Non-limiting examples of a metabolite includes a salt
and ester of the additional ingredient. Other variations may
include changes in Chirality, Isomers, Hydration states relative to
the specific additional ingredient. The usefulness of a metabolite
or a derivative of an additional ingredient that is useful in the
present disclosure, is well-within the ability of a skilled
artisan; such experiments needed to verify that the metabolite or
derivative is useful would be similar to the experiments used to
verify that the specific additional ingredient is useful, e.g., in
the compositions and methods of the present disclosure.
TABLE-US-00001 TABLE 1 Illustrative additional ingredients Catalog
No Drug Names Target Pathway Biological Activity CAS HY-100489 TBHQ
Apoptosis; Apoptosis; TBHQ (tert-Butylhydroquinone) is widely used
1948-33-0 Autophagy; Autophagy; Nrf2 activator, protects against
Doxorubicin ERK; MAPK/ERK (DOX)-induced cardiotoxicity through
activation Ferroptosis; Pathway; NF-.kappa.B; of Nrf2. TBHQ
(tert-Butylhydroquinone) is also Keap1-Nrf2 Stem Cell/Wnt an ERK
activator; rescues Dehydrocorydaline (DHC)-induced cell
proliferation inhibition in melanoma. HY-101036 Choline
(bitartrate) mAChR GPCR/G Protein; Choline (bitartrate) is an
essential nutrient, often 87-67-2 Neuronal associated with the B
vitamins but not yet Signaling officially defined as a B vitamin.
Choline (bitartrate) plays an important role in synthesis of the
neurotransmitter acetylcholine. HY-101103 (2-Hydroxypropyl)- Others
Others (2-Hydroxypropyl)-.beta.-cyclodextrin is a widely
128446-35-5 .beta.-cyclodextrin used drug delivery vehicle to
improve the stability and bioavailability. HY-101530
Polyoxyethylene Bacterial; Anti-infection; Polyoxyethylene stearate
(POES) is a non-ionic 9004-99-3 stearate P-glycoprotein Membrane
emulsifying agent. Transporter/Ion Channel HY-10448 Capsaicin
Autophagy; Autophagy; Capsaicin ((E)-Capsaicin) is a mixture of
404-86-4 TRP Channel Membrane Capsaicin and Dihydrocapsaicin.
Capsaici is a Transporter/Ion TRPV1 agonist with an EC50 of 0.29
.mu.M in Channel; HEK293 cells. Neuronal Signaling HY-107201
.beta.-Cyclodextrin Influenza Anti-infection .beta.-Cyclodextrin is
a cyclic polysaccharide 7585-39-9 Virus composed of seven units of
glucose (.alpha.-D- glucopyranose) linked by .alpha.-(1,4) type
bonds. .beta.- Cyclodextrin has often been used to enhance the
solubility of drugs. .beta.- Cyclodextrin has anti- influenza virus
H1N1 activities. HY-107799 Castor oil Others Others Castor oil is a
natural triglyceride and a solvent. 8001-79-4 Castor oil has a
laxative effect and induces labor in pregnant females. Castor oil
can be used as a solvent, co-solvent, stabilizing agent and polyol
for the formation of polymer-nanoparticle composites. HY-107832
Ketoisophorone Others Others Ketoisophorone (4-Oxoisophorone) is a
key 1125-21-9 intermediate in the synthesis of carotenoids and
flavouring agents. Ketoisophorone is an industrially important
cyclic endione. HY-107846 Xylan Others Others Xylan represents the
main hemicellulose 9014-63-5 component in the secondary plant cell
walls of flowering plants. Xylan is a polysaccharide made from
units of xylose and contains predominantly .beta.-D-xylose units
linked as in cellulose. HY-109521 Manganous chloride tetrahydrate
HY-111095 D-(-)-Lactic Endogenous Metabolic D-(-)-Lactic acid is a
normal intermediate in the 10326-41-7 acid Metabolite
Enzyme/Protease fermentation (oxidation, metabolism) of sugar.
D-(-)-Lactic acid is identified to be a competitive inhibitor of
ProDH (proline dehydrogenase) in plants. HY-111830 Lignin Others
Others Lignin (Lignine) is a natural complex biopolymer 9005-53-2
with biodegradable and biocompatible. Lignin is the main component
of plant cell walls and is a renewable aromatic polymer. Lignin has
strongly antioxidant activity. HY-112624 Dextran Others Others
Dextran (Dextran 40) has an inhibitory effect on 9004-54-0
thrombocyte aggregation and coagulation factors and is used as a
plasma volume expander. HY-113063 3-Methyl-2- Endogenous Metabolic
3-Methyl-2-oxovaleric acid is a neurotoxin, an 1460-34-0 oxovaleric
acid Metabolite Enzyme/Protease acidogen, and a metabotoxin, and
also an abnormal metabolite that arises from the incomplete
breakdown of branched-chain amino acids. HY-114336 Enocyanin
Phosphatase Metabolic Enocyanin is an anthocyanin extracted from
11029-12-2 Enzyme/Protease grapes. Enocyanin shows inhibitory
effect on the leucine aminopeptidase, acid phosphatase, .gamma.-
glutamyl transpeptidase and esterase activity. HY-116084
Trimethylamine Endogenous Immunology/ Trimethylamine N-oxide is a
gut microbe- 1184-78-7 N-oxide Metabolite; Inflammation; dependent
metabolite of dietary choline and NOD-like Metabolic other
trimethylamine-containing nutrients. Receptor Enzyme/Protease;
Trimethylamine N-oxide induces inflammation (NLR); NF-.kappa.B;
Stem by activating the ROS/NLRP3 inflammasome. Reactive Cell/Wnt;
TGF- Trimethylamine N-oxide also accelerates Oxygen beta/Smad
fibroblast-myofibroblast differentiation and Species; TGF- induces
cardiac fibrosis by activating the TGF-.beta./ beta/Smad smad2
signaling pathway. HY-119309 Sucrose octaacetate Others Others
Sucrose octaacetate is an acetylated derivative of 126-14-7 sucrose
with an intensely bitter tasting and can be used as bitter tasting
surrogate. Sucrose octaacetate can be used as food additive and
also used as an adhesive and plasticizer. Sucrose octaacetate also
used in many pesticides, insecticides, and other toxic products as
a deterrent to accidental poisoning. Sucrose octaacetate can also
be used as an in situ seed and a soft template to synthesize
polyaniline (PANI) nanofibers. HY-124190 Isopropyl myristate
110-27-0 HY-125861 Methyl cellulose Others Others Methylcellulose
is a natural polymer which gels 9004-67-5 on heating.
Methylcellulose is not toxic. HY-125865 Casein 9000-71-9 HY-128454
Dimethyl trisulfide Endogenous Metabolic Dimethyl trisulfide is an
organic chemical 3658-80-8 Metabolite Enzyme/Protease compound and
the simplest organic trisulfide found in garlic, onion, broccoli,
and similar plants. Dimethyl trisulfide is a cyanide antidote.
HY-13211 (E)-2-Decenoic Others Others (E)-2-Decenoic acid is an
interesting fatty acid 334-49-6 acid isolated from royal jelly
secretions of honey bees. HY-14608 (S)-Glutamic acid Apoptosis;
Apoptosis; (S)-Glutamic acid acts as an excitatory transmitter
56-86-0 Endogenous Membrane and an agonist at all subtypes of
glutamate Metabolite; Transporter/Ion receptors (metabotropic,
kainate, NMDA, and Ferroptosis; Channel; AMPA). (S)-Glutamic acid
shows a direct activating iGluR Metabolic effect on the release of
DA from dopaminergic Enzyme/Protease; terminals. Neuronal Signaling
HY-14608A L-Glutamic acid Apoptosis; Apoptosis; L-Glutamic acid
monosodium salt acts as an 142-47-2 monosodium salt Ferroptosis;
Membrane excitatory transmitter and an agonist at all iGluR
Transporter/Ion subtypes of glutamate receptors (metabotropic,
Channel; kainate, NMDA, and AMPA). (S)-Glutamic acid Neuronal shows
a direct activating effect on the release of Signaling DA from
dopaminergic terminals. HY-14617 Paradol COX Immunology/ Paradol is
a pungent phenolic substance found in 27113-22-0 Inflammation
ginger and other Zingiberaceae plants. Paradol is an effective
inhibitor of tumor promotion in mouse skin carcinogenesis, binds to
cyclooxygenase (COX)-2 active site. HY-14621 Zingerone NF-.kappa.B
NF-.kappa.B Zingerone (Vanillylacetone) is a nontoxic 122-48-5
methoxyphenol isolated from Zingiber officinale, with potent
anti-inflammatory, antidiabetic, antilipolytic, antidiarrhoeic,
antispasmodic and anti- tumor properties. Zingerone alleviates
oxidative stress and inflammation, down-regulates NF-.kappa.B
mediated signaling pathways. Zingerone acts as an anti-mitotic
agent, and inhibits the growth of neuroblastoma cells. HY-15337
Hesperidin Autophagy; Autophagy; Hesperidin (HP) is a bioflavonoid
that plays a role 520-26-3 Endogenous Immunology/ in plant defense
and is abundant in citrus species, Metabolite; Inflammation; such
as grapefruit, lemon and orange. Hesperidin Reactive Metabolic is
used effectively as a supplemental agent in Oxygen Enzyme/Protease;
complementary therapy protocols, since it possesses Species
NF-.kappa.B biological and pharmacological properties as an
effective antioxidant, anti-inflammatory, anti- carcinogenic, and
anti-hypertensive agent with lipid-lowering activity IC50:
hesperidin (IC50 = 116.68 .mu.mo/L)) in vitro: hesperidin and
linarin are two of the main constituent of Valeriana's extract
exhibiting a high affinity to KATP channel, which are related to
the control of Ca++ concentration and release of GABA in synaptic
nerve terminal, mainly on cells of SN in vivo: Hesperidin was
dissolved in 1% carboxymethyl cellulose (CMC) and administered
orally at a dose of 50 mg/kg for 10 consecutive days. In the
control group, rats were treated with the corn oil and 1% CMC
vehicle. HY-15398 Cholecalciferol Endogenous Metabolic
Cholecalciferol(Vitamin D3) is a naturally occuring 67-97-0
Metabolite; Enzyme/Protease; form of vitamin D; Reported that upon
VD/VDR Vitamin D metabolic activation, Cholecalciferol induces cell
Related differentiation and prevents proliferation of cancer cells.
IC50 value: Target: Vitamin D acts through a receptor that is a
member of the ligand-dependent transcription factor superfamily.
Modulates the proliferation and differentiation of both normal and
cancer cells. Has antiproliferative and antimetastatic effects on
breast, colon, and prostate cancer cells. Activated vitamin D
receptors in intestine and bone maintain calcium absorbance and
homeostasis. HY-16637 Folic acid DNA/RNA Cell Cycle/ Folic
acid(Vitamin M; Vitamin B9) is a B vitamin; 59-30-3 Synthesis; DNA
Damage; is necessary for the production and maintenance Endogenous
Metabolic of new cells, for DNA synthesis and RNA Metabolite
Enzyme/Protease synthesis. HY-17568 Nonivamide TRP Channel Membrane
Nonivamide is a <b<TRPV1 agonist, which 2444-46-4
Transporter/Ion exhibits 4d-EC50 value of 5.1 mg/L in static
Channel; toxicity tests. Neuronal Signaling HY-22167 Methyl
2-hydroxy- Others Others Methyl 2-hydroxy-4-methylvalerate is one
of 40348-72-9 4-methylvalerate dominant volatile compounds in
Zhenjiang aromatic vinegar. Methyl 2-hydroxy-4- methylvalerate is
used for charting flavour HY-23539 Sodium thiosulfate biosynthesis
networks of vinegar microbiota. (pentahydrate) HY-33518 2-
Pyridinemethanethiol HY-34439 2,5- Endogenous Metabolic
2,5-Dimethylpyrazine is an endogenous 123-32-0 Dimethylpyrazine
Metabolite Enzyme/Protease metabolite. HY-34465 5-Methyl-2- Others
Others 5-Methyl-2-thiophenecarboxaldehyde acts as a 13679-70-4
thiophene- candidate to microscopic third order non-linear
carboxaldehyde optical (NLO) material. HY-34544 2-Hexylthiophene
18794-77-9 HY-34751 2- 636-72-6 Thiophenemethanol HY-40135 L-
Endogenous Metabolic L-Hydroxyproline, one of the hydroxyproline
51-35-4 Hydroxyproline Metabolite Enzyme/Protease (Hyp) isomers, is
a useful chiral building block in the production of many
pharmaceuticals. HY-41417 Octanoic acid Endogenous Metabolic
Octanoic acid is an oily liquid with a slightly 124-07-2 Metabolite
Enzyme/Protease unpleasant rancid taste and used commercially in
the production of esters used in perfumery and also in the
manufacture of dyes. HY-41587 Peracetylated 83-87-4 D-glucose
HY-42680 (3S,4S,5R)- Endogenous Metabolic
(3S,4S,5R)-1,3,4,5,6-Pentahydroxyhexan-2-one is 87-81-0
1,3,4,5,6- Metabolite Enzyme/Protease an endogenous metabolite.
Pentahydroxyhexan- 2-one HY-75161 (-)-Menthol Endogenous Membrane
(-)-Menthol is a key component of peppermint oil 2216-51-5
Metabolite; Transporter/Ion that binds and activates transient
receptor potential TRP Channel Channel; melastatin 8 (TRPM8), a
Ca2+-permeable Metabolic nonselective cation channel, to increase
[Ca2+]i. Enzyme/Protease; Antitumor activity. Neuronal Signaling
HY-76063 Methyl 101-41-7 phenylacetate HY-76225 Monoammonium Others
Others Monoammonium glycyrrhizinate hydrate has 53956-04-0
glycyrrhizinate various pharmacological actions such as anti-
hydrate inflammatory, antiallergic, antigastriculcer, and
antihepatitis activities. HY-76542 Vitamin D2 Endogenous Metabolic
Vitamin D2 (Ergocalciferol) is a form of vitamin 50-14-6
Metabolite; Enzyme/Protease; D, used as a vitamin D supplement.
VD/VDR Vitamin D Target: Related Ergocalciferol is a secosteroid
formed by a photochemical bond breaking of a steroid, specifically,
by the action of ultraviolet light on ergosterol. HY-77342 Methyl
anthranilate 134-20-3 HY-77813 Benzyl Antibiotic; Anti-infection;
Benzyl isothiocyanate is a member of natural 622-78-6
isothiocyanate Apoptosis; Apoptosis isothiocyanates with
antimicrobial activity. Bacterial Benzyl isothiocyanate potent
inhibits cell mobility, migration and invasion nature and matrix
metalloproteinase-2 (MMP-2) activity of murine melanoma cells.
HY-77995 o-Anisaldehyde 135-02-4 HY-79369 Succinic anhydride
108-30-5 HY-A0100 Thiamine Others Others Thiamine monochloride
(Vitamin B1) is an 59-43-8 monochloride essential vitamin that
plays an important role in cellular production of energy from
ingested food and enhances normal neuronal actives. HY-A0104
Hypromellose Others Others Hypromellose is a water-soluble
hydrophilic, non- 9004-65-3 ionic cellulose ether used to form
swellable- soluble matrices. HY-B0133 Natamycin Antibiotic;
Anti-infection; Natamycin (pimaricin) is an antifungal macrolide
7681-93-8 Endogenous Metabolic polyene that binds to cell membrane
sterols. Metabolite; Enzyme/Protease Target: Antifungal Fungal
Natamycin (INN), also known as pimaricin and sometimes sold as
Natacyn, is a naturally occurring antifungal agent produced during
fermentation by the bacterium Streptomyces natalensis, commonly
found in soil. Natamycin has a very low solubility in water;
however, natamycin is effective at very low levels. There is an MIC
(minimum inhibitory concentration) of less than 10 ppm for most
molds. Natamycin is classified as a macrolide polyene antifungal
and, as a drug, is used to treat fungal keratitis. It is especially
effective against Aspergillus and Fusarium corneal infections.
Other common members of the polyene macrolide antifungal family are
amphotericin B, nystatin, and filipin. Natamycin is also used in
the food industry as a natural preservative. Natamycin is used to
treat fungal infections, including Candida, Aspergillus,
Cephalosporium, Fusarium and Penicillium. It is applied as a cream,
in eyedrops, or (for oral infections) in a lozenge. Natamycin shows
negligible absorption into the body when administered in these
ways. When taken orally, little or none is absorbed from the
gastrointestinal tract, making it inappropriate for systemic
infections. HY-B0143 Niacin Autophagy; Autophagy; Niacin (Vitamin
B3) is a water-soluble vitamin 59-67-6 Endogenous Metabolic and is
part of the vitamin B group. Metabolite Enzyme/Protease Target:
Others Niacin (also known as vitamin B3 and nicotinic acid) is an
organic compound with the formula C6H5NO2 and, depending on the
definition used, one of the 20 to 80 essential human nutrients. Not
enough niacin in the diet can cause nausea, skin and mouth lesions,
anemia, headaches, and tiredness. Chronic Niacin deficiency leads
to a disease called pellagra. The lack of niacin may also be
observed in pandemic deficiency disease which is caused by a lack
of five crucial vitamins: niacin, vitamin C, thiamin, vitamin D and
vitamin A, and is usually found in areas of widespread poverty and
malnutrition. Niacin has been used for over 50 years to increase
levels of HDL in the blood and has been found to decrease the risk
of cardiovascular events modestly in a number of controlled human
trials. Niacin cannot be directly converted to nicotinamide, but
both compounds could be converted to and are precursors of NAD and
NADP in vivo. Nicotinic acid, nicotinamide, and tryptophan (via
quinoline acid) are co-factors for nicotinamide adenine
dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate
(NADP). NAD converts to NADP by phosphorylation in the presence of
the enzyme NAD+ kinase. NADP and NAD are coenzyme for many
dehydrogenases, participating in many hydrogen transfer processes.
NAD is important in catabolism of fat, carbohydrate, protein, and
alcohol, as well as cell signaling and DNA repair, and NADP mostly
in anabolism reactions such as fatty acid and cholesterol
synthesis. High energy requirements (brain) or high turnover rate
(gut, skin) organs are usually the most susceptible to their
deficiency. HY-B0150 Nicotinamide Endogenous Cell Cycle/
Nicotinamide is a form of vitamin B3 that plays 98-92-0 Metabolite;
DNA Damage; essential roles in cell physiology through facilitating
Sirtuin Epigenetics; NAD+ redox homeostasis and providing Metabolic
NAD+ as a substrate to a class of enzymes that Enzyme/Protease
catalyze non-redox reactions. Nicotinamide is an inhibitor of
SIRT1. HY-B0166 L-Ascorbic acid Apoptosis; Apoptosis; L-Ascorbic
acid is an effective reducing agent and 50-81-7 Reactive
Immunology/ donor antioxidant. Oxygen Inflammation; Species
Metabolic Enzyme/Protease; NF-.kappa.B HY-B0166A L-Ascorbic acid
Apoptosis; Apoptosis; L-Ascorbic acid sodium salt is a more
bioavailable 134-03-2 sodium salt Reactive Immunology/ form of
vitamin C that is an antioxidant agent. Oxygen Inflammation;
Species Metabolic Enzyme/Protease; NF-.kappa.B HY-B0167 Salicylic
acid Apoptosis; Apoptosis; Salicylic acid (2-Hydroxybenzoic acid)
inhibits 69-72-7 Autophagy; Autophagy; cyclo-oxygenase-2 (COX-2)
activity independently COX; Immunology/ of transcription factor
(NF-.kappa.B) activation. Endogenous Inflammation; Metabolite;
Metabolic Mitophagy Enzyme/Protease HY-B0302 Etidronic acid
Apoptosis Apoptosis Etidronic acid (HEDPA) is a bisphosphonate used
2809-21-4 in detergents, water treatment, cosmetics and
pharmaceutical treatment. Target: Others Etidronic acid (HEDPA) is
a chelating agent and may be added to bind to or counter the
effects of substances such as iron, or other metal ions that can
occur in the presence of some soaps. Etidronic acid also acts to
retard oxidation of fatty acids. For clarification, a chelator, or
chelating agent is a binding component added to many cosmetics,
beauty products, and water softeners to form multiple bonds with a
single metal ion and neutralize it. HY-B0314 Talc Others Others
Talc, a naturally occurring mineral composed 14807-96-6 primarily
of magnesium, silicon and oxygen, is used in many cosmetics, from
baby powder to blush. HY-B0315 Vitamin B12 Endogenous Metabolic
Vitamin B12 is a water soluble vitamin with a key 68-19-9
Metabolite Enzyme/Protease role in the normal functioning of the
brain and nervous system, and for the formation of blood. HY-B0342
Meglumine Others Others Meglumine is an amino sugar derived from
6284-40-8 sorbitol. Target: Others Meglumine is often used as an
excipient in pharmaceuticals and in conjunction with iodinated
compounds in contrast media such as diatrizoate meglumine and
iodipamide meglumine. HY-B0351 Taurine Autophagy; Autophagy;
Taurine is an organic acid widely distributed in 107-35-7
Endogenous Metabolic animal tissues. Metabolite Enzyme/Protease
Target: Others Taurine is a major constituent of bile and can be
found in the large intestine and accounts for approximately 0.1% of
total human body weight. Taurine is present in high concentration
in algae and in the animals including insects and arthropods, but
is generally absent or present in traces in the bacterial and plant
kingdoms. In cardiac tissue alone, taurine levels of 20 mM or
higher may be found. Taurine availability protects against
cholestasis induced by monohydroxy bile acids remains confined to
guinea pigs. Oral supplementation of taurine results in increased
plasma taurine concentrations and is associated with normalization
of left ventricular function in both groups of cats. Myocardial
concentrations of taurine are directly related to plasma
concentrations and low plasma concentrations are found to be
associated with myocardial failure in cats, proposing a direct link
occurs between decreased taurine concentration in the myocardium
and decreased myocardial mechanical function. HY-B0361 Aspartame
Others Others Aspartame (SC-18862) is an artificial, non-
22839-47-0 saccharide sweetener used as a sugar substitute in some
foods and beverages. HY-B0389 Dextrose Endogenous Metabolic
Dextrose, a simple sugar (monosaccharide), is an 50-99-7 Metabolite
Enzyme/Protease important carbohydrate in biology. Target: Others
Dextrose(D-glucose), a simple sugar (monosaccharide), is an
important carbohydrate in biology. HY-B0399 L-Carnitine Endogenous
Metabolic L-carnitine (Levocarnitine) is constituent of 541-15-1
Metabolite Enzyme/Protease striated muscle and liver. It is used
therapeutically to stimulate gastric and pancreatic secretions and
in the treatment of hyperlipoproteinemias. Target: Others
L-carnitine (Levocarnitine) is an endogenous molecule involved in
fatty acid metabolism, biosynthesized within the human body using
amino acids: L-lysine and L-methionine, as substrates. L-carnitine
(Levocarnitine) can also be found in many foods, but red meats,
such as beef and lamb, are the best choices for adding carnitine
into the diet. Administering L-carnitine (510 mg/day) to patients
with the disease. L-carnitine (Levocarnitine) treatment
significantly improved the total time for dozing off during the
daytime, calculated from the sleep logs, compared with that of
placebo-treated periods. L-carnitine (Levocarnitine) efficiently
increased serum acylcarnitine levels, and reduced serum
triglycerides concentration. L-carnitine (Levocarnitine) and its
derivatives show promise in the treatment of chronic conditions and
diseases associated with mitochondrial dysfunction but further
translational studies are needed to fully explore their potential.
HY-B0400 D-Sorbitol Endogenous Metabolic D-Sorbitol is a sugar
alcohol that is commonly 50-70-4 Metabolite Enzyme/Protease used as
a sugar substitute. Target: Others D-Sorbitol occurs naturally and
is also produced synthetically from glucose. The food industry uses
D-sorbitol as an additive in the form of a sweetener, humectant,
emulsifier, thickener, or dietary supplement. D-Sorbitol has also
been found in cosmetics, paper, and pharmaceuticals. Naturally,
D-sorbitol occurs widely in plants via photosynthesis, ranging from
algae to higher order fruits of the family
Rosaceae. From Wikipedia. HY-B0430A D-Pantothenic acid Apoptosis
Apoptosis D-Pantothenic acid sodium (Sodium pantothenate) 867-81-2
(sodium) is an essential trace nutrient that functions as the
obligate precursor of coenzyme A (CoA). D- Pantothenic acid sodium
plays key roles in myriad biological processes, including many that
regulate carbohydrate, lipid, protein, and nucleic acid metabolism.
HY-B0456 Riboflavin Endogenous Metabolic Riboflavin is an easily
absorbed micronutrient 83-88-5 Metabolite Enzyme/Protease with a
key role in maintaining health in humans and other animals. Target:
Others Riboflavin (vitamin B2) is the direct precursor of redox
enzyme cofactors flavin mononucleotide (FMN) and flavin adenine
dinucleotide (FAD), which are essential for multiple cell
physiology. Urinary excretion of riboflavin contributes to one-
half of the overall removal of riboflavin from plasma. No sex
differences were observed for any of the pharmacokinetic variables
(P > 0.05). Riboflavin, similar to other vitamins of the B
complex, presents anti-inflammatory activity but its full
characterization has not yet been carried out. Riboflavin (25, 50
or 100 mg/kg, i.p.), administered immediately and 2 h after the
injection of carrageenan, induced antiedema and antinociceptive
effects. The antinociceptive effect was not inhibited by the
pretreatment with cadmium sulfate (1 mg/kg), an inhibitor of
flavokinase. Riboflavin (50 or 100 mg/kg, i.p., 0 and 2 h) also
inhibited the fever induced by lipopolysaccharide (LPS) in rats.
