Many drugs can be administered through the oral route as liquids, capsules
or tablets. As oral administration is a safe, convenient and cost effective route, it is the route
taken for most therapeutics. However oral administration has several limitations. Orally
administered drugs bypass the mouth and the stomach in order to be absorbed into the system
for use. Drug absorption can begin in the mouth and stomach, and can be finally absorbed by
the small intestine, passing the intestinal walls, passing through the liver for processing, and
then finally be transported through the bloodstream to reach its target site. As such, the drugs
can be metabolized before the blood and plasma are reached.
[0002] Drugs can be metabolized by oxidation, reduction, hydrolysis,
conjugation, condensation and other additional processes that can make the drug easier for a
subject to excrete. Some drugs can be metabolized so rapidly that a therapeutically effective
concentration in the blood is not reached.
[0003] A property of orally administered drugs that can affect its ability to reach
its destined tissue or site of treatment can be its absorption and solubility. Solubility behavior
is a challenge for many drugs, which can require pharmaceutical formulations with solubility
enhancers in order to improve its ability to become absorbed by a system for use. Solubility
is a phenomenon of dissolution of solute into a solvent to give a homogenous system and is
important for achieving a desired concentration of drug in a systemic circulation for a desired
pharmacological response. The solubility of a drug is intrinsically related to its size and its
properties. Low aqueous solubility is a problem for many drugs, as a drug will need to be in a
form of a solution at the site of absorption, such as within the gastro-intestinal tract. To date,
more than 40% of chemical entities developed for the pharmaceutical industry are poorly
soluble in water. Solubility however can be increased by the drug solutions of oil in water
emulsion, addition of a hydrophilic carrier, cellulosic derivatives, lipids, phospholipids and
antioxidants. As such, methods are needed to increase the bioavailability of a drug, such as
methods to slow the metabolism of a drug and increase solubility of a drug, in a subject in
need is needed.
SUMMARY
[0004] In one aspect, a method of treating, inhibiting, or ameliorating a disorder
in a subject is provided. The method includes, for example, administering a pharmaceutical
formulation to the subject. The pharmaceutical formulation may include a non-deuterated
form of tetrahydrocurcumin or a deuterated form of tetrahydrocurcumin and a
pharmaceutical vehicle. In some embodiments, the disorder is selected from a group
including fatty liver disease, alcoholic liver disease, kidney disease, diabetic kidney disease,
polycystic kidney disease, hypertension, hypertension with left ventricular hypertrophy, heart
failure, diabetes and diabetes with hyperlipidemia. In some embodiments, the subject has
elevated levels of Galectin- 3, fibrotic markers, markers of oxidative stress, and/or markers
of inflammation in the blood and/or urine. In some embodiments, the subject is taking
analgesics. In some embodiments, the subject is under treatment with one or more antimalarial
drugs. In some embodiments, the pharmaceutical formulation is administered by
oral administration or intravenous administration.
[0005] In another aspect, a method of protecting an organ is provided. The
method includes, for example, identifying a subject in need of protection of an organ and
administering a pharmaceutical formulation to a subject in need thereof, the pharmaceutical
formulation including a non-deuterated form of tetrahydrocurcumin or a deuterated form of
tetrahydrocurcumin and a pharmaceutical vehicle. In some embodiments, the organ is
selected from a group including kidney, liver and heart. In some embodiments, the
administering is performed by oral administration or intravenous administration. In some
embodiments, the subject has a disorder selected from a group including liver disorder, fatty
liver disease, alcoholic liver disease, kidney disease, diabetic kidney disease, polycystic
kidney disease, hypertension, hypertension with left ventricular hypertrophy, diabetes,
diabetes with hyperlipidemia and heart failure. In some embodiments, the subject has an
elevated level of Galectin- 3, fibrotic markers, markers of oxidative stress and/or one or more
markers of inflammation in the blood and/or urine.