Riboflavin is a safe drug, is approved for clinical use and
exacerbates the antinociceptive effect of morphine, may warrant
clinical trials to assess its potential in the treatment of
different painful or inflammatory conditions. HY-B0511 Biotin
Others Others Biotin is an enzyme co-factor present in minute
58-85-5 amounts in every living cell. Target: Others Biotin is
necessary for cell growth, the production of fatty acids, and the
metabolism of fats and amino acids. It plays a role in the citric
acid cycle, which is the process by which biochemical energy is
generated during aerobic respiration. Biotin is a coenzyme for
carboxylase enzymes, involved in the synthesis of fatty acids,
isoleucine, and valine, and in gluconeogenesis. In addition, biotin
is widely used throughout the biotechnology industry to conjugate
proteins for biochemical assays. The dietary biotin intake in
Western populations has been estimated to be 35 to 70 microg/d
(143-287 nmol/d). Recent studies suggest that humans absorb biotin
nearly completely. Conditions that may increase biotin requirements
in humans include pregnancy, lactation, and therapy with
anticonvulsants or lipoic acid. HY-B0647 Butylphthalide Others
Others Butylphthalide(3-n-Butylphthalide) is an anti- 6066-49-5
cerebral-ischemia drug; first isolated from the seeds of celery,
showed efficacy in animal models of stroke. IC50 value: Target:
3-n-butylphthalide alleviates oxidative stress caused by chronic
cerebral ischemia, improves cholinergic function, and inhibits
amyloid beta accumulation, thereby improving cerebral neuronal
injury and cognitive deficits. Intragastric NBP administration to
4-month-old SAMP8 mice for 2 months significantly improved spatial
learning and memory ability. Moreover, the loss of choline
acetyltransferase (ChAT)-positive neurons in the medial septal
nucleus and the vertical limb of the diagonal band in SAMP8 mice
was slowed down, as was the decline in the protein and mRNA
expression of ChAT in the hippocampus, cerebral cortex, and
forebrain. HY-B0717 Tocofersolan Others Others Tocofersolan is a
synthetic polyethylene glycol 9002-96-4 derivative of
.alpha.-tocopherol. HY-B0892 Benzyl alcohol Others Others Benzyl
alcohol is an aromatic alcohol; a colorless 100-51-6 liquid with a
mild pleasant aromatic odor. HY-B0896 Triacetin Endogenous
Anti-infection; Triacetin is an artificial chemical compound, is
the 102-76-1 Metabolite; Metabolic triester of glycerol and acetic
acid, and is the Fungal Enzyme/Protease second simplest fat after
triformin. HY-B0914 10-Undecenoic acid Antibiotic; Anti-infection;
10-Undecenoic acid was used as a starting reagent 112-38-9
Endogenous Metabolic in the syntheses of Pheromone
(11Z)-hexadecenal. Metabolite; Enzyme/Protease Fungal HY-B0934
Ethylparaben Bacterial Anti-infection Ethylparaben is the ethyl
ester of p-hydroxybenzoic 120-47-8 acid, used as an antifungal
preservative. and food additive HY-B0935 Benzyl benzoate Parasite
Anti-infection Benzyl benzoate is used for treatment of paediatric
120-51-4 scabies. HY-B0940 Ethylvanillin Others Others
Ethylvanillin is a flavorant, about three times as 121-32-4 potent
as vanillin and is used in the production of chocolate. HY-B0964
Riboflavin Endogenous Metabolic Riboflavin phosphate sodium
significantly 130-40-5 (phosphate sodium) Metabolite
Enzyme/Protease increases in corneal biomechanical stiffness
HY-B0985 Phenazopyridine Others Others Phenazopyridine
hydrochloride is a chemical, 136-40-3 (hydrochloride) which has a
local analgesic effect, often used to alleviate the pain,
irritation, discomfort, or urgency caused by urinary tract
infections, surgery, or injury to the urinary tract. HY-B0987
Ascorbyl Endogenous Immunology/ Ascothyl palmitate is an ester
formed from 137-66-6 palmitate Metabolite; Inflammation; ascorbic
acid and palmitic acid creating a fat- Reactive Metabolic soluble
form of vitamin C, it is also used as an Oxygen Enzyme/Protease;
antioxidant food additive. Species NF-.kappa.B HY-B1008
4-Aminobenzoic Endogenous Metabolic 4-Aminobenzoic acid is an
intermediate in the 150-13-0 acid Metabolite Enzyme/Protease
synthesis of folate by bacteria, plants, and fungi. HY-B1066
Butylhydroxyanisole Ferroptosis; Apoptosis; Butylhydroxyanisole is
an antioxidant, consisting 25013-16-5 Reactive Immunology/ of a
mixture of two isomeric organic compounds, Oxygen Inflammation;
used as a food additive preservative Species Metabolic
Enzyme/Protease; NF-.kappa.B HY-B1092 Gluconate Others Others
Gluconate Calcium (Calcium D-gluconate) is a 299-28-5 (Calcium)
mineral supplement, manufactured by the neutralization of gluconic
acid with lime or calcium carbonate. HY-B1092A Gluconate (sodium)
Endogenous Metabolic Gluconate sodium (D-Gluconic acid sodium salt)
527-07-1 Metabolite Enzyme/Protease is a corrosion and scale
inhibitor of ordinary steel in simulated cooling water. HY-B1131
Taurocholic acid Endogenous Metabolic Taurocholic acid sodium salt
hydrate (Sodium 345909-26-4 (sodium salt Metabolite Enzyme/Protease
taurocholate hydrate) is a bile acid involved in the hydrate)
emulsification of fats. HY-B1173 (+)-Camphor Bacterial
Anti-infection (+)-Camphor is an ingredient in cooking, and as
464-49-3 an embalming fluid for medicinal purposes, HY-B1211
Dehydroacetic Bacterial; Anti-infection Dehydroacetic acid (Biocide
470F), a pyrone 520-45-6 acid Fungal derivative acts as an
antibacterial and antifungal agent. Dehydroacetic acid possess
phytotoxic activity. HY-B1263 Chlorobutanol Bacterial;
Anti-infection Chlorobutanol is a pharmaceutical preservative
57-15-8 Fungal with sedative-hypnotic actions. Chlorobutanol is
active against a wide variety of Gram-positive and Gram-negative
bacteria, and several mold spores and fungi. HY-B1268 Docusate
(Sodium) HSV Anti-infection Docusate Sodium (Dioctyl sulfosuccinate
sodium 577-11-7 salt) is a laxative used to for the research of
constipation, for constipation due to the use of opiates it may be
used with a stimulant laxative, can be taken by mouth or rectally.
HY-B1278 D-.alpha.-Tocopherol Endogenous Metabolic
D-.alpha.-Tocopherol acetate (D-Vitamin E acetate) can 58-95-7
acetate Metabolite Enzyme/Protease be hydrolyzed to
d-alpha-tocopherol (VE) and absorbed in the small intestine.
HY-B1289 Cetylpyridinium Bacterial Anti-infection Cetylpyridinium
chloride monohydrate is a 6004-24-6 (chloride cationic quaternary
ammonium compound, used in monohydrate) some types of mouthwashes,
toothpastes, throat and nasal sprays, is an antiseptic that kills
bacteria and other microorganisms, effective in preventing dental
plaque and reducing gingivitis. HY-B1337 Choline (chloride) Others
Others Choline chloride is an organic compound and a 67-48-1
quaternary ammonium salt, an acyl group acceptor and choline
acetyltransferase substrate, also is an important additive in feed
especially for chickens where it accelerates growth. HY-B1342
Vitamin A Endogenous Metabolic Retinol, also known as Vitamin A1,
has pleiotropic 68-26-8 Metabolite Enzyme/Protease functions
including vison, immunity, hematopoiesis, reproduction, cell
differentiation/growth, and development. HY-B1384 Retinyl palmitate
Endogenous Metabolic Retinyl palmitate is an ester of Retinol and
is the 79-81-2 Metabolite Enzyme/Protease major form of vitamin A
found in the epidermis. Retinyl palmitate has been widely used in
pharmaceutical and cosmetic formulations. HY-B1389 Lactitol Others
Others Lactitol monohydrate is a disaccharide analogue 81025-04-9
(monohydrate) of lactulose. It has been widely used in the
treatment of constipation & hepatic encephalopathy. Lactitol is
sugar alcohol used as replacement sweeteners. HY-B1391 D-Panthenol
Endogenous Metabolic D-Panthenol is the biologically-active alcohol
of 81-13-0 Metabolite Enzyme/Protease pantothenic acid, which leads
to an elevation in the amount of coenzyme A in the cell. HY-B1411
i-Inositol Endogenous Metabolic i-Inositol is a chemical compound,
associated 87-89-8 Metabolite Enzyme/Protease lipids are found in
many foods, in particular fruit, especially cantaloupe and oranges.
HY-B1425 Ethoxyquin HSP; Reactive Cell Cycle/ Ethoxyquin is an
antioxidant which has been used 91-53-2 Oxygen DNA Damage; in
animal feed for many years and also an Species Immunology/
inhibitor of heat shock protein 90 (Hsp90). Inflammation; Metabolic
Enzyme/Protease; NF-.kappa.B HY-B1431 Butylparaben Bacterial;
Anti-infection; Butylparaben is an organic compound, has proven
94-26-8 Endogenous Metabolic to be a highly successful
antimicrobial preservative Metabolite Enzyme/Protease in cosmetics,
also used in medication suspensions, and as a flavoring additive in
food. HY-B1465 1-Hexadecanol Endogenous Metabolic 1-Hexadecanol is
a fatty alcohol, a lipophilic 36653-82-4 Metabolite Enzyme/Protease
substrate. HY-B1521 Aluminum Others Others Aluminum Hydroxide is an
orally active main 21645-51-2 Hydroxide form of aluminum used as
adjuvant. Aluminum hydroxide-based adjuvant researches including
the repository effect, pro-phagocytic effect, and activation of the
pro-inflammatory NLRP3 pathway. Aluminum Hydroxide also acts as
adjuvant to compensate low inherent immunogenicity of HY-B1550
Benzoin subunit vaccines. 119-53-9 HY-B1610 Sodium citrate
Bacterial Anti-infection Sodium citrate dehydrate is an
anticoagulant and 6132-04-3 (dihydrate) also used as a buffer and
food preservatives. HY-B1620 Polyvinylpyrrol Others Others
Polyvinylpyrrolidone is a compound which has 9003-39-8 idone been
widely tested and used in human and veterinary medicine as an
effective wound healing accelerator and disinfectant when combined
with
iodine and other compounds. HY-B1645 Ferric Ammonium 1185-57-5
Citrate HY-B1651 Iron(II) fumarate Others Others Iron(II) fumarate
(Ferrous fumarate) is the iron (II) 141-01-5 salt of fumaric acid.
Iron(II) fumarate is an orally active dietary supplement and has
the potential for iron deficiency anemia treatment. HY-B1659
Glycerol Endogenous Metabolic Glycerol is a clear, colourless,
viscous, sweet- 56-81-5 Metabolite Enzyme/Protease tasting liquid.
Glycerol is used in sample preparation and gel formation for
polyacrylamide gel electrophoresis. HY-B1673 Pharmatose DCL 14
Endogenous Metabolic Pharmatose DCL 14 is an endogenous metabolite.
64044-51-5 Metabolite Enzyme/Protease HY-B1695 Methyl nicotinate
Others Others Methyl nicotinate, the methyl ester of Niacin found
93-60-7 in alcoholic beverages, that is used as an active
ingredient as a rubefacient in over-the-counter topical
preparations indicated for muscle and joint pain. HY-B1731 Phenyl
Salicylate 118-55-8 HY-B1732 DL-3-Phenylalanine 150-30-1 HY-B1779
Sucrose Endogenous Metabolic Sucrose is a disaccharide which is
composed of 57-50-1 Metabolite Enzyme/Protease two monosaccharides,
glucose and fructose. HY-B1804 Tricaprilin Endogenous Metabolic
Tricaprilin (Trioctanoin) is used in study for 538-23-8 Metabolite
Enzyme/Protease patients with mild to moderate Alzheimer's disease
and has a role as an anticonvulsant and a plant metabolite.
HY-B1812 1,2- Others Others 1,2-Dimethoxybenzene is an naturally
occurring 91-16-7 Dimethoxybenzene insect attractant. HY-B1960
Canthaxanthin Reactive Immunology/ Canthaxanthin is a red-orange
carotenoid with 514-78-3 Oxygen Inflammation; various biological
activities, such as antioxidant, Species Metabolic antitumor
properties. Enzyme/Protease; NF-.kappa.B HY-B2118 Pancreatin Others
Others Pancreatin is the porcine pancreas extract (PPE) 8049-47-6
which contains the main pancreatic digestive enzymes. HY-B2122
Maltitol Others Others Maltitol is a sugar alcohol used as a sugar
substitute. 585-88-6 It has 75-90% of the sweetness of sucrose
(table sugar) and nearly identical properties. Maltitol may also be
used as a plasticizer in gelatin capsules, as an emollient, and as
a humectant. HY-B2123 Lactose Endogenous Metabolic Lactose, a major
sugar in the milk of most 63-42-3 Metabolite Enzyme/Protease
species, could regulate human's intestinal microflora. HY-B2136
Tannic acid Potassium Membrane Tannic acid is a novel hERG channel
blocker with 1401-55-4 Channel Transporter/Ion IC50 of 3.4 .mu.M.
Channel HY-B2163 Astaxanthin PPAR; Cell Cycle/DNA Astaxanthin, a
red dietary carotenoid isolated from 472-61-7 Reactive Damage;
Haematococcus pluvialis, is a modulator of PPAR.gamma. Oxygen
Immunology/ and a potent antioxidant with antiproliferative,
Species Inflammation; neuroprotective and anti-inflammatory
activity. Metabolic Astaxanthin has potential in the study of
various Enzyme/Protease; diseases, such as cancers and Parkinson's
disease, NF-.kappa.B cardiovascular disease. Due to its bright red
colour, Astaxanthin could be used as a food colorant in animal
feeds. HY-B2200 Calcium citrate 5785-44-4 tetrahydrate HY-B2201
Trisodium citrate 68-04-2 HY-B2203 Calcium glycerol 27214-00-2
phosphate HY-B2205 Magnesium silicate 1343-88-0 HY-B2217 Calcium
hydroxide 1305-62-0 HY-B2218 Magnesium 1309-42-8 hydroxide HY-B2219
Stearic acid Endogenous Metabolic Stearic acid is a long chain
dietary saturated fatty 57-11-4 Metabolite Enzyme/Protease acid
which exists in many animal and vegetable fats and oils. HY-B2221
Cellulose 9004-34-6 HY-B2221B Hydroxyethyl Others Others
Hydroxyethyl cellulose is a non-ionic, water 9004-62-0 cellulose
soluble, modified cellulose polymer used as a thickening agent for
aqueous cosmetic and personal care formulations. HY-B2223 Thiamine
nitrate Others Others Thiamine nitrate is an essential vitamin
which 532-43-4 can enhance normal neuronal actives. HY-B2225 Starch
9005-25-8 HY-B2226 Sodium copper HIV; Anti-infection Sodium copper
chlorophyllin B exerts antiviral 28302-36-5 chlorophyllin B
Influenza activities against Influenza virus and HIV with Virus
IC50s of 50 to 100 .mu.M for both of them. HY-B2227A Calcium
lactate 814-80-2 HY-B2228 Proteinase Others Others Proteinase
refers to the enzymes with proteolytic 9001-92-7 activity. HY-B2232
Benzalkonium Bacterial Anti-infection Benzalkonium chloride is a
potent anti-microbial 8001-54-5 (chloride) agent, used as a
preservative in eye drops. HY-B2235 Lecithin Endogenous Metabolic
Lecithin is regarded as a safe, conventional 8002-43-5 Metabolite
Enzyme/Protease phospholipid source. Phospholipids are reported to
alter the fatty acid composition and microstructure of the
membranes in animal cells. HY-B2237 Lysozyme from Bacterial
Anti-infection Lysozyme from chicken egg white is a bactericidal
12650-88-3 chicken egg white enzyme present in chicken eggs, and it
lyses gram-positive bacteria. IC50 & Target: Bacteria In vitro:
Lysozyme is an ubiquitous enzyme. The hen egg is the most abundant
source of lysozyme, which constitutes approximately 3.4% of the
albumen proteins. Lysozyme is a natural antimicrobial that
hydrolyzes the .beta.(1-4) glycosidic linkage between
N-acetylmuramic acid and N- acetylglucosamine found in the
peptidoglycan layer of the bacterial cell wall and causing cell
lysis. The bactericidal effect of lysozyme is primarily limited to
gram-positive bacteria, including pathogens such as Listeria
monocytogenes and certain Clostridium species as well as some
spoilage organisms, including thermophilic spore- forming bacteria
and certain yeasts. The gram- negative bacteria are more resistant
to lysozyme action because of their complex cell wall structure.
HY-B2241 Aluminum 7784-24-9 potassium disulfate dodecahydrate
HY-B2242 Calcium phosphate 7757-93-9 HY-B2243 Dihydrogen 7558-80-7
monosodium phosphate HY-D0195 Acesulfame 55589-62-3 (potassium)
HY-D0227 Trometamol Others Others Trometamol is a biologically
inert amino alcohol 77-86-1 of low toxicity, which buffers carbon
dioxide and acids in vitro and in vivo. Trometamol is an effective
amine compound for pH control in the physiological range. HY-D0249
Sunset Yellow Others Others Sunset Yellow FCF is a
petroleum-derived orange 2783-94-0 FCF azo dye with a pH dependent
maximum absorption at about 480 nm at pH 1 and 443 nm at pH 13.
Sunset Yellow is used in food, cosmetics, and drugs. HY-D0257
Tartrazine Others Others Tartrazine is a synthetic lemon yellow azo
dye 1934-21-0 primarily used as a food coloring. Tartrazine is
water-soluble and has a maximum absorbance in an aqueous solution
at 425 nm. HY-D0259 Erythrosine B Others Others Erythrosine B is an
artificial dye widely used in 16423-68-0 the food and textile
industries. Erythrosine B is also a novel photosensitizer which has
been used to develop animal models. HY-D0307A Amaranth Others
Others Amaranth is a dark red to purple azo dye used as 915-67-3 a
food dye and to color cosmetics. Amaranth is an anionic dye. It can
be applied to natural and synthetic fibers, leather, paper, and
phenol- formaldehyde resins. HY-D0833 Calcium 7758-87-4
orthophosphate HY-D0835 Hydroxylapatite HY-D0887 Disodium Others
Others Disodium 5'-inosinate, obtained from bacterial 4691-65-0
5'-inosinate fermentation of sugars, is as a food additive and
often found in a variety of other snacks. HY-D0914 Fast Green FCF
Others Others Fast Green FCF is a sea green triarylmethane food
2353-45-9 dye. Fast Green FCF is used as a quantitative stain for
histones at alkaline pH after acid extraction of DNA. It is also
used as a protein stain in electrophoresis. Its absorption maximum
is at 625 nm. HY-D0915 Brilliant Blue FCF Others Others Brilliant
Blue FCF has the appearance of a 3844-45-9 reddish-blue powder. It
is soluble in water, and the solution has a maximum absorption at
about 628 nanometers. It is a synthetic dye produced using aromatic
hydrocarbons from petroleum, is a colorant for foods and other
substances. HY-D1005 Poloxamer 407 Others Others Poloxamer 407 is a
nonionic surfactant that is 9003-11-6 100% active and relatively
non-toxic to cells at low concentrations, and frequently used with
dye AM esters such as Indo-1 AM, Fura-2 AM, Calcein AM, Fluo-3 AM,
Fluo-4 AM, Quest Fluo-8? AM and Quest Rhod-4? AM, etc. to improve
their water solubility. HY-D1005A Poloxamer 188 Others Others
Poloxamer 188 is a nonionic linear copolymer 691397-13-4 with
surfactant properties. Poloxamer 188 exhibits anti-thrombotic,
anti-inflammatory, and cytoprotective activities in various tissue
injury models. HY-ER013 Sodium carbonate 497-19-8 HY-I0301
D-(+)-Glucono-1,5- Endogenous Immunology/ D-(+)-Glucono-1,5-lactone
is a polyhydroxy 90-80-2 lactone Metabolite; Inflammation; (PHA)
that is capable of metal chelating, Reactive Metabolic moisturizing
and antioxidant activity. Oxygen Enzyme/Protease; Species
NF-.kappa.B HY-I0501 2'- Bacterial Anti-infection
2'-Aminoacetophenone is an aromatic compound 551-93-9
Aminoacetophenone containing a ketone substituted by one alkyl
group, and a phenyl group. 2'-Aminoacetophenone can be used as a
breath biomarker for the detection of Ps. Aeruginosa infections in
the cystic fibrosis lung. HY-N0060A Ferulic acid Endogenous
Immunology/ Ferulic acid sodium is a novel fibroblast growth
24276-84-4 (sodium) Metabolite; Inflammation; factor receptor 1
(FGFR1) inhibitor with IC50s of FGFR; Metabolic 3.78 and 12.5 .mu.M
for FGFR1 and FGFR2, Reactive Enzyme/Protease; respectively. Oxygen
NF-.kappa.B; Protein Species Tyrosine Kinase/ RTK HY-N0098 Vanillin
Endogenous Metabolic Vanillin (p-Vanillin) is a single molecule
extracted 121-33-5 Metabolite Enzyme/Protease from vanilla beans
and also a popular odor used widely in perfume, food and medicine.
HY-N0119 Naringin NF-.kappa.B NF-.kappa.B Naringin Dihydrochalcone
is an artificial sweetener 18916-17-1 Dihydrochalcone derived from
naringin. Naringin is a major flavanone glycoside obtained from
tomatoes, grapefruits, and many other citrus fruits. Naringin
exhibits biological properties such as antioxidant,
anti-inflammatory, and antiapoptotic activities. Naringin
suppresses NF-.kappa.B signaling pathway. HY-N0129 Sclareolide
Bacterial Anti-infection Sclareolide is isolated from the flower of
Salvia 564-20-5 sclarea with antibacterial and cytotoxic
activities. HY-N0138 Theobromine Adenosine GPCR/G Protein;
Theobromine is a methylxanthine found in cacao 83-67-0 Receptor;
Metabolic beans which can inhibit adenosine receptor A1 Endogenous
Enzyme/Protease (AR1) signaling
Metabolite HY-N0142 Phloretin Endogenous Membrane Phloretin (NSC
407292; RJC 02792) is a flavonoid 60-82-2 Metabolite;
Transporter/Ion extracted from Prunus mandshurica, has anti- GLUT;
SGLT Channel; inflammatory activities. Phloridzin is a specific,
Metabolic competitive and orally active inhibitor of sodium/
Enzyme/Protease glucose cotransporters in the intestine (SGLT1) and
kidney (SGLT2). Phloretin inhibits Yeast- made GLUT1 as well as
Human erythrocyte GLUT1 with IC50values of 49 .mu.M and 61 .mu.M,
respectively. Phloretin has the potential for the treatment of
rheumatoid arthritis (RA)?and allergic airway inflammation.
HY-N0144 Piperine Autophagy; Autophagy; Piperine, a natural
alkaloid isolated from Piper 94-62-2 Endogenous Membrane nigrum L,
inhibits P-glycoprotein and CYP3A4 Metabolite; Transporter/Ion
activities with an IC50 value of 61.94 .+-. 0.054 P-glycoprotein
Channel; .mu.g/mL in HeLa cell. Metabolic Enzyme/Protease HY-N0148
Rutin Autophagy; Anti-infection; Rutin, a naturally occurring
flavonoid glycoside, 153-18-4 Endogenous Autophagy; has
antioxidant, anti-inflammatory, anti-allergic, Metabolite;
Immunology/ anti-angiogenic and antiviral properties. Influenza
Inflammation; Virus; Metabolic Reactive Enzyme/Protease; Oxygen
NF-.kappa.B Species HY-N0154 Neohesperidin Reactive Immunology/
Neohesperidin dihydrochalcone is a synthetic 20702-77-6
dihydrochalcone Oxygen Inflammation; glycoside chalcone, is added
to various foods and Species Metabolic beverages as a low caloric
artificial sweetener. Enzyme/Protease; NF-.kappa.B HY-N0163
Magnolol Autophagy; Anti-infection; Magnolol, a natural lignan
isolated from the stem 528-43-8 Bacterial; Autophagy; Cell bark of
Magnolia officinalis, is a dual agonist of PPAR; Cycle/DNA both
RXR.alpha. and PPAR.gamma., with EC50 values of 10.4 RAR/RXR
Damage; .mu.M and 17.7 .mu.M, respectively. Metabolic
Enzyme/Protease HY-N0168 Hesperetin Apoptosis; Apoptosis;
Hesperetin is a natural flavanone, and acts as a 520-33-2
Autophagy; Autophagy; potent and broad-spectrum inhibitor against
human p38 MAPK MAPK/ERK UGT activity. Hesperetin induces apoptosis
via Pathway p38 MAPK activation. HY-N0184 Glycyrrhizic acid Virus
Protease Anti-infection Glycyrrhizic acid is a triterpenoid
saponinl, acting 1405-86-3 as a direct HMGB1 antagonist, with
anti-tumor, anti-diabetic activities. HY-N0198 Nordihydroguaiarctic
Autophagy; Apoptosis; Nordihydroguaiaretic acid is a 5-lipoxygenase
500-38-9 acid Ferroptosis; Autophagy; (5LOX) (IC50 = 8 .mu.M) and
tyrosine kinase Lipoxygenase Metabolic inhibitor. Enzyme/Protease
HY-N0215 L-Phenylalanine Calcium Membrane L-Phenylalanine
((S)-2-Amino-3-phenylpropionic 63-91-2 Channel; Transporter/Ion
acid) is an essential amino acid isolated from Endogenous Channel;
Escherichia coli. L-Phenylalanine is a .alpha.2.delta. Metabolite;
Metabolic subunit of voltage-dependent Ca+ channels iGluR
Enzyme/Protease; antagonist with a Ki of 980 nM. L-phenylalanine is
Neuronal a competitive antagonist for the glycine- and Signaling
glutamate-binding sites of N-methyl-D-aspartate receptors (NMDARs)
(KB of 573 .mu.M) and non- NMDARs, respectively. L-Phenylalanine is
widely used in the production of food flavors and pharmaceuticals.
HY-N0216 Benzoic acid Bacterial; Anti-infection; Benzoic acid is an
aromatic alcohol existing 65-85-0 Endogenous Metabolic naturally in
many plants and is a common Metabolite; Enzyme/Protease additive to
food, drinks, cosmetics and other Fungal products. It acts as
preservatives through inhibiting both bacteria and fungi. HY-N0229
L-Alanine Endogenous Metabolic L-Alanine is a non-essential amino
acid, involved 56-41-7 Metabolite Enzyme/Protease in sugar and acid
metabolism, increases immunity, and provides energy for muscle
tissue, brain, and central nervous system. HY-N0230 .beta.-Alanine
Endogenous Metabolic .beta.-Alanine is a non-essential amino acid
that is 107-95-9 Metabolite Enzyme/Protease shown to be metabolized
into carnosine, which functions as an intracellular buffer.
HY-N0264 Tetramethylpyrazine Apoptosis Apoptosis
Tetramethylpyrazine (Ligustrazine), an 1124-11-4 alkylpyrazine
isolated from Ligusticum wallichii (Chuan Xiong), is present in
french fries, bread, cooked meats, tea, cocoa, coffee, beer,
spirits, peanuts, filberts, dairy products and soy products as
fragrance and flavouring ingredienexhibits. Tetramethylpyrazine
(Ligustrazine) also has potential nootropic and anti-inflammatory
activities in rats. HY-N0287 Lycopene Reactive Immunology/ Lycopene
is naturally occurring carotenoids 502-65-8 Oxygen Inflammation;
found in tomato, tomato products, and in other Species Metabolic
red fruits and vegetables; exhibits antioxidant Enzyme/Protease;
effects. NF-.kappa.B HY-N0294 Protocatechuic acid Others Others
Protocatechuic acid is a phenolic compound 99-50-3 which exhibits
neuroprotective effect. HY-N0324 Cholic acid Endogenous Metabolic
Cholic acid is a major primary bile acid 81-25-4 Metabolite
Enzyme/Protease produced in the liver and usually conjugated with
glycine or taurine. It facilitates fat absorption and cholesterol
excretion. HY-N0325 DL-Methionine 59-51-8 HY-N0326 L-Methionine
Endogenous Metabolic L-Methionine is the L-isomer of Methionine, an
63-68-3 Metabolite Enzyme/Protease essential amino acid for human
development. Methionine acts as a hepatoprotectant. HY-N0336 3-
Parasite Anti-infection 3-Butylidenephthalide (Butylidenephthalide)
is 551-08-6 Butylidenephthalide a phthalic anhydride derivative
identified in Ligusticum chuanxiong Hort, and has larvicidal
activity (LC50 of 1.56 mg/g for Spodoptera litura larvae). HY-N0337
Eugenol Apoptosis; Anti-infection; Eugenol is an essential oil
found in cloves with 97-53-0 Bacterial; Apoptosis; antibacterial,
anthelmintic and antioxidant Ferroptosis; Immunology/ activity.
Eugenol is shown to inhibit lipid Parasite; Inflammation;
peroxidation. Reactive Metabolic Oxygen Enzyme/Protease; Species
NF-.kappa.B HY-N0349 Methyl Paraben Bacterial; Anti-infection;
Methyl Paraben, isolated from the barks of 99-76-3 Endogenous
Metabolic Tsuga dumosa the methyl ester of p- Metabolite
Enzyme/Protease hydroxybenzoic acid, is a standardized chemical
allergen. Methyl Paraben is a stable, non-volatile compound used as
an antimicrobial preservative in foods, drugs and cosmetics. The
physiologic effect of Methyl Paraben is by means of increased
histamine release, and cell- mediated immunity. HY-N0367
Trans-Anethole Endogenous Metabolic Trans-Anethole ((E)-Anethole),
a phenylpropene 4180-23-8 Metabolite Enzyme/Protease derivative
isolated from Pimpinella, shows estrogenic activity at lower
concentrations and cytotoxic at higher concentrations in cancer
cell lines. Trans-Anethole ((E)-Anethole) contributes a large
component of the odor and flavor of anise and fennel, anise myrtle,
liquorice, camphor, magnolia blossoms, and star anise. HY-N0368
Linalool Apoptosis; Apoptosis; Linalool is natural monoterpene in
essential olis 78-70-6 Endogenous Membrane of coriander, acts as a
competitive antagonist of Metabolite; Transporter/Ion Nmethyl
d-aspartate (NMDA) receptor, with iGluR Channel; anti-tumor,
anti-cardiotoxicity activity. Linalool Metabolic is a PPAR.alpha.
ligand that reduces plasma TG levels Enzyme/Protease; and rewires
the hepatic transcriptome and plasma Neuronal metabolome. Signaling
HY-N0378 D-Mannitol Apoptosis; Apoptosis; D-Mannitol is an osmotic
diuretic agent and a 69-65-8 Endogenous Metabolic weak renal
vasodilator. Metabolite Enzyme/Protease Target: Others D(-)Mannitol
is a sugar alcohol that can be used as an inert osmotic control
substance. The uptake and phosphorylation of d-mannitol is
catalyzed by the mannitol-specific phosphoenolpyruvate- dependent
phosphotransferase systems (PTS). Mannitol can interact with
neutrophils and monocytes. Experiments have shown that it is able
to decrease neutrophil apoptosis in vitro. The compound has been
used in studies as a stimulator of cecal microbial growth and
cellulolytic activity in rabbits. It has been observed that
mannitol can lower the fat digestibility and body fat accumulation
in both normal and cecectomized rats, as well as upregulate
monocyte HLA- DR, monocyte and neutrophil CD11b. Studies show that
the mannitol operon is repressed by the transcription factor,
mannitol operon repressor (MtlR) in Escherichia coli. HY-N0390
L-Glutamine Endogenous Apoptosis; L-Glutamine is a non-essential
amino acid 56-85-9 Metabolite; GPCR/G Protein; present abundantly
throughout the body and is Ferroptosis; Metabolic involved in
gastrointestinal disorders. mGluR Enzyme/Protease; Target: mGluR
Neuronal Glutamine (abbreviated as Gln or Q) is one of Signaling
the 20 amino acids encoded by the standard genetic code. It is not
recognized as an essential amino acid, but may become conditionally
essential in certain situations, including intensive athletic
training or certain gastrointestinal disorders. Its side-chain is
an amide formed by replacing the side-chain hydroxyl of glutamic
acid with an amine functional group, making it the amide of
glutamic acid. Its codons are CAA and CAG. In human blood,
glutamine is the most abundant free amino acid, with a
concentration of about 500-900 .mu.mol/L. Glutamine is synthesized
by the enzyme glutamine synthetase from glutamate and ammonia. The
most relevant glutamine- producing tissue is the muscle mass,
accounting for about 90% of all glutamine synthesized. Glutamine is
also released, in small amounts, by the lung and the brain.
Although the liver is capable of relevant glutamine synthesis, its
role in glutamine metabolism is more regulatory than producing,
since the liver takes up large amounts of glutamine derived from
the gut. The most eager consumers of glutamine are the cells of
intestines, the kidney cells for the acid-base balance, activated
immune cells, and manycancer cells. In respect to the last point
mentioned, different glutamine analogues, such as DON, Azaserine or
Acivicin, are tested as anticancer drugs. HY-N0394 L-Cystine
Endogenous Apoptosis; L-Cystine is an amino acid and intracellular
56-89-3 Metabolite; Metabolic thiol, which plays a critical role in
the regulation Ferroptosis Enzyme/Protease of cellular processes.
HY-N0411 .beta.-Carotene Endogenous Metabolic .beta.-Carotene
(Provitamin A) is an organic 7235-40-7 Metabolite Enzyme/Protease
compound and classified as a terpenoid. It is a precursor (inactive
form) of vitamin A. HY-N0420 Succinic acid Endogenous Metabolic
Succinic acid is an intermediate product of the 110-15-6 Metabolite
Enzyme/Protease tricarboxylic acid cycle, as well as one of
fermentation products of anaerobic metabolism. HY-N0445
2-Hydroxy-4- Tyrosinase Metabolic 2-Hydroxy-4-methoxybenzaldehyde,
a chemical 673-22-3 methoxybenzalde Enzyme/Protease compound and an
isomer of Vanillin, could be hyde used to synthesis Urolithin M7.
2-hydroxy-4- methoxybenzaldehyde is a potent tyrosinase inhibitor
from three East African medicinal plants, Mondia whitei, Rhus
vulgaris Meikle, and Sclerocarya caffra Sond. HY-N0455 L-Arginine
Endogenous Immunology/ L-Arginine is the nitrogen donor for
synthesis of 74-79-3 Metabolite; Inflammation; nitric oxide, a
potent vasodilator that is deficient
NO Synthase Metabolic during times of sickle cell crisis.
Enzyme/Protease Target: Others L-Arginine is an .alpha.-amino acid.
It was first isolated in 1886. The L-form is one of the 20 most
common natural amino acids. At the level of molecular genetics, in
the structure of the messenger ribonucleic acid mRNA, CGU, CGC,
CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or
codons that code for arginine during protein synthesis. In mammals,
arginine is classified as a semiessential or conditionally
essential amino acid, depending on the developmental stage and
health status of the individual. L-Arginine is associated with a
decrease in cardiac index while stroke index is maintained in
patients with severe sepsis. Resolution of shock at 72 hours is
achieved by 40% and 24% of the patients in the L-Arginine and
placebo cohorts, respectively. L-Arginine (450 mg/kg during a
15-minute period) amplifies and sustains the hyperemia (38%) and
increases absolute brain blood flow after eNOS upregulation by
chronic simvastatin treatment (2 mg/kg subcutaneously, daily for 14
days) in SV-129 mice. HY-N0466 Rebaudioside A Endogenous Metabolic
Rebaudioside A is a steviol glycoside, .alpha.- 58543-16-1
Metabolite; Enzyme/Protease glucosidase inhibitor with IC50 of
35.01 .mu.g/ml. Glucosidase can inhibit ATP-sensitive K+-channels.
Target: .alpha.-glucosidase IC 50: 35.01 ug/mL In vitro:
rebaudioside A stimulat the insulin secretion from MIN6 cells in a
dose- and glucose-dependent manner. In conclusion, the
insulinotropic effect of rebaudioside A is mediated via inhibition
of ATP-sensitive K+- channels and requires the presence of high
glucose. In vivo: in vivo mouse micronucleus test at doses up to
750 mg/kg bw and an unscheduled DNA synthesis test in rats at doses
up to 2000 mg/kg bw, rebaudioside A do not cause any genotoxic
effects at any of the doses tested. HY-N0467 Rebaudioside C
Endogenous Metabolic Rebaudioside C(Dulcoside B) is used as natural
63550-99-2 Metabolite Enzyme/Protease sweeteners to diabetics and
others on carbohydrate-controlled diets. HY-N0469 L-Lysine
Endogenous Anti-infection; L-lysine is an essential amino acid with
56-87-1 Metabolite; Metabolic important roles in connective tissues
and Virus Protease Enzyme/Protease carnitine synthesis, energy
production, growth in children, and maintenance of immune
functions. HY-N0473 L-Tyrosine Endogenous Metabolic L-Tyrosine is a
non-essential amino acid which 60-18-4 Metabolite Enzyme/Protease
can inhibit citrate synthase activity in the posterior cortex.
HY-N0486 L-Leucine mTOR PI3K/Akt/mTOR L-Leucine is an essential
branched-chain amino 61-90-5 acid (BCAA), which activates the mTOR
signaling pathway. HY-N0524 Propyl gallate Others Others Propyl
gallate is a common food antioxidant. 121-79-9 Propyl gallate can
inhibit the production of acrolein, glyoxal and methylglyoxal.
HY-N0537 Xylose Endogenous Metabolic Xylose, a natural product, can
be catalyzed into 58-86-6 Metabolite Enzyme/Protease xylulose by
xylose isomerase, and it is the key step for anaerobic ethanolic
fermentation of xylose. HY-N0538 Xylitol Autophagy; Autophagy;
Xylitol is a chemical categorized as a 87-99-0 Endogenous Metabolic
polyalcohol or sugar alcohol. Metabolite Enzyme/Protease Target:
Others Xylitol is a chemical categorized as a polyalcohol or sugar
alcohol (alditol). Xylitol has the formula (CHOH)3(CH2OH)2 and is
an achiral isomer of pentane-1,2,3,4,5-pentol. Xylitol is used as a
diabetic sweetener which is roughly as sweet as sucrose with 33%
fewer calories. Unlike other natural or synthetic sweeteners,
xylitol is actively beneficial for dental health by reducing caries
to a third in regular use and helpful to remineralization. Xylitol
is naturally found in low concentrations in the fibers of many
fruits and vegetables, and can be extracted from various berries,
oats, and mushrooms, as well as fibrous material such as corn husks
and sugar cane bagasse and birch. HY-N0593 Deoxycholic acid
Endogenous GPCR/G Protein; Deoxycholic acid is specifically
responsible for 83-44-3 Metabolite; Metabolic activating the G
protein-coupled bile acid GPCR19 Enzyme/Protease receptor TGR5 that
stimulates brown adipose tissue (BAT) thermogenic activity.
HY-N0614 Sucralose Endogenous Metabolic Sucralose is an intense
organochlorine artificial 56038-13-2 Metabolite Enzyme/Protease
sweetener. HY-N0623 L-Tryptophan Endogenous Metabolic L-Tryptophan
(Tryptophan) is an essential 73-22-3 Metabolite Enzyme/Protease
amino acid that is the precursor of serotonin, melatonin, and
vitamin B3. HY-N0626 Sorbic acid Antibiotic; Anti-infection; Sorbic
acid, isolated from Sorbus aucuparia, is 110-44-1 Bacterial;
Metabolic a naturally occurring, highly efficient, and Endogenous
Enzyme/Protease nonpoisonous?food preservative.?Sorbic acid
Metabolite; generally is an effective inhibitor of most molds
Fungal and yeasts and some bacteria. HY-N0633 Muscone Interleukin
Apoptosis; Muscone is the main active monomer of 541-91-3 Related;
NF-.kappa.B; Immunology/ traditional Chinese medicine musk. Muscone
NOD-like Inflammation; inhibits NF-.kappa.B and NLRP3 inflammasome
Receptor NF-.kappa.B activation. Muscone remarkably decreases the
(NLR); TNF levels of inflammatory cytokines (IL-1.beta.,
TNF-.alpha. Receptor and IL-6), and ultimately improves cardiac
function and survival rate. HY-N0650 L-Serine Endogenous Metabolic
L-Serine ((-)-Serine; (S)-Serine), one of the so- 56-45-1
Metabolite Enzyme/Protease called non-essential amino acids, plays
a central role in cellular proliferation. HY-N0658 L-Threonine
Endogenous Metabolic L-Threonine is a natural amino acid, can be
72-19-5 Metabolite Enzyme/Protease produced by microbial
fermentation, and is used in food, medicine, or feed. HY-N0666
L-Aspartic acid Endogenous Metabolic L-Aspartic acid is is an amino
acid, shown to be 56-84-8 Metabolite Enzyme/Protease a suitable
prodrug for colon-specific drug deliverly. HY-N0667 L-Asparagine
Endogenous Metabolic L-Asparagine ((-)-Asparagine) is a
non-essential 70-47-3 Metabolite Enzyme/Protease amino acid that is
involved in the metabolic control of cell functions in nerve and
brain tissue. HY-N0679 Retinyl acetate Others Others Retinyl
acetate is a synthetic acetate ester form 127-47-9 derived from
retinol and has potential antineoplastic and chemo preventive
activities. HY-N0680 Thiamine Apoptosis; Anti-infection; Thiamine
hydrochloride is an essential micronutrient 67-03-8 hydrochloride
Endogenous Apoptosis; needed as a cofactor for many central
Metabolite; Metabolic metabolic enzymes. HBV Enzyme/Protease
HY-N0681 D-Pantothenic acid Apoptosis; Apoptosis; D-Pantothenic
acid hemicalcium salt (Vitamin 137-08-6 (hemicalcium salt)
Endogenous Metabolic B5 calcium salt), a vitamin, can reduce the
Metabolite Enzyme/Protease patulin content of the apple juice. IC50
value: Target: In vitro: In human dermal fibroblasts from three
different donors, D-Pantothenic acid hemicalcium salt accelerates
the wound healing process by increasing the number of migrating
cells, their distance and hence their speed. In addition, cell
division is increased and the protein synthesis changed. In vivo:
HY-N0682 Pyridoxine Endogenous Metabolic Pyridoxine hydrochloride
(Pyridoxol; Vitamin 58-56-0 (hydrochloride) Metabolite;
Enzyme/Protease; B6) is a pyridine derivative. Pyridoxine
Keap1-Nrf2 NF-.kappa.B (Pyridoxol; Vitamin B6) exerts antioxidant
effects in cell model of Alzheimer's disease via the Nrf-2/HO-1
pathway. HY-N0708 Vanillic acid Bacterial; Anti-infection; Vanillic
acid is a flavoring agent found in edible 121-34-6 Endogenous
Metabolic plants and fruits. Vanillic acid inhibits NF-.kappa.B
Metabolite; Enzyme/Protease; activation. Anti-inflammatory,
antibacterial, and NF-.kappa.B NF-.kappa.B chemopreventive effects.
HY-N0709 Coumarin Influenza Anti-infection Coumarin is the primary
bioactive ingredient in 91-64-5 Virus Radix Glehniae, named
Beishashen in China, which possesses many pharmacological
activities, including anticancer, anti- inflammation and antivirus
activities. HY-N0711 Carvacrol Apoptosis; Anti-infection; Carvacrol
is a monoterpenoid phenol isolated 499-75-2 Endogenous Apoptosis;
from Lamiaceae family plants, with antioxidant, Metabolite;
Metabolic anti-inflammatory and anticancer properties. Fungal;
Notch Enzyme/Protease; Carvacrol causes cell cycle arrest in G0/G1,
Neuronal downregulates Notch-1, and Jagged-1, and Signaling; Stem
induces apoptosis. Cell/Wnt HY-N0717 L-Valine Endogenous Metabolic
L-Valine is one of 20 proteinogenic amino acids. 72-18-4 Metabolite
Enzyme/Protease L-Valine is an essential amino acid. HY-N0729
Linoleic acid Endogenous Metabolic Linoleic acid is a critical
component of 60-33-3 Metabolite Enzyme/Protease polyunsaturated
fatty acids. HY-N0756 Bornyl acetate Apoptosis Apoptosis Bornyl
acetate is a potent odorant, exhibiting 76-49-3 one of the highest
flavor dilution factor (FD factor). HY-N0771 L-Isoleucine
Endogenous Metabolic L-isoleucine is a nonpolar hydrophobic amino
73-32-5 Metabolite Enzyme/Protease acid. L-Isoleucine is an
essential amino acid. HY-N0830 Palmitic acid Endogenous Metabolic
Palmitic acid is a long-chain saturated fatty acid 57-10-3
Metabolite Enzyme/Protease commonly found in both animals and
plants. HY-N0832 L-Histidine Endogenous Metabolic L-Histidine is an
essential amino acid for infants. 71-00-1 Metabolite;
Enzyme/Protease L-Histidine is an inhibitor of mitochondrial
Mitochondrial glutamine transport. Metabolism HY-N1096
Veratraldehyde Others Others Veratraldehyde is an important
chemical used in 120-14-9 perfumery, agrochemical, and
pharmaceutical industries. HY-N1132A D-(+)-Trehalose Others Others
D-(+)-Trehalose dihydrate, isolated from 6138-23-4 dihydrate
Saccharomyces cerevisiae, can be used as a food ingredient and
pharmaceutical excipient. HY-N1390 Syringaldehyde COX Immunology/
Syringaldehyde is a polyphenolic compound 134-96-3 Inflammation
belonging to the group of flavonoids and is found in different
plant species like Manihot esculenta and Magnolia officinalis.
Syringaldehyde moderately inhibits COX-2 activity with an IC50 of
3.5 .mu.g/mL. Anti-hyperglycemic and anti-inflammatory activities.
HY-N1393 2-Methoxybenzoic Endogenous Metabolic 2-Methoxybenzoic
acid (NSC 3778) is used as 579-75-9 acid Metabolite Enzyme/Protease
an internal standard of salicylic acid and its putative
biosynthetic precursors in cucumber leaves. Another known use is in
the synthesis of Benextramine. HY-N1394 p-Anisic acid Bacterial;
Anti-infection; p-Anisic acid (4-Methoxybenzoic acid) is one of
100-09-4 Endogenous Metabolic the isomers of anisic acid, with
anti-bacterial and Metabolite Enzyme/Protease antiseptic
properties. HY-N1406 6-Methylcoumarin Others Others
6-Methylcoumarin is a synthetic fragrance 92-48-8 widely used in
cosmetics. HY-N1415 .beta.-Caryophyllene Cannabinoid GPCR/G
Protein; .beta.-Caryophyllene is a CB2 receptor agonist. 87-44-5
Receptor; Metabolic Endogenous Enzyme/Protease Metabolite Neuronal
Signaling HY-N1420 Rhamnose Endogenous Metabolic Rhamnose
(L-Rhamnose) is a monosaccharide 3615-41-6
Metabolite Enzyme/Protease found in plants and bacteria. Rhamnose-
conjugated immunogens is used in immunotherapies. Rhamnose crosses
the epithelia via the transcellular pathway and acts as a marker of
intestinal absorption. HY-N1423 Glycocholic acid Bcl-2 Family;
Apoptosis; Glycocholic acid is a bile acid with anticancer 475-31-0
Endogenous Metabolic activity, targeting against pump resistance-
Metabolite Enzyme/Protease related and non-pump resistance-related
pathways. HY-N1426 Raspberry ketone PPAR Cell Cycle/ Raspberry
ketone is a major aromatic compound 5471-51-2 DNA Damage of red
raspberry, widely used as a fragrance in cosmetics and as a
flavoring agent in foodstuff; also shows PPAR-.alpha. agonistic
activity. HY-N1428 Citric acid Antibiotic; Anti-infection; Citric
acid is a weak organic tricarboxylic acid 77-92-9 Apoptosis;
Apoptosis; found in citrus fruits. Citric acid is a natural
Bacterial; Metabolic preservative and food tartness enhancer.
Endogenous Enzyme/Protease Metabolite HY-N1428A 2-Hydroxy-1,2,3-
propanetricarboxylic acid monohydrate HY-N1446 Oleic acid
Apoptosis; Apoptosis; Oleic acid is an abundant monounsaturated
fatty 112-80-1 Endogenous Membrane acid. Oleic acid is a Na+/K+
ATPase activator. Metabolite; Transporter/Ion Na+/K+ Channel;
ATPase Metabolic Enzyme/Protease HY-N1500 Pulegone Endogenous
Membrane Pulegone, the major chemical constituent of 89-82-7
Metabolite; Transporter/Ion Calamintha nepeta (L.) Savi essential
oil which TRP Channel Channel; is an aromatic herb with a
mint-oregano flavor, Metabolic is one of avian repellents. The
molecular target Enzyme/Protease; for the repellent action of
Pulegone in avian Neuronal species is nociceptive TRP ankyrin 1
(TRPA1). Signaling Pulegone stimulates both TRPM8 and TRPA1 channel
in chicken sensory neurons and suppresses the former but not the
latter at high concentrations. HY-N1925 Tea polyphenol Others
Others Tea polyphenol is the floorboard of phenolic 84650-60-2
compounds in tea. Tea polyphenol exhibits biological activity
including antioxidant and anti-cancer activities, inhibition of
cell proliferation, induction of apoptosis, cell cycle arrest and
modulation of carcinogen metabolism. HY-N1926 Dihydrocoumarin
Sirtuin Cell Cycle/ Dihydrocoumarin is a compound found in 119-84-6
DNA Damage; Melilotus officinalis. Dihydrocoumarin is a yeast
Epigenetics Sir2p inhibitor. Dihydrocoumarin also inhibits human
SIRT1 and SIRT2 with IC50s of 208 .mu.M and 295 .mu.M,
respectively. HY-N1944 Nerolidol Bacterial; Anti-infection;
Nerolidol is a natural membrane-active sesquiterpene, 7212-44-4
Endogenous Metabolic with antitumor, antibacterial, antifungal
Metabolite; Enzyme/Protease and antipamsitic activity. Fungal;
Parasite HY-N2011 Octyl gallate Bacterial; Anti-infection; Octyl
gallate (Progallin O) is widely used as a 1034-01-1 HSV; Influenza
Immunology/ food additive, with antimicrobial and antioxidant
Virus; Reactive Inflammation; activity. Octyl gallate (Progallin O)
shows Oxygen Metabolic selective and sensitive fluorescent
property. Species Enzyme/Protease; Octyl gallate shows a marked
antiviral effect NF-.kappa.B against HSV-1, vesicular stomatitis
virus (VSV) and poliovirus. HY-N2024 Maltose 69-79-4 HY-N2026
Propylparaben Bacterial; Anti-infection; Propylparaben is an
antimicrobial agent, 94-13-3 Endogenous Metabolic preservative,
flavouring agent. Metabolite Enzyme/Protease HY-N2041 Myristic acid
Endogenous Metabolic Myristic acid is a saturated 14-carbon fatty
acid 544-63-8 Metabolite Enzyme/Protease occurring in most animal
and vegetable fats, particularly butterfat and coconut, palm, and
nutmeg oils. HY-N2067 Vanillyl alcohol Apoptosis Apoptosis Vanillyl
alcohol (p-(Hydroxymethyl)guaiacol), 498-00-0 derived from
vanillin, is a phenolic alcohol and is used as a flavoring agent in
foods and beverages. HY-N2071 Cedrol Cytochrome Anti-infection;
Cedrol is a bioactive sesquiterpene, a potent 77-53-2 P450; Fungal
Metabolic competitive inhibitor of cytochrome P-450 Enzyme/Protease
(CYP) enzymes. Cedrol inhibits CYP2B6- mediated bupropion
hydroxylase and CYP3A4- mediated midazolam hydroxylation with Ki of
0.9 .mu.M and 3.4 .mu.M, respectively. Cedrol also has weak
inhibitory effect on CYP2C8, CYP2C9, and CYP2C19 enzymes. Cedrol is
found in cedar essential oil and poetesses anti- septic,
anti-inflammatory, anti-spasmodic, tonic, astringent, diuretic,
sedative, insecticidal, and anti-fungal activities. HY-N2086 Ethyl
palmitate 628-97-7 HY-N2195 Nootkatone Others Others Nootkatone, a
neuroprotective agent from 4674-50-4 Alpiniae Oxyphyllae Fructus,
has antioxidant and anti-inflammatory effects. Nootkatone improves
cognitive impairment in lipopolysaccharide-induced mouse model of
Alzheimer's disease. HY-N2362 Alanine 302-72-7 HY-N3025 Zinc
sulfate Others Others Zinc sulfate heptahydrate is a hydrate that
is the 7446-20-0 (heptahydrate) heptahydrate form of zinc sulfate.