[0006] In another aspect a method of treating or preventing heart failure in a
subject in need thereof is provided. The method includes, for example, identifying a subject
in need of treatment for or prevention of heart failure and administering pharmaceutical
formulation to a subject in need thereof, the pharmaceutical formulation including a nondeuterated
form of tetrahydrocurcumin or a deuterated form of tetrahydrocurcumin and a
pharmaceutical vehicle. In some embodiments, the subject has chronic kidney disease and/or
hypertension. In some embodiments, the administering is oral administration or intravenous
administration.
[0007] In another aspect a pharmaceutical formulation includes a non-deuterated
form of tetrahydrocurcumin or a deuterated form of tetrahydrocurcumin and a
pharmaceutical vehicle is provided. In some embodiments, the pharmaceutical formulation
includes, for example, a first lipid. In some embodiments, the first lipid is a phospholipid or
polyenylphosphatidylcholine. In some embodiments, the pharmaceutical formulation
includes at least 5% of the first lipid by weight and no more than 95% of the first lipid by
weight. In some embodiments, the pharmaceutical formulation further includes a second
lipid. In some embodiments, the pharmaceutical formulation includes at least 5% of the
second lipid by weight and no more than 95% of the second lipid by weight. In some
embodiments, the pharmaceutical formulation further includes an antioxidant. In some
embodiments, the pharmaceutical formulation includes at least 5% of antioxidant by weight
and no more than 95% of the antioxidant by weight. In some embodiments, the antioxidant is
selected from a group consisting of Vitamin E, Vitamin C and alpha lipoic acid. In some
embodiments, the pharmaceutical formulation further includes curcumin, a terpenoid,
cysteamine, pantethine, and/or baicalin. In some embodiments, the vehicle is a lipophilic
solvent, fatty oil, organic oil, or liposome. In some embodiments, the pharmaceutical
formulation further includes an excipient. In some embodiments, the excipient is a sugar,
lactose, sucrose, mannitol, sorbitol, cellulose preparations of maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
[0008] In a first aspect, a method treating, inhibiting, or ameliorating a disorder in
a subject is provided. In some embodiments, the method includes administering the
pharmaceutical formulation including a non-deuterated form of tetrahydrocurcumin of any of
the embodiments described herein. In some embodiments, the disorder is a liver disorder. In
some embodiments, the disorder is a fatty liver disease. In some embodiments, the disorder is
alcoholic liver disease. In some embodiments, the disorder is a kidney disease. In some
embodiments, the disorder is diabetic kidney disease. In some embodiments, the disorder is
polycystic kidney disease. In some embodiments, the disorder is hypertension. In some
embodiments, the disorder is hypertension with left ventricular hypertrophy. In some
embodiments, the disorder is diabetes. In some embodiments, the disorder is diabetes with
hyperlipidemia. In some embodiments, the subject has elevated Galectin- 3 levels in the
blood and/or urine. In some embodiments, the subject has elevated levels of fibrotic markers.
In some embodiments, the fibrotic markers are in blood. In some embodiments, the fibrotic
markers are in urine. In some embodiments, the subject has an elevated level of a marker of
oxidative stress. In some embodiments, the marker of oxidative stress is in blood. In some
embodiments, the marker of oxidative stress is in urine. In some embodiments, the subject
has an elevated level of a marker of inflammation. In some embodiments, the marker of
inflammation is in blood. In some embodiments, the marker of inflammation is in urine. In
some embodiments, the pharmaceutical formulation is administered to the subject by oral
administration. In some embodiments, the administering is performed by intravenous
administration. In some embodiments, the subject is human. In some embodiments, the
subject is taking analgesics. In some embodiments, the subject is under treatment with one or
more anti-malarial drugs. In some embodiments, the subject has heart failure.
[0009] In a second aspect, a method of protecting an organ is provided. In some
embodiments, the method includes identifying a subject in need of protection of an organ;
and administering the pharmaceutical formulation including a non-deuterated form of
tetrahydrocurcumin of any of the embodiments described herein to a subject in need. In
some embodiments, the method includes identifying a subject in need of protection of an
organ and administering the pharmaceutical formulation including a non-deuterated form of
tetrahydrocurcumin according to any of the embodiments described herein to the subject in
need. In some embodiments, the organ is kidney. In some embodiments, the organ is liver. In
some embodiments, the subject is human. In some embodiments, the organ is heart.