Zinc sulfate heptahydrate is a dietary supplement used for zinc
deficiency and to prevent the condition in those at high risk.
HY-N3075 Phytol Bacterial; Anti-infection Phytol ((E)?-?Phytol), a
diterpene alcohol from 150-86-7 Parasite chlorophyll widely used as
a food additive and in medicinal fields, possesses promising
antischistosomal properties. Phytol has antinociceptive and
antioxidant activitiesas well as anti- inflammatory and
antiallergic effects. Phytol has antimicrobial activity against
Mycobacterium tuberculosis and Staphylococcus aureus. HY-N3544
Caryophyllene Endogenous Metabolic Caryophyllene oxide, isolated
from from Annona 1139-30-6 oxide Metabolite Enzyme/Protease
squamosa L. bark., possesses analgesic and anti- inflammatory
activity. HY-N4100 Trilobatin HIV; SGLT Anti-infection; Trilobatin,
a natural sweetener derived from?Lithocarpus 4192-90-9 Membrane
polystachyus?Rehd, Trilobatin?is Transporter/Ion an HIV-1 entry
inhibitor targeting the HIV-1 Channel Gp41 envelope.
Neuroprotective effects. Trilobatin is also a SGLT1/2 inhibitor
that selectively induces the proliferation of human hepatoblastoma
cells. HY-N5132 (-)-Fenchone Others Others (-)-Fenchone, a bicyclic
monoterpene, is widely 7787-20-4 distributed in plants and found in
essential oils from Thuja occidentalis. (-)-Fenchone is oxidized to
6-endo-hydroxyfenchone, 6-exo- hydroxyfenchone and
10-hydroxyfenchone derivatives by CYP2A6 and CYP2B6 in human liver
microsomes with CYP2A6 playing a more important role than CYP2B6.
HY-N5142 .alpha.-Terpineol Bacterial Anti-infection
.alpha.-Terpineol is isolated from Eucalyptus globulus 98-55-5
Labill, exhibits strong antimicrobial activity against
periodontopathic and cariogenic bacteria. .alpha.-Terpineol
possesses antifungal activity against T. mentagrophytes, and the
activity might lead to irreversible cellular disruption. HY-N6056
Pentanoic acid 109-52-4 HY-N6655 DL-Methionine Others Others
DL-methionine methylsulfonium chloride is a 3493-12-7
methylsulfonium naturally occurring methionine derivative. DL-
(chloride) methionine methylsulfonium chloride protects gastric
mucosal from ethanol-induced damage. HY-N6810 Thymol Bacterial
Anti-infection Thymol is the main monoterpene phenol 89-83-8
occurring in essential oils isolated from plants belonging to the
Lamiaceae family, and other plants such as those belonging to the
Verbenaceae, Scrophulariaceae, Ranunculaceae and Apiaceae families.
Thymol has antioxidant, anti-inflammatory, antibacterial and
antifungal effects. HY-N6952 Geraniol Endogenous Anti-infection;
Geraniol, an olefinic terpene, was found to 106-24-1 Metabolite;
Metabolic inhibit growth of Candida albicans and Fungal
Enzyme/Protease Saccharomyces cerevisiae strains. HY-N6996 Methyl
Eugenol Others Others Methyl Eugenol, a phenylpropanoid chemical in
93-15-2 leaves, fruits, stems, and/or roots, may be released when
that corresponding part of a plant is damaged as a result of
feeding by an herbivore. Methyl Eugenol is used for male
annihilation of the oriental fruit fly. HY-N7000 Perillyl alcohol
Apoptosis; Apoptosis; Perillyl alcohol?is a monoterpene isolated
from 536-59-4 Endogenous Metabolic the essential oils of lavendin,
peppermint, Metabolite Enzyme/Protease spearmint, cherries, celery
seeds, and several other plants. Perillyl alcohol?is active in
inducing apoptosis in tumor cells without affecting normal cells.
HY-N7063 Nerol Apoptosis; Anti-infection; Nerol is a constituent of
neroli oil. Nerol Nerol 106-25-2 Endogenous Apoptosis; triggers
mitochondrial dysfunction and induces Metabolite; Immunology/
apoptosis via elevation of Ca2+ and ROS. Fungal; Inflammation;
Antifungal activity. Mitochondrial Metabolic Metabolism;
Enzyme/Protease; Reactive NF-.kappa.B Oxygen Species HY-N7079
Erythorbic acid Others Others Erythorbic acid (D-Isoascothic acid),
produced 89-65-6 from sugars derived from different sources, such
as beets, sugar cane, and corn, is a food additive used
predominantly in meats, poultry, and soft drinks. HY-N7079A Sodium
erythorbate Others Others Sodium erythorbate (D-Isoascothic acid
sodium), 6381-77-7 produced from sugars derived from different
sources, such as beets, sugar cane, and corn, is a food additive
used predominantly in meats, poultry, and soft drinks. HY-N7083
Citral Others Others Citral is a monoterpene found in Cymbopogon
5392-40-5 citratus essential oil, with antihyperalgesic,
anti-nociceptive and anti-inflammatory effects. HY-N7090 Benzyl
cinnamate HY-N7092 D-Fructose Others Others D-Fructose
(D(-)-Fructose) is a naturally 57-48-7 occurring monosaccharide
found in many plants. HY-N7117 1,4-Cineole Endogenous Membrane
1,4-Cineole is a widely distributed, natural, 470-67-7 Metabolite;
Transporter/Ion oxygenated monoterpene. 1,4-Cineole, present TRP
Channel Channel; in eucalyptus oil, activates both human TRPM8
Metabolic and human TRPA1. Enzyme/Protease; Neuronal Signaling
HY-N7124 Benzyl acetate Others Others Benzyl acetate is a
constituent of jasmin and of 140-11-4 the essential oils of
ylang-ylang and neroli. Natural sources of Benzyl acetate include
varieties of flowers like jasmine (Jasminum), and fruits like pear,
apple. HY-N7393 Isomalt Lactate Metabolic Isomalt (Palatinitol), a
well-tolerated, non-toxic 64519-82-0 Dehydrogenase Enzyme/Protease
polyol and a protein-stabilizing excipient, stabilizes lactate
dehydrogenase (LDH) moderately during freeze-drying, and performs
better during storage. Isomalt is traditionally used as a
sweetening agent in the food industry and as a tabletting excipient
for pharmaceutical purposes. HY-P1645 Papain Cathepsin Metabolic
Papain is a cysteine protease of the peptidase C1 9001-73-4
Enzyme/Protease family, which is used in food, pharmaceutical,
textile, and cosmetic industries. HY-W001132 Indole Endogenous
Metabolic Indole is an endogenous metabolite. 120-72-9 Metabolite
Enzyme/Protease HY-W001245 4-Methylthiazole 693-95-8
HY-W002045 1-(4- 122-84-9 Methoxyphenyl)propan- 2-one HY-W002097
1-(5- 13679-74-8 Methylthiophen-2- yl)ethan-1-one HY-W004058
(Tetrahydrofuran-2- 97-99-4 yl)methanol HY-W004282 Undecanoic
Endogenous Anti-infection; Undecanoic acid (Undecanoate) is a
monocarboxylic 112-37-8 acid Metabolite; Metabolic acid with
antimycotic property, which Fungal Enzyme/Protease inhibits the
production of exocellular keratinase, lipase and the biosynthesis
of several phospholipids in T. rubrum. HY-W004283 Pentadecanoic
acid Endogenous Metabolic Pentadecylic acid is a saturated fatty
acid with a 1002-84-2 Metabolite Enzyme/Protease 15-cathon
backbone. HY-W004292 1-Undecanol 112-42-5 HY-W004298
10-Undecen-1-ol Others Others 10-Undecen-1-ol, converted from
ricinoleic acid, 112-43-6 can be used as a comonomer for the
introduction HY-W004842 Benzo [b]furan-2- of functional groups.
4265-16-1 carboxaldehyde HY-W004975 5- 13708-12-8 Methylquinoxaline
HY-W005288 4-Vinylphenol 2628-17-3 HY-W005344 Ethyl 2-(2-methyl-
6413-10-1 1,3-dioxolan-2- yl)acetate HY-W005513 N,N-Bis(2- 120-40-1
hydroxyethyl)dodecanamide HY-W006057 3-Methyl-2- Endogenous
Metabolic 3-Methyl-2-oxobutanoic acid is a precursor of 759-05-7
oxobutanoic acid Metabolite Enzyme/Protease pantothenic acid in
Escherichia coli. HY-W007355 Skatole Aryl Anti-infection; Skatole
is produced by intestinal bacteria, 83-34-1 Hydrocarbon Autophagy;
regulates intestinal epithelial cellular functions Receptor;
Immunology/ through activating aryl hydrocarbon receptors
Autophagy; Inflammation; and p38. Bacterial; MAPK/ERK Endogenous
Pathway; Metabolite; Metabolic Fungal; p38 Enzyme/Protease MAPK
HY-W007446 3-Phenylpropanal 104-53-0 HY-W007606 Tyramine Endogenous
Metabolic Tyramine is an amino acid that helps regulate 51-67-2
Metabolite Enzyme/Protease blood pressure. Tyramine occurs
naturally in the body, and it's found in certain foods. HY-W007617
Ethyl 3-oxo-3- 94-02-0 phenylpropanoate HY-W007692 Acetylpyrazine
Others Others Acetylpyrazine (2-Acetylpyrazine) is fused to
22047-25-2 form many polycyclic compounds, as useful structures in
pharmaceuticals and perfumes. Acetylpyrazine is a component of the
folates (vitamin B compounds). HY-W007704 Methyl 4630-82-4
cyclohexanecarboxylate HY-W007828 Methyl 3- 103-25-3
phenylpropanoate HY-W007888 2-Hydroxy-4- 698-27-1
methylbenzaldehyde HY-W007926 2-Oxobutanoic Endogenous Metabolic
2-Oxobutanoic acid is a product in the 600-18-0 acid Metabolite
Enzyme/Protease enzymatic cleavage of cystathionine. HY-W008270
2(5H)-Furanone 497-23-4 HY-W008591 2-Methoxypyridine 1628-89-3
HY-W009156 Hydroxycitric acid 6100-05-6 (tripotassium hydrate)
HY-W009384 1,4- 105-95-3 Dioxacycloheptadecane- 5,17-dione
HY-W009417 Cedryl acetate Glucosidase Metabolic Cedryl acetate is a
tricyclic sesquiterpene 77-54-3 Enzyme/Protease isolated from the
plant Psidium caudatum. Cedryl acetate shows .alpha.-glucosidase
inhibitory activity. HY-W009516 Dibenzyl disulfide 150-60-7
HY-W009811 Tridecan-2-one 593-08-8 HY-W009948 Vanillin acetate
Others Others Vanillin acetate is easily synthesized from 881-68-5
vanillin by treatment with acetic anhydride. HY-W010054 2- 93-18-5
Ethoxynaphthalene HY-W010141 1-(4- 645-13-6
Isopropylphenyl)ethanone HY-W010201 Citronellol Reactive
Immunology/ Citronellol ((.+-.)-Citronellol) is a monoterpene
106-22-9 Oxygen Inflammation; Pelargonium capitatum. Citronellol
((.+-.)- Species Metabolic Citronellol) induces necroptosis of
cancer cell Enzyme/Protease; via up-regulating TNF-.alpha.,
RIP1/RIP3 activities, NF-.kappa.B down-regulating
caspase-3/caspase-8 activities and increasing ROS (reactive oxygen
species) accumulation. HY-W010293 Ethyl 4- 539-88-8 oxopentanoate
HY-W010320 Ethyl maltol Others Others Ethyl maltol
(2-Ethyl-3-hydroxy-4H-pyran-4- 4940-11-8 one), an odor-active (OA)
compound, is an important food additive and the main component of a
type of incense added to food. HY-W010392 Ethyl 2- 7452-79-1
methylbutanoate HY-W010435 Sulcatone 110-93-0 HY-W010476 2,3,5-
14667-55-1 Trimethylpyrazine HY-W010483 2-Phenylethylamine 64-04-0
HY-W010489 2-Phenylacetaldehyde Endogenous Metabolic
2-Phenylacetaldehyde is an endogenous 122-78-1 Metabolite
Enzyme/Protease metabolite. HY-W010531 trans-Hex-2-enoic 13419-69-7
acid HY-W010533A 2-Methyl-2- 3142-72-1 pentenoic acid HY-W010540
4,5- 3581-91-7 Dimethylthiazole HY-W010542 Azepan-2-one 105-60-2
HY-W010553 2,5-Dimethyl- Others Others 2,5-Dimethyl-3(2H)-furanone
is a flavouring 14400-67-0 3(2H)-furanone substance without
genotoxicity. HY-W010562 2-Methoxypyrazine HY-W010594
Tetrahydrothiophen- Endogenous Metabolic Tetrahydrothiophen-3-one
is an endogenous 1003-04-9 3-one Metabolite Enzyme/Protease
metabolite. HY-W010607 cis-3-Hexen-1-ol Others Others
cis-3-Hexen-1-ol ((Z)-3-Hexen-1-ol) is a green 928-96-1 grassy
smelling compound found in many fresh fruits and vegetables.
cis-3-Hexen-1-ol is widely used as an added flavor in processed
food to provide a fresh green quality. cis-3-Hexen-1-ol is an
attractant to various insects. HY-W010611 3-Methylbut-2- Endogenous
Metabolic 3-Methylbut-2-enoic acid is an endogenous 541-47-9 enoic
acid Metabolite Enzyme/Protease metabolite. HY-W010627
2,5-Dimethyl-1H- 14400-67-0 pyrrole HY-W010970 5'-Guanylic acid
Endogenous Metabolic 5'-Guanylic acid disodium salt (5'-GMP
5550-12-9 (disodium salt) Metabolite Enzyme/Protease disodium salt)
is composed of guanine, ribose, and phosphate moieties and it is a
nucleotide monomer in messenger RNA. Guanosine derivatives are
involved in intracellular signal transduction and have been
identified in repetitive genomic sequences in telomeres, in
ribosomal DNA, immunoglobulin heavy-chain switch regions, and in
the control regions of proto-oncogenes. HY-W011053 Neotame
165450-17-9 HY-W011678 Octadecan-1-amine 124-30-1 HY-W012499
N-Acetyl-L- Endogenous Metabolic N-Acetyl-L-methionine, a human
metabolite, is 65-82-7 methionine Metabolite Enzyme/Protease
nutritionally and metabolically equivalent to L- methionine.
L-methionine is an indispensable amino acid required for normal
growth and development. HY-W012530 2-Oxo-3- Endogenous Metabolic
2-Oxo-3-phenylpropanoic acid is used in the 156-06-9
phenylpropanoic Metabolite Enzyme/Protease synthesis of
3-phenyllactic acid (PLA) by acid lactate dehydrogenase. HY-W012556
Ethyl 3- 2305-25-1 hydroxyhexanoate HY-W012575 2,4- Endogenous
Metabolic 2,4-Dihydroxybenzoic acid is a degradation 89-86-1
Dihydroxybenzoic Metabolite Enzyme/Protease product of cyaniding
glycoside from tart acid cheeries in cell culture. HY-W012595
Benzylideneacetone 122-57-6 HY-W012634 Benzo[d]thiazole 95-16-9
HY-W012653 4'- 122-00-9 Methylacetophenone HY-W012657 4- 4748-78-1
Ethylbenzaldehyde HY-W012658 2- Endogenous Metabolic
2-Methylacetophenone is an endogenous 577-16-2 Methylacetophenone
Metabolite Enzyme/Protease metabolite. HY-W012701 Ethyl 3-
5405-41-4 hydroxybutyrate HY-W012722 4-Methyl-2- Endogenous
Metabolic 4-Methyl-2-oxopentanoic acid, an abnormal 816-66-0
oxopentanoic acid Metabolite Enzyme/Protease metabolite, is both a
neurotoxin and a metabotoxin. HY-W012732 Isoquinoline HY-W012788
Maltol Endogenous Metabolic Maltol, a type of aromatic compound,
exists in 118-71-8 Metabolite Enzyme/Protease high concentrations
in red ginseng. Maltol is a potent antioxidative agent and
typically is used to enhance flavor and preserve food. HY-W012813
1-(5-Methylfuran- 1193-79-9 2-yl)ethanone HY-W012836 4-Ethylphenol
Endogenous Metabolic 4-Ethylphenol is a volatile phenolic compound
123-07-9 Metabolite Enzyme/Protease associated with off-odour in
wine. HY-W012889 DL-Valine 516-06-3 HY-W012956 1-(1H-Pyrrol-2-
1072-83-9 yl)ethanone HY-W012980 3-Methylbutanoic Endogenous
Metabolic 3-Methylbutanoic acid is a natural fatty acid and
503-74-2 acid Metabolite Enzyme/Protease known to effect on
neonatal death and possible Jamaican vomiting sickness in human.
HY-W012995 5-Hexen-1-ol 821-41-0 HY-W012999 Tiglic acid Endogenous
Metabolic Tiglic acid is a monocarboxylic unsaturated 80-59-1
Metabolite Enzyme/Protease organic acid found in croton oil and in
several other natural products. Tiglic aci has a role as a plant
metabolite. HY-W013014 3-Methyl-2- Endogenous Metabolic
3-Methyl-2-cyclopenten-1-one is an endogenous 2758-18-1
cyclopenten-1-one Metabolite Enzyme/Protease metabolite. HY-W013035
3-Methyl-2-buten- Endogenous Metabolic 3-Methyl-2-buten-1-ol is an
endogenous 556-82-1 1-ol Metabolite Enzyme/Protease metabolite.
HY-W013040 Pyrazine 290-37-9 HY-W013573 S-Allyl-L- Apoptosis
Apoptosis S-Allyl-L-cysteine, one of the organosulfur 21593-77-1
cysteine compounds found in AGE, possess various biological effects
including neurotrophic activity, anti-cancer activity,
anti-inflammatory activity. HY-W013627 (2E,4E)-Deca-2,4- 25152-84-5
dienal HY-W013636 2-Ketoglutaric acid Endogenous Metabolic
2-Ketoglutaric acid (Alpha-Ketoglutaric acid) 328-50-7 Metabolite;
Enzyme/Protease is an intermediate in the production of ATP or
Tyrosinase GTP in the Krebs cycle. 2-Ketoglutaric acid also acts as
the major carbon skeleton for nitrogen-assimilatory reactions.
2-Ketoglutaric acid is a reversible inhibitor of tyrosinase (IC50 =
15 mM). HY-W013807 Dibutyl sebacate Others Others Dibutyl sebacate
(Dibutyl decanedioate) is a 109-43-3 dibutyl ester of sebacic acid,
mainly used as a plasticizer in production of plastics. HY-W014102
L-Alanyl-L- Endogenous Metabolic L-Alanyl-L-glutamine, a glutamine
dipeptide, is 39537-23-0 glutamine Metabolite Enzyme/Protease
benefit for the antioxidant system, attenuating inflammation, and
may modulate the heat shock protein (HSP) response in catabolic
situations. HY-W014207 Ethyl undecanoate 627-90-7
HY-W014325 TRPM8 antagonist TRP Channel Membrane TRPM8 antagonist
WS-3 is an agonist of 39711-79-0 WS-3 Transporter/Ion TRPM8 with an
EC50 of 3.7 .mu.M. Channel; Neuronal Signaling HY-W014388 1,3-
102-04-5 Diphenylpropan-2- one HY-W015301 Dimethyl adipate 627-93-0
HY-W015309 Decanoic acid Endogenous Metabolic Decanoic acid belongs
to the class of organic 334-48-5 Metabolite Enzyme/Protease
compounds known as medium-chain fatty acids. HY-W015342 Methyl
anisate 121-98-2 HY-W015371 Ethyl phenylacetate 101-97-3 HY-W015410
Disodium succinate Others Others Disodium succinate is
the?disodium?salt 150-90-3 of?Succinic acid. Succinic acid is an
intermediate product of the tricarboxylic acid cycle, as well as
one of fermentation products of anaerobic metabolism. HY-W015611
L-(+)- Endogenous Metabolic L-(+)-Arabinose selectively inhibits
intestinal 5328-37-0 Arabinose Metabolite Enzyme/Protease sucrase
activity in a noncompetitive manner and suppresses the plasma
glucose increase due to sucrose ingestion. HY-W015618 2',4'-
89-74-7 Dimethylacetophenone HY-W015695 4-Methyl-5- 137-00-8
thiazoleethanol HY-W015709 Ethyl hex-3-enoate 2396-83-0 HY-W015777
(4- 105-13-5 Methoxyphenyl)methanol HY-W015780 1,4- 150-78-7
Dimethoxybenzene HY-W015786 4-Ethoxyphenol 622-62-8 HY-W015820
Isobenzofuran- 87-41-2 1(3H)-one HY-W015861 p-Tolylmethanol
589-18-4 HY-W015883 Fumaric acid Endogenous Metabolic Fumaric acid,
associated with fumarase 110-17-8 Metabolite Enzyme/Protease
deficiency, is identified as an oncometabolite or an endogenous,
cancer causing metabolite. HY-W016081 Allyl cinnamate 1866-31-5
HY-W016089 Ethyl 2-(2,4- 6290-17-1 dimethyl-1,3- dioxolan-2-
yl)acetate HY-W016319 (S)-2- 138-15-8 aminopentanedioic acid
hydrochloride HY-W016610 2-Ethoxy-5- 94-86-0 propenylphenol
HY-W016806 Sodium 4- (methoxycarbonyl)phenolate HY-W016976 Allyl
heptanoate 142-19-8 HY-W017018 L-Ornithine Endogenous Metabolic
L-Ornithine hydrochloride is a free amino acid 3184-13-2
(hydrochloride) Metabolite Enzyme/Protease that plays a central
role in the urea cycle and is also important for the disposal of
excess nitrogen. HY-W017077 4-Methylbiphenyl Endogenous Metabolic
4-Methylbiphenyl is an endogenous metabolite. 644-08-6 Metabolite
Enzyme/Protease HY-W017140 2-(sec-Buty1)-3- 24168-70-5
methoxypyrazine HY-W017141 2-Isobutyl-3- 24683-00-9 methoxypyrazine
HY-W017212 Methyl cinnamate AMPK; Anti-infection; Methyl cinnamate
(Methyl 3-phenylpropenoate), 103-26-4 Bacterial; Epigenetics; an
active component of Zanthoxylum armatum, Tyrosinase Metabolic is a
widely used natural flavor compound. Enzyme/Protease; Methyl
cinnamate (Methyl 3-phenylpropenoate) PI3K/Akt/mTOR possesses
antimicrobial activity and is a tyrosinase inhibitor that can
prevent food browning. Methyl cinnamate (Methyl 3-phenylpropenoate)
has antiadipogenic activity through mechanisms mediated, in part,
by the CaMKK2-AMPK signaling pathway. HY-W017232 6- 5263-87-6
Methoxyquinoline HY-W017278 2-((Isopropylthio) 1883-78-9
methyl)furan HY-W017316 Terpinen-4-ol Endogenous Metabolic
Terpinen-4-ol (4-Carvomenthenol), a naturally 562-74-3 Metabolite
Enzyme/Protease occurring monoterpene, is the main bioactive
component of tea-tree oil. Terpinen-4-ol suppresses inflammatory
mediator production by activated human monocytes. Terpinen-4-ol
significantly enhances the effect of several chemotherapeutic and
biological agents. HY-W017370 Carveol 99-48-9 HY-W017371
p-Dithiane-2,5-diol 40018-26-6 HY-W017374 4-Ethy1-2- 2785-89-9
methoxyphenol HY-W017428 4-Ethoxybenzaldehyde 10031-82-0 HY-W017522
Adipic acid Endogenous Metabolic Adipic acid is found to be
associated with HMG- 124-04-9 Metabolite Enzyme/Protease CoA lyase
deficiency, carnitine-acylcarnitine translocase deficiency,
malonyl-CoA decarboxylase deficiency, and medium Chain acyl-CoA
dehydrogenase deficiency, which are inborn errors of metabolism.
HY-W017562 5- 104-50-7 Butyldihydrofuran- 2(3H)-one HY-W017592 2-
1073-29-6 (Methylthio)phenol HY-W017611 4-Propylphenol 645-56-7
HY-W017613 (Ethoxymethyl) 539-30-0 benzene HY-W018501 Methyl
p-tert- 3549-23-3 butylphenylacetate HY-W018653 Cyclohexaneacetic
5292-21-7 acid HY-W018758 1-Phenylpropane- Others Others
1-Phenylpropane-1,2-dione, isolated from young 579-07-7 1,2-dione
Ephedra sinica Stapf (Ephedraceae), is biosynthetic precursors of
the ephedrine alkaloids. HY-W018772 D-Ribose(mixture Endogenous
Metabolic D-Ribose(mixture of isomers) is an energy 50-69-1 of
isomers) Metabolite Enzyme/Protease enhancer, and acts as a sugar
moiety of ATP, and widely used as a metabolic therapy supplement
for chronic fatigue syndrome or cardiac energy metabolism.
D-Ribose(mixture of isomers) is active in protein glycation,
induces NF-.kappa.B inflammation in a RAGE-dependent manner.
HY-W019711 trans- Endogenous Metabolic trans-Cinnamaldehyde can be
used to prepare 14371-10-9 Cinnamaldehyde Metabolite
Enzyme/Protease highly polyfunctionalized furan ring by reaction of
alkyl isocyanides with dialkyl acetylenedicalboxylate.
trans-Cinnamaldehyde can be used to synthesize trans-cinnamaldehyde
-.beta.- cyclodextrin complex, an antimicrobial edible coating that
increases the shelf life of fresh-cut fruits. HY-W019894 Manganese
7773-01-5 dichloride HY-W019901 Anhydrous 7778-18-9 calcium sulfate
HY-W020014 Pyruvic aldehyde 78-98-8 HY-W026742 Ethyl anthranilate
87-25-2 HY-W027751 2-Methylanisole 578-58-5 HY-W027872 Piperonyl
acetone 55418-52-5 HY-W032013 1-Octanol Calcium Membrane 1-Octanol
(Octanol), a saturated fatty alcohol, is 111-87-5 Channel;
Transporter/Ion a T-type calcium channels (T-channels) inhibitor
Endogenous Channel; with an IC50 of 4 .mu.M for native T- currents.
Metabolite Metabolic 1-Octanol is a highly attractive biofuel with
Enzyme/Protease; diesel-like properties. Neuronal Signaling
HY-W035362 Cyclopentadecanolide 106-02-5 HY-W038287 2- 95-21-6
Methylbenzoxazole HY-W039157 2-Acetyl-3- 32974-92-8 ethylpyrazine
HY-W039718 1-(2,4- 38205-60-6 Dimethylthiazol- 5-yl)ethan-1-one
HY-W040226 Indigo carmine Others Others Indigo carmine is an
efficient reagent for the 860-22-0 determination of ozone by
chemlluminescence (CL). HY-W040240 (35,4R,5S)- Endogenous Metabolic
(3S,4R,5S)-1,3,4,5,6-Pentahydroxyhexan-2- 87-79-6 1,3,4,5,6-
Metabolite Enzyme/Protease one is an endogenous metabolite.
Pentahydroxyhexan- 2-one HY-W040790 2,6- 108-50-9 Dimethylpyrazine
HY-W040948 2-Ethylpyrazine 13925-00-3 HY-W040971 Creosol Endogenous
Metabolic Creosol is an endogenous metabolite. 93-51-6 Metabolite
Enzyme/Protease HY-W041301 4,4,7a-Trimethyl- 15356-74-8 5,6,7,7a-
tetrahydrobenzofuran- 2(4H)-one HY-W041470 4-Methyl-1-phenyl-
5349-62-2 2-pentanone HY-W041533 5,6,7,8- 34413-35-9
Tetrahydroquinoxaline HY-W041912 Ethyl 2- 620-80-4 benzylidene-3-
oxobutanoate HY-W052009 Methyl 2- hydroxyethyl cellulose HY-W067358
2-Methylpyrazine 109-08-0 HY-W067695 Octahydro-2H- 4430-31-3
chromen-2-one HY-W086991 3-Methyl-2- 1193-18-6 cyclohexenone
HY-W087045 Benzyl formate 104-57-4 HY-W087922 Tridodecylamine
102-87-4 HY-W087943 Methyl octanoate 111-11-5 HY-W087984
Heptane-1-thiol 1639-09-4 HY-W087985 Isopentyl 2050-01-3
isobutyrate HY-W087987 2-Pentylthiophene 4861-58-9 HY-W088065
Sodium formate 141-53-7 HY-W088319 Butyramide 541-35-5 HY-W088425
Methyl 3- 13532-18-8 (methylthio)propanoate HY-W088436
1-(1-Methyl-1H- 932-16-1 pyrrol-2-yl)ethan-1- one HY-Y0016
Rhodamine B Others Others Rhodamine B is a staining fluorescent
dye, 81-88-9 commonly used for dyeing textiles, paper, soap,
leather, and drugs. HY-Y0035 4,4-Dimethoxy-2- 5436-21-5 butanone
HY-Y0045 2-Acetylthiazole 24295-03-2 HY-Y0073 4- HBV Anti-infection
4-Hydroxyacetophenone (P-hydroxyacetophenone) 99-93-4
Hydroxyacetophenone is a key hepatoprotective and choleretic
compound in Artemisia capillaris and A. morrisonensis, also has an
anti-hepatitis B virus effect and anti-inflammatory effect.
HY-Y0078 Cinnamyl Alcohol PPAR Cell Cycle/DNA Cinnamyl Alcohol is
an active component from 104-54-1 Damage chestnut flower, inhibits
increased PPAR.gamma. expression, with anti-obesity activity.
HY-Y0110 2-Naphthol Endogenous Metabolic 2-Naphthol is a metabolite
of naphthalene, 135-19-3 Metabolite Enzyme/Protease catalyzed by
cytochrome P450 (CYP) isozymes (CYP 1A1, CYP 1A2, CYP 2A1, CYP 2E1
and CYP 2F2). HY-Y0121 SemaSORB 9827 103-36-6 HY-Y0172 Butylated
Ferroptosis Apoptosis Butylated hydroxytoluene is an antioxidant
128-37-0 hydroxytoluene widely used in foods and in food-related
products. Butylated hydroxytoluene is a Ferroptosis inhibitor.
HY-Y0189 Methyl Salicylate COX Immunology/ Methyl Salicylate
(Wintergreen oil) is a topical 119-36-8 Inflammation analgesic and
anti-inflammatory agent. Also used as a pesticide, a denaturant, a
fragrance ingredient, and a flavoring agent in food and tobacco
products. A systemic acquired resistance (SAR) signal in tobacco. A
topical
nonsteroidal anti-inflammatory drug (NSAID). Methyl salicylate
lactoside is a COX inhibitor. HY-Y0190 (2R,3R)-Diethyl 87-91-2 2,3-
dihydroxysuccinate HY-Y0248A Farnesol Antibiotic; Anti-infection;
Farnesol is a sesquiterpene alcohol that modulates 4602-84-0
Bacterial; Metabolic cell-to-cell communication in Candida
albicans, Endogenous Enzyme/Protease and has the activity in
inhibiting bacteria. Metabolite HY-Y0252 L-Proline Endogenous
Metabolic L-Proline is one of the twenty amino acids used 147-85-3
Metabolite Enzyme/Protease in living organisms as the building
blocks of proteins. HY-Y0264 4-Hydroxybenzoic Bacterial;
Anti-infection; 4-Hydroxybenzoic acid, a phenolic derivative of
99-96-7 acid Endogenous Metabolic benzoic acid, could inhibit most
gram-positive Metabolite Enzyme/Protease and some gram-negative
bacteria, with an IC50 of 160 .mu.g/mL. HY-Y0267 Phenoxyacetic acid
Endogenous Metabolic Phenoxyacetic acid is an endogenous
metabolite. 122-59-8 Metabolite Enzyme/Protease HY-Y0271 Urea
Endogenous Metabolic Urea is a powerful protein denaturant via both
57-13-6 Metabolite Enzyme/Protease direct and indirect mechanisms.
A potent emollient and keratolytic agent. Used as a diuretic agent.
Blood urea nitrogen (BUN) has been utilized to evaluate renal
function. Widely used in fertilizers as a source of nitrogen and is
an important raw material for the chemical industry. HY-Y0272
Saccharin Bacterial Anti-infection Saccharin is an orally active,
non-caloric 81-07-2 artificial sweeteners (NAS). Saccharin has
bacteriostatic and microbiome-modulating properties. HY-Y0283
Antistrumin 7681-114 HY-Y0284 Diethyl phthalate HY-Y0287 Carbonate
(calcium) 471-34-1 HY-Y0289 1-Dodecanol 112-53-8 HY-Y0293
L-Tartaric acid Endogenous Metabolic L-Tartaric acid
(L-(+)-Tartaric acid) is an 87-69-4 Metabolite Enzyme/Protease
endogenous metabolite. HY-Y0308 Hydrogen 7558-79-4 disodium
phosphate HY-Y0313 p- Endogenous Membrane p-Hydroxybenzaldehyde is
a one of the major 123-08-0 Hydroxybenzaldehyde Metabolite;
Transporter/Ion components in Dendrocalamus asper bamboo GABA
Channel; shoots, with antagonistic effect on GABAA Receptor
Metabolic receptor of the .alpha.1.beta.2.gamma.2S subtype at high
Enzyme/Protease; concentrations. Neuronal Signaling HY-Y0316 Sodium
dodecyl 151-21-3 sulfate HY-Y0319B Acetic acid 127-08-2 (potassium)
HY-Y0337 L-Cysteine Endogenous Apoptosis; L-Cysteine is a
thiol-containing non-essential 52-90-4 Metabolite; Metabolic amino
acid that is oxidized to form cystine. Ferroptosis Enzyme/Protease
HY-Y0337A L-Cysteine Endogenous Metabolic L-Cysteine hydrochloride
is a conditionally 52-89-1 (hydrochloride) Metabolite
Enzyme/Protease essential amino acid, which acts as a precursor for
biologically active molecules such as hydrogen sulphide (H2S),
glutathione and taurine. L-Cysteine hydrochloride suppresses
ghrelin and reduces appetite in rodents and humans. HY-Y0344 Sodium
chloride 7647-14-5 HY-Y0366 Lauric acid Bacterial; Anti-infection;
Lauric acid is a middle chain-free fatty acid with 143-07-7
Endogenous Metabolic strong bactericidal properties. The EC50s for
P. Metabolite Enzyme/Protease acnes, S. aureus, S. epidermidis, are
2, 6, 4 .mu.g/ mL, respectively. HY-Y0367 Maleic Acid Bacterial;
Anti-infection; Maleic Acid is a Glutamate Decarboxylase 110-16-7
Endogenous Metabolic (GAD) inhibitor of E. coli and L.
monocytogenes. Metabolite Enzyme/Protease HY-Y0479 L-Lactic acid
Antibiotic; Anti-infection; L-Lactic acid is a buildiing block
which can be 79-33-4 Bacterial; Metabolic used as a precursor for
the production of the Endogenous Enzyme/Protease bioplastic polymer
poly-lactic acid. Metabolite HY-Y0481A Stannous dichloride
(dihydrate) HY-Y0498 Aluminum oxide HY-Y0537 Potassium chloride
7447-40-7 HY-Y0543 5-Methylfurfural Others Others 5-Methylfurfural
is a naturally occurring 620-02-0 substance, found in cigarette
smoke condensate, licorice essential oil, stored dehydrated orange
powder, baked potato flour, volatile compounds of roast beef, aroma
concentrate of sponge cake, bread and in coffee, tea and cocoa. A
flavoring agent. HY-Y0546 Benzophenone 119-61-9 HY-Y0569 D-Gluconic
acid Endogenous Metabolic D-Gluconic acid is the carboxylic acid by
the 526-95-4 Metabolite Enzyme/Protease oxidation with antiseptic
and chelating properties. HY-Y0600 Thioanisole 100-68-5 HY-Y0624
4-Pentenoic acid 591-80-0 HY-Y0682 Ethylenediamin etetraacetic acid
HY-Y0682A Ethylenediamin 6381-92-6 etetraacetic acid disodium salt
dihydrate HY-Y0703 Sodium Others Others Sodium carboxymethyl
cellulose (Viscosity: 800- 9004-32-4 carboxymethyl 1200 mPa s) is
the sodium salt of cellulose cellulose arboxymethyl and frequently
used as viscous (Viscosity: 800- agent, paste and barrier agent.
1200 mPa s) HY-Y0708 Calcium hydrogen phosphate dihydrate HY-Y0740
4- Endogenous Metabolic 4-Methoxybenzaldehyde is a naturally
occurring 123-11-5 Methoxybenzaldehyde Metabolite Enzyme/Protease
fragrant phenolic compound that is soluble in acetone.
4-Methoxybenzaldehyde has been found in many plant species
including horseradish, anise, star anise. 4-Methoxybenzaldehyde is
a possible neurotoxicant and it has shown effects that include
mortality, attractancy, and interference with host seeking.
HY-Y0743 1-(Pyridin-2- 1122-62-9 yl)ethan-1-one HY-Y0751
1-(Pyridin-3- 350-03-8 yl)ethanone HY-Y0756 Carbonic acid 144-55-8
monosodium salt HY-Y0760 3-Methoxybenzoic Endogenous Metabolic
3-Methoxybenzoic acid can be used in the 586-38-9 acid Metabolite
Enzyme/Protease synthesis of 3-methoxybenzoates of europium (III)
and gadolinium (III). HY-Y0781 Pyruvic acid Endogenous Metabolic
Pyruvic acid is an intermediate metabolite in the 127-17-3
Metabolite Enzyme/Protease metabolism of carbohydrates, proteins,
and fats. HY-Y0790 Cuminaldehyde Endogenous Metabolic Cuminaldehyde
is the major component of 122-03-2 Metabolite Enzyme/Protease
Cuminum cyminum, a natural aldehyde with inhibitory effect on
alpha-synuclein fibrillation and cytotoxicity. Cuminaldehyde shows
anticancer activity. HY-Y0808 Dimethyl succinate 106-65-0 HY-Y0813
Iron 7439-89-6 HY-Y0836 Diethyl succinate Others Others Diethyl
succinate (Diethyl Butanedioate) is used 123-25-1 at physiological
pH and crosses biological membranes, incorporates into cells in
tissue culture and is metabolized by the TCA cycle. Diethyl
succinate is known to be non-toxic and used in fragrances and
flavoring. HY-Y0839 Levulinic acid Endogenous Metabolic Levulinic
acid is a precursor for the synthesis of 123-76-2 Metabolite
Enzyme/Protease biofuels, such as ethyl levulinate. HY-Y0873 PEG300
Others Others PEG300 (Polyethylene glycol 300), a neutral
25322-68-3 polymer of molecular weight 300, is a water- soluble,
low immunogenic and biocompatible polymer formed by repeating units
of ethylene glycol. HY-Y0892 4-Hydroxybenzyl Apoptosis; Apoptosis;
4-Hydroxybenzyl alcohol is a phenolic 623-05-2 alcohol Endogenous
Metabolic compound widely distributed in various kinds of
Metabolite Enzyme/Protease plants. Anti-inflammatory, anti-oxidant,
anti- nociceptive activity. Neuroprotective effect. Inhibitor of
tumor angiogenesis and growth. HY-Y0921 (.+-.)-1,2- Others Others
(.+-.)-1,2-Propanediol is an aliphatic alcohol and 57-55-6
Propanediol frequently used as an excipient in many drug
formulations to increase the solubility and stability of drugs.
HY-Y0932 Isophorone 78-59-1 HY-Y0946 Acetamide Endogenous Metabolic
Acetamide is used primarily as a solvent and a 60-35-5 Metabolite
Enzyme/Protease plasticizer. HY-Y0949 Methyl 2- Endogenous
Metabolic Methyl 2-furoate (Methyl furan-2-carboxylate) is 611-13-2
furoate Metabolite Enzyme/Protease a building block in chemical
synthesis. A flavoring agent in food. Found in cranberries, guava
fruits, raisins and other fruits. Also present in baked potato,
roasted filberts, roasted peanut, tomatoes, coffee, cocoa, okra,
etc. HY-Y0961 Copper(I) iodide 7681-65-4 HY-Y0966 Glycine
Endogenous Membrane Glycine is an inhibitory neurotransmitter in
the 56-40-6 Metabolite; Transporter/Ion CNS and also acts as a
co-agonist along with iGluR Channel; glutamate, facilitating an
excitatory potential at Metabolic the glutaminergic
N-methyl-D-aspartic acid Enzyme/Protease; (NMDA) receptors.
Neuronal Signaling HY-Y0989 Acetophenone 98-86-2 HY-Y1011
2-Ethylhexan-1-ol 104-76-7 HY-Y1069 (S)-2- Endogenous Metabolic
(S)-2-Hydroxysuccinic acid is a dicalboxylic 97-67-6
Hydroxysuccinic Metabolite Enzyme/Protease acid in naturally
occurring form, contributes to acid the pleasantly sour taste of
fruits and is used as a food additive. HY-Y1088 Hydrocinnamic
Endogenous Metabolic Hydrocinnamic acid is the major rhizospheric
501-52-0 acid Metabolite Enzyme/Protease compound with known growth
regulatory HY-Y1093 Ethyl acetoacetate activities. 141-97-9
HY-Y1103 Iron(II) sulfate 7782-63-0 heptahydrate HY-Y1116 Magnesium
oxide 1309-48-4 HY-Y1177 Diphenyl disulfide 882-33-7 HY-Y1220
Dipotassium 584-08-7 carbonate HY-Y1311 Malic acid Endogenous
Metabolic Malic acid is a dicarboxylic acid that is naturally
6915-15-7 Metabolite Enzyme/Protease found in fruits such as apples
and pears. It plays a role in many sour or tart foods. HY-Y1316
Sodium benzoate 532-32-1 HY-Y1362 Ethyl pyruvate 617-35-6 HY-Y1366
Hydroxyacetone 116-09-6 HY-Y1373 Cyclohexanecarboxylic Endogenous
Metabolic Cyclohexanecarboxylic acid is a Valproate 98-89-5 acid
Metabolite Enzyme/Protease structural analogue with anticonvulsant
action. HY-Y1426 2'- Others Others 2'-Hydroxyacetophenone is found
in alcoholic 118-93-4 Hydroxyacetophenone beverages.
2'-Hydroxyacetophenone is present in tomato, cassia, fried beef,
rum, whiskey, cocoa, coffee and black tea. 2'- Hydroxyacetophenone
is a flavouring ingredient. Building block in chemical synthesis.
HY-Y1673 Potassium bromide 7758-02-3 HY-Y1683 DL-Menthol GABA
Membrane DL-Menthol is a relative configuration of (-)- 89-78-1
Receptor Transporter/Ion Menthol. DL-Menthol induces surgical
Channel; anesthesia for fish that relates to the activation of
Neuronal GABAA receptor. Signaling HY-Y1718 NSC 25955 Endogenous
Metabolic NSC 25955 is an endogenous metabolite. 638-53-9
Metabolite Enzyme/Protease HY-Y1809 1- Endogenous Metabolic
1-Hydroxyoctadecane is an endogenous metabolite. 112-92-5
Hydroxyoctadecane Metabolite Enzyme/Protease HY-Y1829
Hydratropaldehyde 93-53-8 HY-Y1878 Copper sulfate 7758-98-7
HY-Y1879 Manganese 7785-87-7 sulfate HY-Y1880 Carbonic acid sodium
salt, hydrate HY-Y1883 Hydrol SW 9002-93-1 HY-Y1885 Tetrasodium
7722-88-5 pyrophosphate HY-Y1888 Corn oil Others Others Corn oil,
extracted from the germ of corn, 8001-30-7 can be used as a carrier
for drug molecules. HY-Y1890 Cremophor EL Others Others Cremophor
EL is a polyethoxylated surfactant. 61791-12-6 HY-Y1891 Tween 80
Others Others Tween 80 is a surfactant which can also reduce
9005-65-6 bacterial attachment and inhibit biofilm formation.
HY-Y1892 Gelucire 44/14 Others Others Gelucire 44/14 is a potential
and safe absorption 121548-04-7 enhancer for improving the
absorption of poorly a bsorbable drugs including insulin and
calcitonin by pulmonary delivery. HY-Z0041 Benzaldehyde 1125-88-8
dimethyl acetal HY-Z0453 Methyl 2- 606-45-1 methoxybenzoate
HY-Z0478 (-)-Limonene Others Others (-)-Limonene ((S)-(-)-Limonene)
is a 5989-54-8 monoterpene found in many pine-needle oils and in
turpentine. (-)-Limonene can induce a mild bronchoconstrictive
effect. TCG0275 Copper (II) 527-09-3 Gluconate
[0047] Additional information about the additional ingredients
listed in Table 1 (e.g., the ingredient's target, pathway, and/or
biological activity) can be determined from publicly available
databases and websites. As an example, the American Chemical
Society's website (see, the World Wide Web at cas.org), the
Chemical Book (at the World Wide Web chemicalbook.com), and/or Med
Chem Express (see, the World Wide Web at medchemexpress.com)
provide relevant information for the additional ingredients; this
information can be obtained by searching the website using an
ingredient's name or CAS number. The contents of these websites,
with respect to the additional ingredients listed in Table 1, are
incorporated by references in their entireties.
[0048] Compositions of the present disclosure are formulated to be
suitable for in vivo administration to a mammal. Such compositions
can optionally comprise a suitable amount of a pharmaceutically
acceptable excipient so as to provide the form for proper
administration. Pharmaceutical excipients can be aqueous liquids,
such as water or saline. Pharmaceutical excipients can be lipid
based, e.g., comprising a liquid or solid oil. In addition,
auxiliary, stabilizing, thickening, lubricating, and coloring
agents can be used. The pharmaceutically acceptable excipients are
sterile when administered to a subject. Water is a useful excipient
when any composition described herein is administered parentally or
in some oral formulations. In embodiments, the compositions
described herein are suspended in a saline buffer (including,
without limitation Ringer's, TBS, PBS, HEPES, HBSS, and the like).
Saline solutions and aqueous dextrose and glycerol solutions can
also be employed as liquid excipients, specifically for injectable
solutions. Suitable pharmaceutical excipients also include starch,
glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium
chloride, dried skim milk, glycerol, propylene, glycol, water,
ethanol and the like. Any composition described herein, if desired,
can also comprise pH buffering agents.
[0049] In embodiments, the compositions of the present disclosure
are formulated for oral administration, for injection, or for
topical administration. Administering the composition may comprise
intravenous injection or infusion, intraperitoneal injection,
intramuscular injection, or subcutaneous injection.
[0050] The compositions suitable for parenteral administration
(e.g., intravenous injection or infusion, intraarterial injection
or infusion, intramuscular injection, intraperitoneal injection,
subcutaneous injection, and intra-arterial injection or infusion)
include, for example, solutions, suspensions, dispersions,
emulsions, and the like, or in another acceptable format used in
methods well known in the art.
[0051] Compositions suitable for enteral administration (e.g., oral
administration) may be formulated as a liquid, a suspension, a gel,
a geltab, a semisolid, a tablet, a sachet, a lozenge, a pill, or a
capsule, or in another acceptable format used in methods well known
in the art.
[0052] In some embodiments, the active ingredient (disulfiram) and
the potentiating ingredient (cinnamaldehyde) are formulated into a
single composition, e.g., for oral administration. In some cases,
disulfiram and cinnamaldehyde are combined into a single tablet or
pill during manufacturing of the tablet or pill or by a compounding
company/laboratory. Alternately, disulfiram and cinnamaldehyde are
combined into a single capsule by combining the contents of
capsules containing disulfiram and capsules containing
cinnamaldehyde. Additionally, powders or pellets of disulfiram and
cinnamaldehyde may be otherwise obtained and compounded into
pills/tablets or combined into capsules.
[0053] As described above, a composition of the present disclosure
may further comprise one or more additional ingredients (e.g., from
Table 1). The one or more additional ingredients may be formulated
into the single tablet, pill, or capsule with disulfiram and
cinnamaldehyde.
[0054] In other embodiments, the active ingredient that is
disulfiram and potentiating ingredient that is cinnamaldehyde are
formulated into distinct compositions, e.g., for oral
administration. In some cases, disulfiram is present in a single
tablet, pill, or capsule and the cinnamaldehyde is present in
another tablet, pill, or capsule. Further, a third composition,
tablet, pill, or capsule may include one or more additional
ingredients (e.g., from Table 1).
[0055] When the composition is for oral administration and is in
solid form (e.g., a pill, tablet, or capsule), the composition may
comprise delay-release components. For example, a pill, tablet, or
capsule may comprise a coating that slows release of the agents
and/or prevents release of disulfiram and/or the one or more
additional ingredients until the pill, tablet, or capsule has
arrived at a desired location of the mammal's digestive system.
[0056] Compositions suitable for topical administration can be
formulated in a solution, gel, lotion, ointment, cream, suspension,
paste, liniment, powder, tincture, aerosol, patch, or the like in a
pharmaceutically or cosmetically acceptable format used in methods
well known in the art.
[0057] Compositions may be suitable for administration via
inhalation. Such formulation will likely be in liquid form and will
be delivered in a spray bottle, in an inhaler, or in a nebulizer.
Inhaled compositions are particularly suited for diseases and
disorder, including infections, that affect the mammal's
respiratory system and/or are transmitted via the mammal's
respiratory system.
[0058] The dosage of any herein-disclosed composition or
compositions can depend on several factors including the
characteristics of the mammal to be administered. Examples of
characteristics include species, strain, breed, sex, age, weight,
size, health, and/or disease status. Moreover, the dosage may
depend on whether the administration is the first time the subject
received a composition of the present disclosure or if the subject
has previously received a composition of the present disclosure.
Additionally, pharmacogenomic (the effect of genotype on the
pharmacokinetic, pharmacodynamic or efficacy profile of a
composition) information about a particular subject may affect
dosage used. Furthermore, the exact individual dosages can be
adjusted somewhat depending on a variety of factors, including the
specific composition being administered, the time of
administration, the route of administration, the nature of the
formulation, and the rate of excretion. Some variations in the
dosage can be expected.
[0059] Moreover, the dosage may depend on the specific ingredients
administered.
[0060] In embodiments, the active agent (disulfiram) and/or the
potentiating ingredient (cinnamaldehyde) are encapsulated in a
microcapsules. Disulfiram may be encapsulated in one microcapsule
and cinnamaldehyde may be encapsulated into another microcapsule.
Disulfiram and cinnamaldehyde may be encapsulated into one
microcapsule. Disulfiram may be encapsulated in one microcapsule
and cinnamaldehyde may not be encapsulated. Disulfiram may not be
encapsulated and cinnamaldehyde may be encapsulated in a
microcapsule. The microcapsule may be a liposome, an albumin
microsphere, a microemulsion, a nanoparticle (e.g., a lipid
nanoparticle), and a nanocapsule. In embodiments, microcapsules,
e.g., lipid nanoparticles and liposomes, include lipids selected
from one or more of the following categories: cationic lipids;
anionic lipids; neutral lipids; multi-valent charged lipids; and
zwitterionic lipids. In some cases, a cationic lipid and/or
cationic polymer may be used to facilitate a charge-charge
interaction with disulfiram and/or the one or more additional
ingredients. The microcapsule may comprise a PEGylated lipid.
Examples of microcapsules and methods for manufacturing the same
are described in the art. See, e.g., Prui et al., Crit Rev Ther
Drug Carrier Syst., 2009; 26(6): 523-580; Wakasar, J Drug Target,
2018, 26(4):311-318, Langer, 1990, Science 249:1527-1533; Treat et
al., in "Liposomes in the Therapy of Infectious Disease and
Cancer", Lopez-Berestein and Fidler (eds.), Liss, New York, pp.
353-365 (1989); Pelaz et al. "Diverse applications of
nanomedicine." (2017): 2313-2381; the contents of each of which is
incorporated herein by reference in its entirety.
[0061] Further, one or more additional ingredients (e.g., from
Table 1) may be encapsulated and the disulfiram and/or
cinnamaldehyde may be encapsulated, the one or more additional
ingredients may be unencapsulated and disulfiram and/or
cinnamaldehyde may be unencapsulated, and/or combinations
thereof.
[0062] In embodiments, a composition may comprise one or more of
capralactone, polylactide (PLA), polylactic-co-glycolic (PLGA),
polyethylene glycol (PEG), polylactic-co-hydroxymethylglycolic acid
(PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose,
gelatin-microcapsules, a poloxamer, or polymethylmethacrylate.
[0063] Disulfiram, as active agent, and cinnamaldehyde, as
potentiating ingredient, may be administered to a subject in need
thereof once per day, twice per day, or thrice per day. Disulfiram
and cinnamaldehyde may be administered to a subject in need thereof
once a week, twice a week, three times a week, four times a week,
five times a week, or six times a week. Disulfiram and
cinnamaldehyde may be administered to a subject in need thereof
once a month, twice a month, three times a month, or four times a
month.
[0064] When disulfiram and cinnamaldehyde are administered
separately, i.e., in distinct compositions, the administration
route of the first composition and the second composition may be
the same or may be different. In one example, the first composition
and the second composition are administrated orally. In one
example, the first composition and the second composition are
administrated by inhalation. In another example, the first
composition is administrated orally and the second composition is
by injection, inhalation, or topically. In yet another example, the
first composition is administrated by inhalation and the second
composition is by injection, orally, or topically.
[0065] Another aspect of the present disclosure is a composition
comprising disulfiram as active agent and cinnamaldehyde as
potentiating ingredient for use in any herein disclosed method. Yet
another aspect of the present disclosure is a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde for use in any herein disclosed method.
[0066] Compositions of the present disclosure are formulated to be
suitable for contacting a cell or an immune cell in vitro or ex
vivo. In such embodiments, disulfiram and the one or more
additional ingredients are formulated into a solution. The solute
chosen depends on characteristics of the compound. For example, a
water-soluble compound may be included in an aqueous solution,
which comprises water or saline. A water-insoluble compound may be
included in a non-aqueous solution, e.g., which comprises a
lipid-based fluid or other hydrocarbon-based fluid. Disulfiram and
the one or more additional ingredients may be formulated into a
single solution. Alternately, disulfiram and the one or more
additional ingredients may be formulated into distinct
solutions.
[0067] Effectiveness of disulfiram and a specific additional
ingredients may be validated in a pyroptosis inhibition assay. See,
e.g., Example 3.
[0068] Illustrative Metal Additional Ingredients
[0069] In embodiments, the one or more additional ingredients is a
metal. The metal may be selected from aluminum, calcium, copper,
iron, magnesium, manganese, potassium, sodium, or zinc. Disulfiram
has been shown to chelate certain metals and/or to be useful in the
context of cancer treatments. See, e.g., Viola-Rhenals et al.
"Recent Advances in Antabuse (Disulfiram): The Importance of its
Metal-binding Ability to its Anticancer Activity", Curr Med Chem.
2018 Feb. 12; 25(4): 506-524; WO2018081309A1; and WO2019094053A1.
The contents of each of which is incorporated herein by reference
in its entirety.
[0070] The metal may be in the form of any metal salt or metal
ester described in the present FDA's list of food additives, e.g.,
as listed in Table 1.
[0071] In embodiments, the metal is aluminum, calcium, copper,
iron, magnesium, manganese, potassium, sodium, or zinc.
[0072] In embodiments, aluminum is in the form of aluminum
hydroxide, aluminum oxide, or aluminum potassium disulfate
dodecahydrate.
[0073] In embodiments, calcium is in the form of anhydrous calcium
sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium
gluconate, calcium glycerol phosphate, calcium hydrogen phosphate
dihydrate, calcium hydroxide, calcium lactate, calcium
orthophosphate, or calcium phosphate.
[0074] In embodiments, copper is in the form of copper (II)
gluconate, copper sulfate, or copper (I) iodide.
[0075] In embodiments, iron is in the form of ferric ammonium
citrate, iron, iron (II) fumarate, or iron (II) sulfate
heptahydrate.
[0076] In embodiments, magnesium is in the form of magnesium
hydroxide, magnesium oxide, or magnesium silicate.
[0077] In embodiments, manganese is in the form of manganese
dichloride or manganese sulfate.
[0078] In embodiments, potassium is in the form of dipotassium
carbonate, potassium bromide, or potassium chloride.
[0079] In embodiments, sodium is in the form of disodium
5'-inosinate, disodium succinate, sodium benzoate, sodium
carbonate, sodium chloride, sodium citrate (dihydrate), sodium
dodecyl sulfate, sodium formate, sodium gluconate, sodium
thiosulfate (pentahydrate), or trisodium citrate.
[0080] In embodiments, zinc is in the form of zinc sulfate
(heptahydrate).
[0081] In some embodiments, the dosage of disulfiram may be about
0.1-60 units and the amount of the one or more additional
ingredients, which is a metal, may be about 1 unit, where
disulfiram ranges from 5-500 mg. The amount of a metal (is an
above-described form) may between 0.1 mg to 30 mg. In an
embodiment, the amount of the metal is between 1.5 mg and 3 mg. In
embodiments, the metal is copper or zinc and approximately 1.5 mg
of the metal is administered.
[0082] Illustrative Methods
[0083] The present disclosure provides a method for increasing
lifespan in a mammal, for preventing or treating disease including
an aging-related disorder in a mammal, for reducing a symptom of
aging in a mammal, and/or boosting an immune system in a mammal.
The methods comprise administering to the mammal a therapeutically
effective amount of disulfiram as active agent and cinnamaldehyde
as potentiating ingredient. Disulfiram and cinnamaldehyde may be
administered with one or more of the additional ingredients listed
in Table 1.
[0084] In embodiments, route of administration is oral, by
injection, inhalation, or topical. In embodiments, the injection is
intravenous injection or infusion, intraperitoneal injection,
intramuscular injection, or subcutaneous injection.
[0085] In embodiments, one composition comprising disulfiram is
administered and a second composition comprising cinnamaldehyde is
administered. In other embodiments, one composition comprising both
disulfiram and cinnamaldehyde is administered.
[0086] In embodiments, the mammal is near or has reached
maturity.
[0087] In embodiments, the mammal is nearing or has reached halfway
to its expected lifespan for the mammal's species, size, sex, age,
and/or health status. In embodiments, the mammal has reached an age
that is at least 60%, 70%, 80%, 90%, or 100% of its expected
lifespan for the mammal's species, size, sex, age, and/or health
status.
[0088] In embodiments, increasing lifespan comprises an at least 5%
increase in lifespan relative to the expected or median lifespan of
a mammal of similar species, sex, age, and/or health status. In
embodiments, increasing lifespan comprises an at least 10%, at
least 15%, at least 20%, or at least 25% increase in lifespan.
[0089] In embodiments, the mammal is a human, mouse, rat, guinea
pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human
primate, such as a monkey, chimpanzee, or baboon. In embodiments,
the mammal is a human.
[0090] Without wishing to be bound by theory, the active agent
disulfiram and the potentiating ingredient cinnamaldehyde (with or
without one or more additional ingredients, e.g., of Table 1)
mitigates dysfunction of or rejuvenates a signaling pathway
disrupted by aging where the dysfunction can ultimately lead to
aging-related disorders. In embodiments, the aging-related disorder
or symptom of aging selected from one or more of actinic keratosis,
age-related macular degeneration (AMD), alopecia, Alzheimer's
disease, arthritis, atherosclerosis and cardiovascular disease,
benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer
(e.g., a skin cancer such as basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC)), cardiomyopathy, cataracts, chronic
obstructive pulmonary disease (COPD), idiopathic pulmonary
fibrosis, constipation, decrease in overall energy, decrease in
visual acuity, delirium, dementia, depression, dermal atrophy
(thinning of the skin), diminished peripheral vision, dry eye,
greater risk of heat stroke or hypothermia, hearing loss,
hypertension, increased susceptibility to infection (including
influenza and pneumonia), lentigines (aging spots), memory loss,
metabolic syndrome, muscle atrophy (e.g., Sarcopenia and myopenia),
frailty, muscle repair or rejuvenation deficiency, muscular
dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging,
reduced metabolism (including increased risk for obesity), reduced
reflexes and coordination including difficulty with balance,
respiratory disease (including acute lung injury (ALI) and/or acute
respiratory distress syndrome (ARDS)), rheumatoid arthritis,
sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes,
urologic changes (including incontinence), vaginal atrophy,
whitening or graying of hair, prolonged/inefficient wound healing,
wrinkling/sagging skin (including loss of skin elasticity), and
xerosis cutis (skin dryness). In embodiments, the aging-related
disorder or symptom of aging is actinic keratosis, dermal atrophy
(thinning of the skin), lentigines (aging spots), photoaging,
vaginal atrophy, prolonged/inefficient wound healing, wrinkles,
and/or xerosis cutis (skin dryness) and the administration route is
oral or topical. In embodiments, the mammal has at least one
aging-related disorder or symptom of aging. A non-human mammal may
have an aging-related disorder or symptom of aging that is
homologous to the aging-related disorder or symptom of aging listed
above.
[0091] In an embodiment, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde (with or without one or more additional ingredients,
e.g., of Table 1) are administered to a mammal, e.g., a human, for
preventing or treating a respiratory disease or disorder, e.g.,
acute lung injury (ALI) and/or acute respiratory distress syndrome
(ARDS). Administration of the composition(s) is by intravenous
injection or infusion, intraperitoneal injection, intramuscular
injection, or subcutaneous injection, with a dose depending on the
quantity of composition(s) needing to be administered. Alternately,
the composition(s) are administered orally, by inhalation, or
topically. Combinations of administration routes may be used.
Treatment is identified as an improvement in the administered
mammal in one or more of the following symptoms severe shortness of
breath, labored and unusually rapid breathing, low blood pressure,
and confusion and extreme tiredness. The improvement may be
relative to the pre-administration state for the mammal. The
underlying cause for the ALI and/or ARDS may be sepsis (e.g., a
serious and widespread infection of the bloodstream); inhalation of
a harmful substance (e.g., smoke, chemical fumes, asbestos, dust,
particulates, vomit, and water); viral or bacterial pneumonia
(which may affect up to all five lobes of the lungs) and other
respiratory disorders including those caused by a coronavirus
(e.g., SARS, MERS, and COVID-19), influenzas (influenza A,
influenza B, or parainfluenza), pneumococcal infection, adenovirus,
respiratory syncytial virus (RSV), enterovirus and/or other
respiratory viral infections; and a head, chest or other major
injury; or another cause (e.g., pancreatitis which is inflammation
of the pancreas, a massive blood transfusion, and severe burns). In
some embodiments, ALI differs from ARDS in that ALI exists during
early stage of a respiratory disease and ARDS exists during a later
state of the respiratory disease. In some, the composition or
compositions prevent or treat idiopathic pulmonary fibrosis and/or
chronic obstructive pulmonary disease.
[0092] In an embodiment, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde (with or without one or more additional ingredients,
e.g., of Table 1) are administered to a mammal, e.g., a human, for
treating dry eye. The composition(s) may be administered topically
(e.g., via eye drops or an eye ointment), with a dose depending on
the quantity of composition(s) needing to be administered.
[0093] In an embodiment, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde (with or without one or more additional ingredients,
e.g., of Table 1) are administered to a mammal, e.g., a human, for
treating alopecia. The composition(s) may be administered topically
(e.g., gel, lotion, ointment, cream, suspension, paste, liniment,
powder, tincture, or aerosol or via an impregnated solid support
(e.g., a patch)), with a dose depending on the quantity of
composition(s) needing to be administered. The composition may be
administered orally, by injection, or by inhalation.
[0094] In an embodiment, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde (with or without one or more additional ingredients,
e.g., of Table 1) are administered to a mammal, e.g., a human, for
treating a skin disorder, e.g., wrinkles, which may be a result of
photoaging or related to actinic keratosis. Other skin disorders
include dermal atrophy (thinning of the skin), lentigines (aging
spots), vaginal atrophy, prolonged/inefficient wound healing,
and/or xerosis cutis (skin dryness). The composition(s) may be
formulated as a gel, lotion, ointment, cream, suspension, paste,
liniment, powder, tincture, or aerosol or administered via an
impregnated solid support (e.g., a patch)). The composition(s) may
be administered orally or topically, with a dose depending on the
quantity of composition(s) needing to be administered. Alternately,
the composition(s) may be administered by injection or by
inhalation. Combinations of administration routes may be used.
[0095] In an embodiment, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde (with or without one or more additional ingredients,
e.g., of Table 1) are administered to a mammal, e.g., a human, for
treating a skin cancer, e.g., (e.g., basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC)). The compositions may be
administered topically, with a dose depending on the quantity of
composition needing to be administered. The compositions may be
formulated as a gel, lotion, ointment, cream, suspension, paste,
liniment, powder, tincture, or aerosol or administered via an
impregnated solid support (e.g., a patch)). Alternately, the
composition may be administered orally, by injection, or by
inhalation. Combinations of administration routes may be used.
[0096] In embodiments, a therapeutically effective amount of
disulfiram as active agent and cinnamaldehyde as potentiating
ingredient (with or without one or more additional ingredients,
e.g., of Table 1) treats or prevents a disease or a symptom
thereof; as examples, the disease may be asthma, deafness, or a
viral infections and a symptom thereof may be sepsis.
[0097] In embodiments, a therapeutically effective amount of the
active agent disulfiram and the potentiating ingredient
cinnamaldehyde (with or without one or more additional ingredients,
e.g., of Table 1) boosts the immune system in the mammal.
[0098] As shown in Example 2, cells from older donors treated with
disulfiram exhibited phenotypes of younger cells in response to
viral infection. Further, disulfiram reduced inflammasome-mediated
pyroptotic cell death. Importantly, the combination of disulfiram
and cinnamaldehyde showed a synergistic effect on reduction of
inflammasome activation, as shown in Example 3.
[0099] In embodiments, boosting the immune system increases an
effective immune response against an infectious agent. In
embodiments, the infectious agent is a virus, a bacterium, a
fungus, a protozoan, a helminth, a prion, or a parasite. In
embodiments, the bacterium is Bordatella pertussis or
Streptococcocus pneumoniae or the virus is a Chickenpox virus,
Coronavirus, Hepatitis A virus, Hepatitis B virus, Human
papillomavirus, Human immunodeficiency virus (HIV), influenza,
Japanese encephalitis virus, Measles, mumps, or rubella virus,
Poliovirus, Rabies virus, Respiratory syncytial virus (RSV),
Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow
fever virus. In embodiments, the Coronavirus is Sars-CoV-2. In
embodiments, when the infectious agent affects the mammal's
respiratory system or is transmitted via the mammal's respiratory
system and the route of administration is by inhalation.
[0100] In embodiments, the route of administration is oral or by
inhalation.
[0101] In embodiments, the mammal has a healthy immune system. In
embodiments, the mammal has an unhealthy immune system,
dysfunctional immune system, and/or weakened immune system.
[0102] The present disclosure provides an in vivo method for
increasing lifespan of a cell and/or boosting activity of an immune
cell comprising contacting the cell or the immune cell with
disulfiram as active agent and cinnamaldehyde as potentiating
ingredient. In some embodiments, the immune cell is contacted with
disulfiram and cinnamaldehyde and one or more of the additional
ingredients listed in Table 1. In such in vivo methods, disulfiram
and cinnamaldehyde (with or without one or more additional
ingredients) are administered to a subject, e.g., parenterally or
enterally, and disulfiram and cinnamaldehyde (with or without the
one more additional ingredients) contacts the cell or immune cell
within the subject, e.g., by being carried through the subject's
blood stream or the subject's lymphatic system or within
extracellular spaces.
[0103] The present disclosure provides an in vitro or ex vivo
method for increasing lifespan of a cell and/or boosting activity
of an immune cell, the method comprises contacting the cell or the
immune cell with a disulfiram as active agent and cinnamaldehyde as
potentiating ingredient (with or without one or more of the
additional ingredients listed in Table 1). Here, the cell or the
immune cell is in a culturing vessel, e.g., a petri dish, tissue
culture plate, or culture flask, and disulfiram and cinnamaldehyde
(at least) are added to a medium (e.g., growth medium or buffer
solution) surrounding the cell or immune cell.
[0104] In some methods, the one or more additional ingredients is a
metal (e.g., copper and zinc).
[0105] Boosting the immune system Another aspect of the present
disclosure is a method for boosting the immune system in a
mammal.
[0106] The method for boosting an immune system in a mammal
comprises administering to the mammal a therapeutically effective
amount of disulfiram as active agent and cinnamaldehyde as
potentiating ingredient, with or without one or more of the
additional ingredients listed in Table 1.
[0107] In embodiments, boosting the immune system increases an
effective immune response against an infectious agent. In
embodiments, the infectious agent is a virus, a bacterium, a
fungus, a protozoan, a helminth, a prion, or a parasite. In
embodiments, the bacterium is Bordatella pertussis or
Streptococcocus pneumoniae. In embodiments, the virus is selected
from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado
tick fever virus (CTFV), Coronaviruse, Crimean-Congo hemorrhagic
fever virus, Cytomegalovirus, Dengue viruses (DEN-1, DEN-2, DEN-3
and DEN-4), Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A
virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV),
Flaviviruses, Guanarito virus, Heartland virus, Hendra virus,
Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis
D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and
HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and
human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV),
Human metapneumovirus (hMPV), Human papillomaviruses (HPV), Human
parainfluenza viruses (HPIV), Influenza, Japanese encephalitis
virus, JC virus, Junin virus, Lassa virus, Lymphocytic
choriomeningitis virus (LCMV), Machupo virus, Marburg virus,
Measles virus, Middle East respiratory syndrome coronavirus,
Molluscum contagiosum virus (MCV), Monkeypox virus, Mumps virus,
Nipah virus, Norovirus, Orthomyxoviridae species, Parvovirus B19,
Poliovirus, Rabies virus, Respiratory syncytial virus (RSV),
Rhinovirus, Rift Valley fever virus, Rotavirus, Rubella virus,
Sabia virus, SARS coronavirus, Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), Shingles virus, Sin Nombre virus,
Smallpox, Varicella zoster virus (VZV), Variola major or Variola
minor, Venezuelan equine encephalitis virus, West Nile virus,
Yellow fever virus, and Zika virus. In embodiments, the Coronavirus
is Sars-CoV-2.
[0108] In embodiments, when the infectious agent affects the
mammal's respiratory system or is transmitted via the mammal's
respiratory system and the route of administration is by
inhalation.
[0109] In embodiments, the route of administration is oral or by
inhalation.
[0110] In some cases, the mammal has a healthy immune system. In
other cases, the mammal has an unhealthy immune system,
dysfunctional immune system, and/or weakened immune system.
[0111] In embodiments, the term dysfunctional immune system may be
an overactive immune system, e.g., resulting in a cytokine storm;
such overactive immune systems are observed in certain viral
infections, e.g., in some severe coronavirus patients. In various
embodiments, "boosting the immune system", relates to "boosting" a
proper (e.g., non-pathological) immune response. That is,
minimizing an overactive immune response.
[0112] In embodiments, the mammal is nearing or has reached halfway
to its expected lifespan for the mammal's species, size, sex, age,
and/or health status. In embodiments, the aged mammal has reached
an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected
lifespan for the mammal's species, size, sex, age, and/or health
status.
[0113] Of course, any mammal may benefit from a boost in the immune
system. Thus, the compositions and methods for boosting the immune
system can be used with aged and with non-aged mammals.
[0114] In embodiments, the route of administration is oral, by
injection, inhalation, or topical. The administration route may
comprise intravenous injection or infusion, intraperitoneal
injection, intramuscular injection, or subcutaneous injection.
[0115] In embodiments, one composition comprising the active agent
that is disulfiram is administered and a second composition
comprising the potentiating ingredient that is cinnamaldehyde. In
other embodiments, one composition comprising both disulfiram and
cinnamaldehyde is administered. In some embodiments, one or more
additional ingredients, e.g., of Table 1, is included in the
composition with disulfiram and cinnamaldehyde, in the composition
with disulfiram, in the composition with cinnamaldehyde, or in a
composition without disulfiram or cinnamaldehyde.
[0116] In methods for boosting the immune system in a mammal, the
one or more additional ingredients may be a metal (e.g., copper and
zinc).
[0117] Improving a Vaccine Response
[0118] The present disclosure also provides a method for improving
effectiveness of a vaccine in a mammal in need thereof. The method
comprises administering a therapeutically effective amount of
disulfiram as active agent and cinnamaldehyde as potentiating
ingredient, with or without one or more of the additional
ingredients listed in Table 1. Here, the mammal may
contemporaneously and/or subsequently be administered a
vaccine.
[0119] In embodiments, disulfiram and cinnamaldehyde (with or
without one or more additional ingredients, e.g., of Table 1) and
the vaccine are administered contemporaneously. In embodiments, the
vaccine is administered subsequent to administering disulfiram and
cinnamaldehyde, with or without one or more additional
ingredients.
[0120] In embodiments, a therapeutically effective amount of
disulfiram and cinnamaldehyde (with or without the one or more of
the additional ingredients) boosts the immune system in the
mammal.
[0121] In embodiments, boosting the immune system increases an
immune response against a component contained in the vaccine. In
embodiments, the increased immune response promotes future immunity
against the component contained in the vaccine.
[0122] It has been reported in the art that aged mammals respond
less strongly to vaccines than mammal who are less aged.
Accordingly, methods for improving effectiveness of a vaccine in an
aged mammal are needed.
[0123] In embodiments, an aged mammal is nearing or has reached
halfway to its expected lifespan for the mammal's species, size,
sex, age, and/or health status. In embodiments, the aged mammal has
reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its
expected lifespan for the mammal's species, size, sex, age, and/or
health status.
[0124] Influenza is problematic in older adults with increased risk
for serious complications and hospitalization. In addition,
approximately 90% of flu-related deaths occur in this population,
with influenza and pneumonia being the eighth leading cause of
death among persons over 65 years of age in the United States. Even
when death is avoided, older adults have an increased risk for
secondary complications and morbidities from flu infection.
Depending on how successful the WHO predicts the influenza strains
causing seasonal epidemics, the produced vaccines show efficacy
rates between 60% and 90%. However, vaccine effectiveness in adults
aged 65 and older is usually significantly lower, ranging from an
average of 28% protection against fatal and nonfatal complications
(with large dispersion), 39% protection against typical
influenza-like illness, and 49% protection against disease with
confirmed virus infection. Influenza vaccine effectiveness is a
significant problem in elderly as compared to young individuals and
is associated with high rates of complicated illness including
pneumonia, heart attacks, and strokes in the >65-year-old
population.
[0125] Furthermore, the outbreak of the novel coronavirus
(SARS-CoV-2) has had devastating effects on the aged and those with
pre-existing health conditions. A mammal would particularly benefit
from a composition of the present disclosure and methods of
administering the same to improve effectiveness of a SARS-CoV-2
vaccine.
[0126] Of course, mammals who are not aged may benefit from
improved effectiveness of a vaccine. Thus, the compositions and
methods for improving effectiveness of a vaccine can be used with
non-aged mammals.
[0127] In some cases, the mammal has an unhealthy immune system,
dysfunctional immune system, and/or weakened immune system. In
other cases, the mammal has a healthy immune system.
[0128] In embodiments, the term dysfunctional immune system may be
an overactive immune system, e.g., resulting in a cytokine storm;
such overactive immune systems are observed in certain viral
infections, e.g., in some severe coronavirus patients. In various
embodiments, "improving a vaccine response", relates to "improving"
a proper (e.g., non-pathological) immune response to a vaccine and,
later, when a subject is contacted with an infectious agent. That
is, minimizing an overactive immune response and promoting a proper
immune response.
[0129] In embodiments, the increased immune response promotes
future immunity against the component contained in the vaccine. In
embodiments, the component contained in the vaccine is an antigen
obtained from, related to, homologous to, or expressed by an
infectious agent.
[0130] In embodiments, the vaccine is a Chickenpox vaccine,
Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine,
Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human
Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza
vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella
(including MMR combined vaccine) vaccine, Meningococcal disease
vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies
vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus
vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine,
Varicella virus vaccine, Whooping cough (part of the DTaP combined
vaccine) vaccine, or Yellow fever vaccine. In embodiments, the
vaccine is a coronavirus vaccine, e.g., directed against
Sars-CoV-2.
[0131] In embodiments, disulfiram and cinnamaldehyde (with or
without one or more of the additional ingredients) is administered
orally, by injection, by inhalation, or topically. In embodiments,
the vaccine is administered orally, by injection, by inhalation, or
topically. In embodiments, the injection is intravenous injection
or infusion, intraperitoneal injection, intramuscular injection, or
subcutaneous injection.
[0132] In embodiments, one composition comprising disulfiram as
active agent is administered and a second composition comprising
cinnamaldehyde as potentiating ingredient is administered. Here, a
third composition comprising on or more additional ingredients,
e.g., of Table 1, is administrated. In other embodiments, one
composition comprising both disulfiram and cinnamaldehyde (with or
without the one or more additional ingredients) is
administered.
[0133] In methods for improving effectiveness of a vaccine, the one
or more additional ingredients may be a metal (e.g., copper and
zinc).
[0134] 2. Reducing the Predicted Age of Cell
[0135] An aspect of the present disclosure is a method for reducing
a predicted biological age of a cell.
[0136] The method comprises contacting the cell with a
therapeutically effective amount of the active agent disulfiram and
the potentiating ingredient cinnamaldehyde, with or without one or
more additional ingredients listed in Table 1.
[0137] As shown in Example 2, cells from older donors treated with
disulfiram exhibited phenotypes similar to younger donors. For
instance, disulfiram significantly reduced several proinflammatory
cytokines and significantly reduced the percentage of mitochondria
with reticular shape. In addition, T cells from older donors
treated with disulfiram exhibited a younger phenotype as compared
to untreated controls.
[0138] In embodiments, the cell is in vitro, ex vivo, or in
vivo.
[0139] In methods for reducing a predicted biological age of a
cell, the one or more additional ingredients may be a metal (e.g.,
copper and zinc).
[0140] Assays and formulations used in methods for reducing a
predicted biological age of a cell may be related to those
described in US20190228840, the entire contents of which is
incorporated by reference its entirety.
[0141] Aging-Related Disorders
[0142] The herein-disclosed compositions and methods treat,
prevent, reduce the severity of, and/or delay the onset of various
aging-related disorders, e.g., chronic diseases and
disabilities/conditions of aging. Illustrative aging-related
disorders include actinic keratosis, age-related macular
degeneration (AIMD), alopecia, Alzheimer's disease, arthritis,
atherosclerosis and cardiovascular disease, benign prostatic
hyperplasia (BPH), bone atrophy, cachexia, cancer (e.g., a skin
cancer including basal cell carcinoma (BCC) and squamous cell
carcinoma (SCC)), cardiomyopathy, cataracts, chronic obstructive
pulmonary disease (COPD), constipation, decrease in overall energy,
decrease in visual acuity, delirium, dementia, depression, dermal
atrophy (thinning of the skin), diminished peripheral vision, dry
eye, greater risk of heat stroke or hypothermia, hearing loss,
hypertension, increased susceptibility to infection (including
influenza and pneumonia), lentigines (aging spots), memory loss,
metabolic syndrome, muscle atrophy (e.g., Sarcopenia and myopenia),
frailty, muscle repair or rejuvenation deficiency, muscular
dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging,
reduced metabolism (including increased risk for obesity), reduced
reflexes and coordination including difficulty with balance,
respiratory disease (including acute lung injury (ALI) and/or acute
respiratory distress syndrome (ARDS)), rheumatoid arthritis,
sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes,
urologic changes (including incontinence), vaginal atrophy,
whitening or graying of hair, wrinkling/sagging skin (including
loss of skin elasticity), and xerosis cutis (skin dryness). Aged
non-human subjects experience similar, homologous, and/or
equivalent aging-related disorders.
[0143] Without wishing to be bound by theory, disulfiram and the
one or more additional ingredients mitigates dysfunction of or
rejuvenates a signaling pathway disrupted by aging where the
dysfunction can ultimately lead to aging-related disorders.
[0144] 3. Inhibiting Pyroptosis
[0145] In any of the herein-disclosed aspects and embodiments, use
of disulfiram as active agent and cinnamaldehyde as potentiating
ingredient, with or without one or more additional ingredients,
e.g., of Table 1, inhibits pyroptosis of a cell.
[0146] Pyroptosis is a highly inflammatory form of programmed cell
death that occurs most frequently upon infection with intracellular
pathogens and is likely to form part of the antimicrobial innate
immune response. Pyroptosis results in a distinct morphology by a
unique mechanism compared to those of other forms of cell death.
For example, unlike apoptosis-type programmed cell death, in a cell
that undergoes pyroptosis, gasdermin D pores are formed on the
plasma membrane, resulting in water influx and cell lysis, and in
some cases, release of IL-1.beta., IL-18 and HMGB1.
[0147] The potentiating ingredient cinnamaldehyde enhances
disulfiram's ability to inhibit pyroptosis, as shown in Example
3.
[0148] Subjects
[0149] In embodiments, the subject is a mammal, e.g., a human,
mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep,
or non-human primate, such as a monkey, chimpanzee, or baboon. In
embodiments, the mammal is a non-rodent. In embodiments, the mammal
is a dog. In embodiments, the subject is a non-human animal, and
therefore the invention pertains to veterinary use. In a specific
embodiment, the non-human animal is a household pet, e.g., a dog.
In another specific embodiment, the non-human animal is a livestock
animal. In embodiments, the mammal is a human.
[0150] In embodiments, the mammal has reached maturity. As used
herein, the term mature or maturity, and the like, refers to a
mammal that is capable of sexual reproduction and/or a mammal that
has achieved its adult height and/or length.
[0151] In embodiments, the mammal is nearing or has reached halfway
to its expected lifespan for the mammal's species, size, sex, age,
and/or health status. The mammal may have reached an age that is at
least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the
mammal's species, size, sex, age, and/or health status.
[0152] In embodiments, the human is an adult human. In embodiments,
the human has an age in a range of from about 10 to about 15 years
old, from about 15 to about 20 years old, from about 20 to about 25
years old, from about 25 to about 30 years old, from about 30 to
about 35 years old, from about 35 to about 40 years old, from about
40 to about 45 years old, from about 45 to about 50 years old, from
about 50 to about 55 years old, from about 55 to about 60 years
old, from about 60 to about 65 years old, from about 65 to about 70
years old, from about 70 to about 75 years old, from about 75 to
about 80 years old, from about 80 to about 85 years old, from about
85 to about 90 years old, from about 90 to about 95 years old or
from about 95 to about 100 years old, or older.
[0153] In some cases, the mammal has an unhealthy immune system,
dysfunctional immune system, and/or weakened immune system. In
other cases, the mammal has a healthy immune system.
Further Embodiments
[0154] Embodiment 1: A method for increasing lifespan in a mammal,
for preventing or treating disease including an aging-related
disorder in a mammal, for reducing a symptom of aging in a mammal,
and/or boosting an immune system in a mammal comprising:
administering to the mammal one or more compositions that each or
together comprise an active agent that is disulfiram and a
potentiating ingredient that is cinnamaldehyde.
[0155] Embodiment 2: An in vivo, in vitro, or ex vivo method for
increasing lifespan of a cell and/or boosting activity of an immune
cell comprising contacting the cell or the immune cell with one or
more compositions that each or together comprise an active agent
that is disulfiram and a potentiating ingredient that is
cinnamaldehyde.
[0156] Embodiment 3: The method of embodiment 1 or embodiment 2,
wherein one composition is administered that consists essentially
of disulfiram and cinnamaldehyde.
[0157] Embodiment 4: The method of embodiment 1 or embodiment 2,
wherein more than one composition is administered with a first
composition consisting essentially of disulfiram and with a second
composition consisting essentially of cinnamaldehyde.
[0158] Embodiment 5: The method of any one of embodiments 1 to 4,
wherein the one or more compositions independently further
comprises one or more additional ingredients from Table 1.
[0159] Embodiment 6: The method of any one of embodiments 1 to 5,
wherein the administering is oral, by injection, inhalation, or
topical.
[0160] Embodiment 7: The method of any one of embodiments 1 to 6,
wherein the mammal is near or has reached maturity.
[0161] Embodiment 8: The method of any one of embodiments 1 to 6,
wherein the mammal is nearing or has reached halfway to its
expected lifespan for the mammal's species, size, sex, age, and/or
health status.
[0162] Embodiment 9: The method of any one of embodiments 1 to 6,
wherein the mammal has reached an age that is at least 60%, 70%,
80%, 90%, or 100% of its expected lifespan for the mammal's
species, size, sex, age, and/or health status.
[0163] Embodiment 10: The method of any one of embodiments 1 to 9,
wherein the mammal is a human, mouse, rat, guinea pig, dog, cat,
horse, cow, pig, rabbit, sheep, or non-human primate, such as a
monkey, chimpanzee, or baboon.
[0164] Embodiment 11: The method of embodiment 10, wherein the
mammal is a human.
[0165] Embodiment 12: The method of any one of embodiments 1 to 11,
wherein increasing lifespan comprises an at least 5% increase in
lifespan relative to the expected or median lifespan of a mammal of
similar species, sex, age, and/or health status.
[0166] Embodiment 13: The method of embodiment 12, wherein
increasing lifespan comprises an at least 10%, at least 15%, at
least 20%, or at least 25% increase in lifespan.
[0167] Embodiment 14: The method of any one of embodiments 1 to 13,
wherein the aging-related disorder or symptom of aging selected
from one or more of actinic keratosis, age-related macular
degeneration (AIMD), alopecia, Alzheimer's disease, arthritis,
atherosclerosis and cardiovascular disease, benign prostatic
hyperplasia (BPH), bone atrophy, cachexia, cancer (e.g., a skin
cancer including basal cell carcinoma (BCC) and squamous cell
carcinoma (SCC)), cardiomyopathy, cataracts, chronic obstructive
pulmonary disease (COPD), constipation, decrease in overall energy,
decrease in visual acuity, delirium, dementia, depression, dermal
atrophy (thinning of the skin), diminished peripheral vision, dry
eye, greater risk of heat stroke or hypothermia, hearing loss,
hypertension, increased susceptibility to infection (including
influenza and pneumonia), lentigines (aging spots), memory loss,
metabolic syndrome, muscle atrophy (e.g., Sarcopenia and myopenia),
frailty, muscle repair or rejuvenation deficiency, muscular
dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging,
reduced metabolism (including increased risk for obesity), reduced
reflexes and coordination including difficulty with balance,
respiratory disease (including acute lung injury (ALI) and/or acute
respiratory distress syndrome (ARDS)), rheumatoid arthritis,
sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes,
urologic changes (including incontinence), vaginal atrophy,
whitening or graying of hair, prolonged/inefficient wound healing,
wrinkling/sagging skin (including loss of skin elasticity), and
xerosis cutis (skin dryness); or the disease includes asthma,
deafness, or a viral infections and/or a symptom of the disease
comprises sepsis.
[0168] Embodiment 15: The method of embodiment 14, wherein the
aging-related disorder or symptom of aging is actinic keratosis,
dermal atrophy (thinning of the skin), lentigines (aging spots),
photoaging, vaginal atrophy, prolonged/inefficient wound healing,
wrinkles, and/or xerosis cutis (skin dryness) and wherein the
administering is oral or topical.
[0169] Embodiment 16: The method of embodiment 14 or embodiment 15,
wherein the mammal has at least one aging-related disorder or
symptom of aging.
[0170] Embodiment 17: The method of any one of embodiments 1 to 16,
wherein the disulfiram and the cinnamaldehyde boosts the immune
system in the mammal.
[0171] Embodiment 18: The method of embodiment 17, wherein boosting
the immune system increases an effective immune response against an
infectious agent.
[0172] Embodiment 19: The method of embodiment 18, wherein the
infectious agent is a virus, a bacterium, a fungus, a protozoan, a
helminth, a prion, or a parasite.
[0173] Embodiment 20: The method of embodiment 19, wherein the
bacterium is Bordatella pertussis or Streptococcus pneumoniae or
the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus,
Hepatitis B virus, Human papillomavirus, Human immunodeficiency
virus (HIV), influenza (e.g., Influenza A, Influenza B, and
parainfluenza), Japanese encephalitis virus, Measles, mumps, or
rubella virus, Poliovirus, Rabies virus, Respiratory syncytial
virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus,
or Yellow fever virus.
[0174] Embodiment 21: The method of embodiment 20, wherein the
Coronavirus is Sars-CoV-2.
[0175] Embodiment 22: The method of any one of embodiments 18 to
21, wherein the infectious agent affects the mammal's respiratory
system or is transmitted via the mammal's respiratory system and
wherein the administering is orally or by inhalation.
[0176] Embodiment 23: The method of any one of embodiments 1 to 22,
wherein the mammal has a healthy immune system.
[0177] Embodiment 24: The method of any one of embodiments 1 to 22,
wherein the mammal has an unhealthy immune system, dysfunctional
immune system, and/or weakened immune system.
[0178] Embodiment 25: A method for improving effectiveness of a
vaccine in a mammal in need thereof, the method comprises
administering a therapeutically effective amount of one or more
compositions that each or together comprise an active agent that is
disulfiram and a potentiating ingredient that is cinnamaldehyde,
wherein the mammal contemporaneously and/or subsequently will be
administered a vaccine.
[0179] Embodiment 26: The method of embodiment 25, wherein one
composition is administered that consists essentially of disulfiram
and cinnamaldehyde.
[0180] Embodiment 27: The method of embodiment 25, wherein more
than one composition is administered with a first composition
consisting essentially of the disulfiram and with a second
composition consisting essentially of cinnamaldehyde.
[0181] Embodiment 28: The method of any one of embodiments 25 to
27, wherein the one or more compositions independently further
comprises one or more additional ingredients from Table 1.
[0182] Embodiment 29: The method of any one of embodiments 25 to
28, wherein the one or more compositions and the vaccine are
administered contemporaneously.
[0183] Embodiment 30: The method of any one of embodiments 25 to
29, wherein the vaccine is administered subsequent to administering
the one or more composition.
[0184] Embodiment 31: The method of any one of embodiments 25 to
30, wherein the therapeutically effective amount of the one or more
compositions boosts the immune system in the mammal.
[0185] Embodiment 32: The method of embodiment 31, wherein boosting
the immune system increases an immune response against a component
contained in the vaccine.
[0186] Embodiment 33: The method of embodiment 32, wherein the
increased immune response promotes future immunity against the
component contained in the vaccine.
[0187] Embodiment 34: The method of any one of embodiments 25 to
33, wherein the component contained in the vaccine is an antigen
obtained from, related to, homologous to, or expressed by an
infectious agent.
[0188] Embodiment 35: The method of any one of embodiments 25 to
34, wherein the vaccine is a Chickenpox vaccine, Coronavirus
vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B
vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus
(HIV) vaccine, Human papillomavirus vaccine, influenza vaccine,
Japanese encephalitis vaccine, Measles, mumps, or rubella
(including MMR combined vaccine) vaccine, Meningococcal disease
vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies
vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus
vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine,
Varicella virus vaccine, Whooping cough (part of the DTaP combined
vaccine) vaccine, or Yellow fever vaccine.
[0189] Embodiment 36: The method of embodiment 34, wherein the
vaccine is a coronavirus vaccine, e.g., Sars-CoV-2.
[0190] Embodiment 37: The method of any one of embodiments 25 to
36, wherein the mammal has a healthy immune system.
[0191] Embodiment 38: The method of any one of embodiments 25 to
36, wherein the mammal has an unhealthy immune system,
dysfunctional immune system, and/or weakened immune system.
[0192] Embodiment 39: The method of any one of embodiments 25 to
38, wherein the administering of the one or more compositions is
oral, by injection, inhalation, or topical.
[0193] Embodiment 40: The method of any one of embodiments 25 to
39, wherein the administering of the vaccine is oral, by injection,
inhalation, or topical.
[0194] Embodiment 41: The method of any one of embodiments 1 to 40,
wherein the disulfiram is administered in a dose from about 5 to
about 500 mg.
[0195] Embodiment 42: The method of any one of embodiments 1 to 41,
wherein the cinnamaldehyde is administered in a dose from about
0.01% to about 45% of the weight of the disulfiram.
[0196] Embodiment 43: The method of any one of embodiments 1, 2,
4-25, or 27-42, wherein the one or more compositions independently
further comprises a metal.
[0197] Embodiment 44: The method of embodiment 43, wherein the
metal aluminum, calcium, copper, iron, magnesium, manganese,
potassium, sodium, or zinc.
[0198] Embodiment 45: The method of embodiment 44, wherein the
metal is aluminum hydroxide, aluminum oxide, aluminum potassium
disulfate dodecahydrate, anhydrous calcium sulfate, calcium
carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium
glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium
hydroxide, calcium lactate, calcium orthophosphate, calcium
phosphate, copper (II) gluconate, copper sulfate, copper (I)
iodide, ferric ammonium citrate, iron, iron (II) fumarate, iron
(II) sulfate heptahydrate, magnesium hydroxide, magnesium oxide,
magnesium silicate, manganese dichloride, manganese sulfate,
dipotassium carbonate, potassium bromide, potassium chloride,
disodium 5'-inosinate, disodium succinate, sodium benzoate, sodium
carbonate, sodium chloride, sodium citrate (dihydrate), sodium
dodecyl sulfate, sodium formate, sodium gluconate, sodium
thiosulfate (pentahydrate), trisodium citrate, or zinc sulfate
(heptahydrate).
[0199] Embodiment 46: The method of embodiment 45 wherein the metal
is copper (II) gluconate, copper sulfate, copper (I) iodide, or
zinc sulfate (heptahydrate).
[0200] Embodiment 47: The method of any one of embodiments 42 to
46, wherein the amount of the metal is between about 0.1 mg to
about 30 mg.
[0201] Embodiment 48: The method of embodiment 47, wherein the
amount of the metal is between about 1.5 mg and 3 mg.
[0202] Embodiment 49: The method of embodiment 48, wherein the
metal is copper or zinc and approximately 1.5 mg of the metal is
administered per dose.
[0203] Embodiment 50: A method for reducing a predicted biological
age of a cell comprising contacting the cell with a therapeutically
effective amount of one or more compositions that each or together
comprise an active agent that is disulfiram and a potentiating
ingredient that is cinnamaldehyde.
[0204] Embodiment 51: The method of embodiment 50, wherein one
composition is administered that consists essentially of disulfiram
and cinnamaldehyde.
[0205] Embodiment 52: The method of embodiment 50, wherein more
than one composition is administered with a first composition
consisting essentially of disulfiram and with a second composition
consisting essentially of cinnamaldehyde.
[0206] Embodiment 53: The method of any one of embodiments 50 to
52, wherein the one or more compositions independently further
comprises one or more additional ingredients from Table 1.
[0207] Embodiment 54: The method of any one of embodiments 50 to
53, wherein the cell is in vitro, ex vivo, or in vivo.
[0208] Embodiment 55: The method of any one of embodiments 1 to 54,
wherein the disulfiram inhibits pyroptosis of a cell.
[0209] Embodiment 56: The method of embodiment 55, wherein the
cinnamaldehyde potentiates disulfiram's inhibition of pyroptosis of
a cell.
[0210] Embodiment 57: The method of any one of embodiments 1 to 56,
wherein the one or more compositions inhibits pyroptosis of a
cell.
[0211] Embodiment 58: One or more compositions that each or
together comprise an active agent that is disulfiram and a
potentiating ingredient that is cinnamaldehyde for use in the
method of any one of embodiments 1 to 56.
[0212] Embodiment 59: The one or more compositions of embodiment
58, wherein the disulfiram is in an amount from about 5 mg to about
500 mg.
[0213] Embodiment 60: The one or more compositions of embodiment 58
or embodiment 59, wherein the cinnamaldehyde is in an amount from
about 0.01% to about 45% of the weight of the disulfiram.
[0214] Embodiment 61: A composition comprising an active agent that
is disulfiram and a potentiating ingredient that is
cinnamaldehyde.
[0215] Embodiment 62: The composition of embodiment 61, wherein the
composition consists essentially of disulfiram and
cinnamaldehyde.
[0216] Embodiment 63: The composition of embodiment 61 or
embodiment 62, further comprising one or more additional
ingredients from Table 1.
[0217] Embodiment 64: The composition of any one of embodiments 61
to 63, wherein the disulfiram is in an amount from about 5 mg to
about 500 mg.
[0218] Embodiment 65: The composition of any one of embodiments 61
to 64, wherein the cinnamaldehyde is in an amount from about 0.01%
to about 45% by weight of the disulfiram.
REFERENCES
[0219] The following references are incorporated into this
disclosure: Hu et al., "FDA-approved disulfiram inhibits pyroptosis
by blocking gasdermin D pore formation." Nature Immunology (2020):
1-10; Liu et al., "Inflammasome-activated gasdermin D causes
pyroptosis by forming membrane pores." Nature. 2016;
535(7610):153-158; McCarthy A. "Disulfiram inhibits inflammatory
gatekeeper protein: Could it be helpful in COVID-19". Boston
Children's Press Release. 10 May 2020; WO2020006229A1;
WO2016/086008; Lin, et al. "Disulfiram can inhibit MERS and SARS
coronavirus papain-like proteases via different modes". Antiviral
Res. 2018; 150:155-163; Loo and Clarke "Blockage of drug resistance
in vitro by disulfiram, a drug used to treat alcoholism." J Natl
Cancer Inst. 2000; 92(11):898-902; Sauna et al., "The molecular
basis of the action of disulfiram as a modulator of the multidrug
resistance-linked ATP binding cassette transporters MDR1 (ABCB1)
and MRP1 (ABCC1)." Mol Pharmacol. 2004; 65(3):675-684; and Cheung
et al., "Cinnamic compound metabolism in human skin and the role
metabolism may play in determining relative sensitisation potency".
J Dermatol Sci. 2003 February; 31(1):9-19. Each of the
above-mentioned documents is incorporated by reference in its
entirety
Definitions
[0220] The terminology used herein is for the purpose of describing
particular cases only and is not intended to be limiting.
[0221] The term "disulfiram" includes the compound disulfiram
itself as well as its metabolites and/or derivatives. The term
"additional ingredient(s)" includes the additional ingredient(s) as
well as its/their metabolites, derivatives, and/or precursors.
[0222] As used herein, unless otherwise indicated, the terms "a",
"an" and "the" are intended to include the plural forms as well as
the single forms, unless the context clearly indicates
otherwise.
[0223] The terms "comprise", "comprising", "contain," "containing,"
"including", "includes", "having", "has", "with", or variants
thereof as used in either the present disclosure and/or in the
claims, are intended to be inclusive in a manner similar to the
term "comprising."
[0224] By preventing is meant, at least, avoiding the occurrence of
a disease and/or reducing the likelihood of acquiring the disease.
By treating is meant, at least, ameliorating or avoiding the
effects of a disease, including reducing a sign or symptom of the
disease.
[0225] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, e.g., the limitations of the
measurement system. For example, "about" can mean 10% greater than
or less than the stated value. In another example, "about" can mean
within 1 or more than 1 standard deviation, per the practice in the
given value. Where particular values are described in the
application and claims, unless otherwise stated the term "about"
should be assumed to mean an acceptable error range for the
particular value.
[0226] By "one or more" is meant at least one, e.g., one, two,
three, four, five, six, seven, eight, nine, ten or more.
[0227] The "boosting the immune system", in various embodiments,
relates to "boosting" a proper (e.g., non-pathological) immune
response. In some cases, this will minimize an overactive immune
response. In embodiments, the term dysfunctional immune system may
be an overactive immune system, e.g., resulting in a cytokine
storm; such overactive immune systems are observed in certain viral
infections, e.g., in some severe coronavirus patients. In other
cases, this will improve, activate, and/or enhance a proper immune
response, e.g., when exposed to a vaccine comprising an antigen
obtained from, related to, homologous to, or expressed by an
infectious agent, when exposed to an infectious agent, and/or when
exposed to an atypical cell in need of being attacked by an immune
cell.
[0228] Any aspect or embodiment described herein can be combined
with any other aspect or embodiment as disclosed herein.
EXAMPLES
[0229] The following examples are given for the purpose of
illustrating various embodiments of the invention and are not meant
to limit the present invention in any fashion. The present
examples, along with the methods described herein are presently
representative of preferred embodiments, are exemplary, and are not
intended as limitations on the scope of the invention. Changes
therein and other uses which are encompassed within the spirit of
the invention as defined by the scope of the claims will occur to
those skilled in the art.
Example 1: Identification of Combinations of Disulfiram and
Potentiating Ingredients Useful in Methods of the Present
Disclosure
[0230] In this example, disulfiram and potentiating ingredients
capable of increasing lifespan in a mammal, of preventing or
treating a disease including an aging-related disorder in a mammal,
of reducing a symptom of aging in a mammal, and/or of boosting an
immune system were identified.
[0231] Sets of cultured cells--fibroblasts, peripheral blood
mononuclear cells (PBMCs including lymphocytes and monocytes,
and/or myoblasts--having either characteristics of young cells or
characteristics of old cells were contacted with a combination of
disulfiram and one or more potentiating ingredients from Table 1.
The ability of disulfiram and one or more potentiating ingredients
to reverse aging in the cells, e.g., reducing the characteristics
of old cells and promoting characteristics of a young cells was
assayed (also known as reducing the predicted age of the cells).
Disulfiram and one or more potentiating ingredients were used at
various concentrations ranging from 0.000005 to 80 .mu.M. In some
cases, the concentration of disulfiram was as high as 80 .mu.M and
the concentration of the potentiating ingredient was as high as 25
.mu.M. Combinations of disulfiram and one or more potentiating
ingredients showing the ability to reverse aging were further
validated.
[0232] Assays and formulations used in this example are related to
those described in US20190228840, the entire contents of which is
incorporated by reference its entirety.
[0233] In this experiment, cinnamaldehyde was identified as a
potentiating ingredient.
Example 2: Phenotypic Effect of Disulfiram on Immune Cells
[0234] In this example, disulfiram was shown to modify quantifiable
parameters in virally infected cells from older donors that
reflects those observed in cells from younger donor.
[0235] Whole blood from younger and older donors was collected into
EDTA tubes and then diluted with an equal volume of
phosphate-buffered saline (PBS)+2% fetal bovine serum (FBS) and
layered over Ficoll using SepMate.TM.-50 tubes (STEMCELL
Technologies Inc., Vancouver, Canada).
[0236] Cells were centrifuged at 1200 g for 10 min at room
temperature, and the top plasma layer was removed. Peripheral blood
mononuclear cells (PBMCs) were collected, washed with PBS+2% FBS,
and counted using acridine orange/propidium iodide using a
Cellometer.RTM. Vision CBA (Nexcelom Bioscience, Lawrence, Mass.,
USA). PBMCs were cryopreserved in CryoStor.RTM. CS10 (BioLife
Solutions, Bothell, Wash., USA), frozen using CoolCell.RTM. FTS30
freezing containers (BioCision, San Rafael, Calif., USA), and
stored in the liquid nitrogen vapor phase until use.
[0237] Specific cell types were isolated from the PBMC fraction
using the following kits (STEMCELL Technologies Inc.) per
manufacturer's recommendations: EasySep.TM. Human T Cell Enrichment
Kit (T cells); EasySep.TM. Human B Cell Enrichment Kit (B cells);
EasySep.TM. Human NK Cell Enrichment Kit (NK cells); and
EasySep.TM. Human Monocyte Enrichment Kit (monocytes). T cells
(CD3+), B cells (CD19+), natural killer (NK) cells (CD59+), and
monocytes (CD14+) were isolated based on their customarily defined
gene expression markers. Isolated cells were counted using acridine
orange/propidium iodide on a Cellometer Vision CBA and then
cryopreserved as described above until use.
[0238] After cells undertook a 30-min adhesion onto a 384-well
assay plate, 10 .mu.L of 5.times. trigger medium (including
vesicular stomatitis virus encoding a red fluorescent protein
(rVSV-.DELTA.G-mCherry), DMSO, test compound, and FBS) was added to
the assay plate using a 384-well pipetting head to achieve a final
concentration of rVSV-.DELTA.G-mCherry at 10.times. MOI, 0.1% DMSO,
10% FBS, and 0.33 .mu.M or 5.3 .mu.M compound concentration. The
assay plate was centrifuged for 1 min at 138.times.g and incubated
for 24 h at 37.degree. C. with 5% humidity.
[0239] rVSV-.DELTA.G-mCherry infected monocytes and macrophages,
which subsequently created a highly inflamed environment for the
lymphocytes and other cells. rVSV-.DELTA.G-mCherry was used because
of its ability to model the innate immune activation pathways of
prevalent respiratory RNA viruses and because it was safe to use in
a high-throughput laboratory with biosafety level one.
[0240] Virally infected cells were contacted with different
concentrations of disulfiram (e.g., 0.00 .mu.M, 0.02 .mu.M, 0.10
.mu.M, 0.33 .mu.M, 1.65 .mu.M, 6.25 .mu.M, and 25.02 .mu.M).
[0241] Cytokine levels in the cellular supernatant were evaluated
using the FirePlex-HT assay system with the Human Cytokines
FirePlex-HT Panel 1 (ab234897; Abcam). Morphological/cellular
phenotypes were assayed.
[0242] Disulfiram demonstrated notable effects on cellular
phenotypes in older immune cells that were suggestive of a
rejuvenation of the response to infection.
[0243] Disulfiram significantly reduced several proinflammatory
cytokines when compared with old untreated controls. MCP1,
IL-1.beta., IL-6, and TNF.alpha. all significantly decreased in at
least 2 doses (FIG. 1A). Again, the reduction in MCP1 followed a
downward dose response (0.02 .mu.M [P=0.35]; 0.1 .mu.M [P=0.04];
0.33 .mu.M [P<0.001]; 1.65 .mu.M [P<0.001]; 6.25 .mu.M
[P<0.001]; 25.02 .mu.M [P<0.001]; FIG. 1A). IL-1.beta. was
significantly reduced after the second lowest dose, then stayed
significantly low for all higher doses (0.02 .mu.M [P=0.28]; 0.1
.mu.M [P=0.005]; 0.33 .mu.M [P=0.001]; 1.65 .mu.M [P=0.004]; 6.25
.mu.M [P=0.004]; 25.02 .mu.M [P<0.001]; FIG. 1A). These
anti-inflammatory effects caused disulfiram showing its potential
to improve older viral immune responses to infection.
[0244] Disulfiram improved the appearance of virally infected
cells. Untreated and treated PBMCs were exposed to 10.times. MOI
rVSV, yet, at several doses, disulfiram made the cells appear like
they were responding to a lower viral load. Compared with old
controls, which appeared to be responding to 10.times. MOI rVSV,
the higher doses of disulfiram made the cells appear to be
responding to a lower viral load (0.02 .mu.M [P=0.63]; 0.1 .mu.M
[P=0.01]; 0.33 .mu.M [P=0.43]; 1.65 .mu.M [P=0.05]; 6.25 .mu.M
[P<0.001]; 25.02 .mu.M [P<0.001]). The higher doses of
disulfiram also significantly reduced the percentage of the
mitochondria with a reticular shape (0.02 .mu.M [P=0.04]; 0.1 .mu.M
[P=0.42]; 0.33 .mu.M [P<0.001]; 1.65 .mu.M [P<0.001]; 6.25
.mu.M [P<0.001]; 25.02 .mu.M [P<0.001]; FIG. 1B). Both of
these effects restore important phenotypes of the older viral
immune response.
[0245] T cells treated with disulfiram also exhibited a much
younger phenotype compared with old untreated controls. The first
two doses of disulfiram saw a significant rejuvenating effect on
the T-cell age scores in the multi-phenotype aging profiles (0.02
.mu.M [P<0.001]; 0.1 .mu.M [P=0.005]; FIG. 1C). The higher doses
of disulfiram also saw significant, beneficial reductions in the
T-cell age score (0.33 .mu.M [P<0.001]; 1.65 .mu.M [P<0.001];
6.25 .mu.M [P<0.001]; 25.02 .mu.M [P<0.001]; FIG. 1C).
[0246] Similar trends were seen with the "on-age" and "off-age"
scores. Compared with controls, the "on-age" T-cell score
significantly shifted in the young direction after treatment with
disulfiram (0.02 .mu.M [P=0.003]; 0.1 .mu.M [P=0.11]; 0.33 .mu.M
[P<0.001]; 1.65 .mu.M [P<0.001]; 6.25 .mu.M [P<0.001];
25.02 .mu.M [P<0.001]; FIG. 1D). The "off-age" score also had a
significant effect but only in the higher doses (0.02 .mu.M
[P=0.26]; 0.1 .mu.M [P=0.44]; 0.33 .mu.M [P<0.001]; 1.65 .mu.M
[P=0.008]; 6.25 .mu.M [P=0.003]; 25.02 .mu.M [P=0.01]; FIG. 1D).
All these beneficial shifts in age-related phenotypes show the
strong beneficial potential of disulfiram for treating dysfunction
in the older viral immune response.
[0247] Machine learning model predictions of the immune response
resulting from different viral loads (at 0.1.times., 1.times., and
10.times. MOI) were notably different with disulfiram treatment
compared with untreated control cells. At higher disulfiram
concentrations, the model indicated that monocytes responded at a
lower MOI than did untreated control cells.
[0248] Together, disulfiram restored multiple aspects of the viral
immune response of older adults to a younger state demonstrating
its usefulness in therapeutic methods of the present
disclosure.
[0249] Disulfiram also appeared to operate via several
anti-inflammatory mechanisms, including an ability to inhibit NLRP3
inflammasome-mediated pyroptotic cell death. The
inflammasome-blocking mechanisms of disulfiram ultimately inhibits
pyroptosis by stopping formation of pores in the cell membrane that
lead to cell lysis and release of proinflammatory molecules such as
IL-10 and IL-18. The data presented herein show that disulfiram
restores aspects of the old viral immune response.
[0250] These data demonstrated significant anti-inflammatory and
rejuvenating effects by disulfiram. Disulfiram reduced the
proinflammatory cytokines MCP1, IL-1.beta., IL-6, and TNF.alpha.
while also rejuvenating several other features in aging profile
such as T-cell age score, viral load response, and mitochondrial
function. These immunomodulatory mechanisms could be related to the
ability of disulfiram to block the final step in
inflammasome-mediated pyroptosis and cytokine release. Disulfiram
may also operate by ultimately reducing pore formation on the cell
membrane of neutrophils, which would allow for the release of
neutrophil extracellular traps (NETs), a process known as NETosis.
Both of these mechanisms make disulfiram an attractive treatment
for hyperinflammatory infections such as COVID-19 and sepsis.
Disulfiram has already been shown to protect mice from lethal
lipopolysaccharide-induced septic shock. By targeting any of these
mechanisms, disulfiram may be a useful agent for treating
infection, e.g., caused by a virus such as SARS-CoV2.
[0251] Sera from patients with severe COVID-19 demonstrated
increased NETs and an autopsy of a lung specimen from a patient
with COVID-19 showed extensive neutrophil infiltration.
Proinflammatory cytokines in patients with severe COVID-19 were
significantly higher than in moderate cases. This includes elevated
levels of IL-1.beta. that result from inflammasome activation.
Given the relationship between NETosis, the inflammasome, and
COVID-19 pathology, the ability of disulfiram to target these
pathways, treatments with disulfiram could provide substantial
clinical benefit.
[0252] In addition to improving host response, disulfiram may have
antiviral effects on SARS-CoV2. Disulfiram has been shown to
inhibit papain-like proteases of deadly coronaviruses such as
Middle East respiratory syndrome coronavirus (MERS-CoV) and
SARS-CoV1, which may disrupt the replication and IFN suppression
mechanisms of these viruses. This experiment is performed by
contacting the virus-infected cells with different concentrations
of disulfiram in combination of cinnamaldehyde. Cell parameters
such as cytokine levels and morphological/cellular phenotypes are
assayed to demonstrate potential to improve old immune response to
infection.
Example 3: Synergistic Effect of Disulfiram and Cinnamaldehyde
[0253] A luciferase assay was performed as described briefly: 125 k
THP1 pyroptosis reporter cells/ml final density were plated on 384
well plates and incubated with disulfiram, cinnamaldehyde, or
disulfiram and cinnamaldehyde for 20 minutes. 1 .mu.g/ml LPS was
added to the wells, and the plate was incubated for 3 hours,
followed by addition of 10 .mu.M nigericin. After three hours,
supernatants were harvested and the presence of HMGB1 luciferase
reporter protein was quantified using QUANTI-Luc.
[0254] FIG. 2 shows the effect on pyroptosis of the combination of
disulfiram and cinnamaldehyde as compared to each individual
compound. FIG. 3 shows the potentiating effects of varying constant
concentrations of cinnamaldehyde added to disulfiram titration
curves.
[0255] Inhibition of pyroptosis was assessed by inducing
inflammasome activation in THP1 HMGB1 Lucia cells (Invivogen).
These cells code for a luciferase reporter protein (HMGB1) that is
released from cells during pyroptosis. HMGB1 levels in the
supernatant can therefore be used to quantify pyroptosis.
[0256] Concentration matrices of disulfiram titration curves mixed
with titration curves of cinnamaldehyde were tested. Disulfiram
curves at each concentration of cinnamaldehyde were plotted and fit
using a log(agonist) vs. response variable slope (four parameters)
least squares fit model. The diagonal of each matrix was
representative of a dose response curve of disulfiram plus
cinnamaldehyde combinations titrated at a constant ratio.
[0257] Synergy Assessment of Disulfiram Combinations
[0258] Synergy fold ratio was measured by calculating the ratio of
actual effect over expected effect: [(cinnamaldehyde+disulfiram)/no
treatment]/[(disulfiram alone/no treatment).times.(cinnamaldehyde
alone/no treatment)] at each concentration combination. Values
greater than 1 were considered synergistic.
[0259] Synergy using the Loewe additivity model was calculated
using synergyfinder package on R (software environment for
statistical computing and graphics; see the World Wide Web (at)
/bioconductor.org/packages/release/bioc/vignettes/synergyfinder/inst/doc/-
synergyfinder.pdf, the contents of which is incorporated by
reference in its entirety). The Loewe additivity model assumes the
null hypothesis that a combination of drugs is the same as
increasing the concentration of either drug alone (i.e. the effect
is simply additive rather than the drugs interacting to produce a
greater effect). [0260] y.sub.e is the effect as if a drug is
combined with itself, i.e.,
y.sup.e=y.sub.1(x.sub.1+x.sub.2)=y.sub.2(x.sub.1+x.sub.2).
[0261] Using R, the synergy score is calculated using ye, and
determined to be the difference between the observed effect and the
expected effect. Score negativity or positivity determines whether
the combination is synergistic or antagonist, respectively. Loewe
S. (1953), The problem of synergism and antagonism of combined
drugs. Arzneimittelforschung 3, 285-290; Loewe, S. (1928). Die
quantitativen probleme der pharmakologie. Ergebnisse Physiol. 27,
47-187, the contents of which is incorporated by referenced in its
entirety.
[0262] FIG. 4A to 4C show the synergistic effect of the combination
of disulfiram and cinnamaldehyde mediated inhibition of
pyroptosis.
[0263] IC50 Calculations
[0264] IC50s were calculated using the log(agonist) vs. response
variable slope (four parameters) least squares fit model from the
GraphPad Prism software package.
[0265] The percent difference between disulfiram alone and each
disulfiram+cinnamaldehyde curve was calculated, and two replicates
for each condition were averaged. Statistical significance was
determined using a standard Student's t-test (unpaired,
2-tailed).
[0266] Individual curves for disulfiram alone, cinnamaldehyde
alone, and the combination of the two were plotted as log of the
relative concentrations of each. In these experiments, disulfiram
and cinnamaldehyde were titrated equally with different starting
concentrations of disulfiram and cinnamaldehyde and so the relative
ratio of disulfiram:cinnamaldehyde was maintained across the entire
curve. The concentrations were normalized so that 1 is set as the
median for each curve, and the curves are plotted as 1.5.times.
dilution series.
[0267] Curves of disulfiram+constant concentrations of
cinnamaldehyde were plotted using the log of disulfiram
concentration.
[0268] FIG. 5 is a table showing the percent leftward shift in IC50
mediated by cinnamaldehyde relative to disulfiram alone in a
dose-dependent matter, while cinnamaldehyde alone has no effect on
pyroptosis inhibition or IC50. Accordingly, these data show
synergistic effects on pyroptotic inhibition when cells are
subjected to a combination of disulfiram and cinnamaldehyde.
Example 4: Methods that Comprise Administering Disulfiram and
Cinnamaldehyde
[0269] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal, e.g., a human, for
increasing lifespan, for preventing or treating a disease including
an aging-related disorder, for reducing a symptom of aging, and/or
boosting an immune system (e.g., for treating an infection).
[0270] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0271] Administration of the compositions is by intravenous
injection or infusion, intraperitoneal injection, intramuscular
injection, or subcutaneous injection, with a dose depending on the
quantity of composition needing to be administered. Alternately,
the compositions are administered orally, by inhalation, or
topically. Combinations of administration routes may be used.
[0272] The mammal's lifespan is measured and the presence, absence,
and/or severity of various aging-related disorders are determined;
these are compared to control mammals and/or to historical controls
to determine the effectiveness of the composition administered.
[0273] The mammal may be aged or not aged.
[0274] The mammal may have a healthy immune system or the mammal
may have an unhealthy immune system, dysfunctional immune system,
and/or weakened immune system.
[0275] Illustrative diseases treated in this example may be asthma,
deafness, or a viral infections and an illustrative symptom thereof
may be sepsis.
[0276] Assays and formulations used in this example are related to
those described in US20190228840, the entire contents of which is
incorporated by reference its entirety.
Example 5: Methods for Preventing and/or Treating a Respiratory
Disease or Disorder
[0277] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal, e.g., a human, for
preventing and/or treating a respiratory disease or disorder, e.g.,
acute lung injury (ALI) and/or acute respiratory distress syndrome
(ARDS).
[0278] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0279] Administration of the compositions is by intravenous
injection or infusion, intraperitoneal injection, intramuscular
injection, or subcutaneous injection, with a dose depending on the
quantity of composition needing to be administered. Alternately,
the compositions are administered orally, by inhalation, or
topically. Combinations of administration routes may be used.
[0280] Treatment is identified as an improvement in the
administered mammal in one or more of the following symptoms severe
shortness of breath, labored and unusually rapid breathing, low
blood pressure, and confusion and extreme tiredness. The
improvement may be relative to the pre-administration state for the
mammal.
[0281] The mammal may be aged or not aged.
[0282] The underlying cause for the ALI and/or ARDS may be sepsis
(e.g., a serious and widespread infection of the bloodstream);
inhalation of a harmful substance (e.g., smoke, chemical fumes,
asbestos, dust, particulates, vomit, and water); viral or bacterial
pneumonia (which may affect up to all five lobes of the lungs) and
other respiratory disorders including those caused by a coronavirus
(e.g., SARS, MERS, and COVID-19), influenzas (influenza A,
influenza B, or parainfluenza), pneumococcal infection, adenovirus,
respiratory syncytial virus (RSV), enterovirus and/or other
respiratory viral infections; and a head, chest or other major
injury; or another cause (e.g., pancreatitis which is inflammation
of the pancreas, a massive blood transfusion, and severe
burns).
[0283] In some embodiments, ALI differs from ARDS in that ALI
exists during early stage of a respiratory disease and ARDS exists
during a later state of the respiratory disease.
[0284] In some embodiments, the composition or compositions prevent
or treat idiopathic pulmonary fibrosis and/or chronic obstructive
pulmonary disease.
Example 6: Methods for Improving a Vaccine Response
[0285] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal, e.g., a human, for
improving effectiveness of a vaccine that is administered to the
mammal.
[0286] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0287] The compositions may be administered by intravenous
injection or infusion, intraperitoneal injection, intramuscular
injection, or subcutaneous injection, with a dose depending on the
quantity of composition needing to be administered. Alternately,
the composition may be administered orally, by inhalation, or
topically. Combinations of administration routes may be used.
[0288] Administration of the vaccine may be by intravenous
injection or infusion, intraperitoneal injection, intramuscular
injection, or subcutaneous injection, with a dose depending on the
quantity of composition needing to be administered. Alternately,
the vaccine may be administered orally, by inhalation, or
topically.
[0289] In some cases, the composition(s) comprising the combination
of disulfiram and/or cinnamaldehyde and the vaccine are
administered contemporaneously. In other cases, the vaccine is
administered subsequent to the administration of the combination(s)
of disulfiram and/or one or more additional ingredients. In some
cases, the vaccine is administered before the administration of the
combination(s) of disulfiram and/or cinnamaldehyde. A subject may
be administered vaccines and/or combination(s) of disulfiram and/or
one cinnamaldehyde multiple times and in any order.
[0290] The vaccine may be a Chickenpox vaccine, Coronavirus
vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B
vaccine, Haemophilus influenzae type b vaccine, Human
immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine,
influenza vaccine, Japanese encephalitis vaccine, Measles, mumps,
or rubella (including MMR combined vaccine) vaccine, Meningococcal
disease vaccine, Pneumococcal disease vaccine, Polio vaccine,
Rabies vaccine, Respiratory syncytial virus (RSV) vaccine,
Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus
vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP
combined vaccine) vaccine, or Yellow fever vaccine. In embodiments,
the vaccine is a coronavirus vaccine. In embodiments, the
coronavirus vaccine is directed against Sars-CoV-2.
[0291] The mammal may be aged or not aged.
[0292] The mammal may have a healthy immune system or the mammal
may have an unhealthy immune system, dysfunctional immune system,
and/or weakened immune system.
[0293] The mammal's ability to fend off a subsequent infection is
determined and compared to mammals and/or historical controls who
were only administered the vaccine.
[0294] The mammal's ability to later produce antibodies directed to
an infectious agent (related to the vaccine) is determined and
compared to mammals and/or historical controls who were only
administered the vaccine.
Example 7: Methods for Treating Skin Disorders
[0295] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal, e.g., a human, for
treating a skin disorder.
[0296] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0297] The compositions may be administered orally or topically,
with a dose depending on the quantity of composition needing to be
administered. The compositions may be formulated as a gel, lotion,
ointment, cream, suspension, paste, liniment, powder, tincture, or
aerosol or administered via an impregnated solid support (e.g., a
patch)). Alternately, the composition may be administered by
injection or by inhalation. The composition(s) may be administered
orally. Combinations of administration routes may be used.
[0298] The mammal has a skin disorder, e.g., wrinkles, which may be
a result of photoaging or related to actinic keratosis. Other skin
disorders the mammal may have includes dermal atrophy (thinning of
the skin), lentigines (aging spots), vaginal atrophy,
prolonged/inefficient wound healing, and/or xerosis cutis (skin
dryness). In examples, the mammal has moderate skin aging (i.e.,
Glogau Classification III).
[0299] The composition's or compositions' ability to treat a skin
disorder, e.g., wrinkles, is determined and compared to the mammal
before administration and/or to historical controls who were not
administered the composition or compositions. For example, the
determination relates to a change in the Glogau Classification.
Example 8: Methods for Treating Dry Eye
[0300] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal for improving treating
dry eye.
[0301] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0302] The compositions may be administered topically, with a dose
depending on the quantity of composition needing to be
administered. The compositions may be formulated as eye drops or as
eye ointments.
[0303] The composition's or compositions' ability to treat dry
eyes, is determined and compared to mammal before administration
and/or to historical controls who were not administered the
composition or compositions.
Example 9: Methods for Treating Alopecia
[0304] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal, e.g., a human, for
treating alopecia.
[0305] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0306] The compositions may be administered topically, with a dose
depending on the quantity of composition needing to be
administered. The compositions may be formulated as a gel, lotion,
ointment, cream, suspension, paste, liniment, powder, tincture, or
aerosol or administered via an impregnated solid support (e.g., a
patch)). Alternately, the composition may be administered by
injection or by inhalation. The composition(s) may be administered
orally. Combinations of administration routes may be used.
[0307] The composition's or compositions' ability to treat
alopecia, is determined and compared to the mammal before
administration and/or to historical controls who were not
administered the composition or compositions.
Example 10: Methods for Treating a Skin Cancer
[0308] In this example, a composition comprising disulfiram and
cinnamaldehyde, or distinct compositions of a first composition
comprising disulfiram and a second composition comprising
cinnamaldehyde are administered to a mammal, e.g., a human, for
treating a skin cancer, e.g., (e.g., basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC)).
[0309] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0310] The compositions may be administered topically, with a dose
depending on the quantity of composition needing to be
administered. The compositions may be formulated as a gel, lotion,
ointment, cream, suspension, paste, liniment, powder, tincture, or
aerosol or administered via an impregnated solid support (e.g., a
patch)). Alternately, the composition may be administered by
injection or by inhalation. The composition(s) may be administered
orally. Combinations of administration routes may be used.
[0311] The composition's or compositions' ability to treat the skin
cancer, e.g., BCC and SCC, is determined and compared to the mammal
before administration and/or to historical controls who were not
administered the composition or compositions.
Example 11: Methods that Comprise Administering a First Composition
and a Second Composition
[0312] In this example, a first composition comprises a
therapeutically effective amount of disulfiram and a second
composition comprising cinnamaldehyde are administered to a mammal
for increasing lifespan, for preventing or treating a disease
including an aging-related disorder, for reducing a symptom of
aging, and/or boosting an immune system.
[0313] The dose of disulfiram is from about 5 mg to about 500 mg.
The dose of the cinnamaldehyde is from about 0.001 mg to about 223
mg.
[0314] The first composition is administered orally, by inhalation,
injection, or topically. The second composition is administered
orally, by inhalation, injection, or topically. The administration
route of the first composition and the second composition may be
the same or may be different.
[0315] The first composition may be administered before the second
composition is administered.
[0316] The first composition may be administered after the second
composition is administered.
[0317] The first composition and the second composition may be
administered contemporaneously (either by combining the two
compositions or by administering the two compositions at nearly the
same time).
[0318] The mammal's lifespan is measured and the presence, absence,
and/or severity of various aging-related disorders are determined;
these are compared to control mammals and/or to historical controls
to determine the effectiveness of the first composition
administered.
* * * * *