[0010] In some embodiments, the administering is performed by oral
administration. In some embodiments, the administering is performed by intravenous
administration. In some embodiments, the subject has a liver disorder. In some embodiments,
the subject has a fatty liver disease. In some embodiments, the subject has alcoholic liver
disease. In some embodiments, the subject has a kidney disease. In some embodiments, the
subject has diabetic kidney disease. In some embodiments, the subject has polycystic kidney
disease. In some embodiments, the subject has heart failure.
[0011] In some embodiments, the subject has hypertension. In some
embodiments, the subject has hypertension with left ventricular hypertrophy. In some
embodiments, the subject has diabetes. In some embodiments, the subject has diabetes with
hyperlipidemia.
[0012] In some embodiments, the subject has an elevated level of Galectin- 3 in
the blood. In some embodiments, the subject has an elevated level of one or more fibrotic
markers. In some embodiments, the one or more fibrotic markers are in blood. In some
embodiments, at least one of the one or more fibrotic markers is in urine. In some
embodiments, the subject has an elevated level of one or more markers of oxidative stress. In
some embodiments, at least one of the markers of oxidative stress is in blood. In some
embodiments, at least one of the markers of oxidative stress is in urine. In some
embodiments, the subject has an elevated level of one or more markers of inflammation. In
some embodiments, at least one of the elevated markers of inflammation is in blood. In some
embodiments, at least one of the elevated markers is in urine.
[0013] In a third aspect, a method of preventing heart failure in a subject in need
is provided. The method can include identifying a subject in need of prevention of heart
failure and administering the pharmaceutical formulation including a non-deuterated form of
tetrahydrocurcumin of any one of the embodiments described herein to a subject in need. In
some embodiments, the subject has chronic kidney disease and/or hypertension. In some
embodiments, the subject is human. In some embodiments, the administering is performed by
oral administration. In some embodiments, the administering is performed by intravenous
administration.
[0014] In a fourth aspect, a pharmaceutical formulation is provided. In some
embodiments, the pharmaceutical formulation includes a non-deuterated form of
tetrahydrocurcumin and a pharmaceutical vehicle. In some embodiments, the pharmaceutical
formulation includes a first lipid. In some embodiments, the first lipid is a phospholipid. In
some embodiments, the first lipid is polyenylphosphatidylcholine. In some embodiments, the
pharmaceutical formulation includes at least 5% of the first lipid by weight. In some
embodiments, the pharmaceutical formulation includes no more than 95% of the first lipid by
weight. In some embodiments, the pharmaceutical formulation further includes a second
lipid. In some embodiments, the pharmaceutical formulation includes at least 5% of the
second lipid by weight. In some embodiments, the pharmaceutical formulation includes no
more than 95% of the second lipid by weight. In some embodiments, the second lipid is
omega-3. In some embodiments, the second lipid is omega-3 from fish or flaxseed. In some
embodiments, the pharmaceutical formulation includes an antioxidant. In some
embodiments, the pharmaceutical formulation includes at least 5% of antioxidant by weight.
In some embodiments, the pharmaceutical formulation includes no more than 95% of the
antioxidant by weight. In some embodiments, the antioxidant is Vitamin E. In some
embodiments, the antioxidant is Vitamin C. In some embodiments, the antioxidant is alpha
lipoic acid. In some embodiments, the pharmaceutical formulation further includes curcumin.
In some embodiments, the pharmaceutical formulation further includes a terpenoid. In some
embodiments, the pharmaceutical formulation further includes cysteamine. In some
embodiments, the pharmaceutical formulation further includes pantethine. In some
embodiments, the curcumin is deuterated. In some embodiments, the vehicle is a lipophilic
solvent, fatty oil, organic oil, or liposome. In some embodiments, the pharmaceutical
formulation further includes an excipient. In some embodiments, the excipient is a sugar,
lactose, sucrose, mannitol, sorbitol, cellulose preparations of maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In some
embodiments, the pharmaceutical formulation further includes baicalin.
[0015] In a fifth aspect, a non- deuterated form of tetrahydrocurcumin is
provided.
[0016] In a sixth aspect, a deuterated form of tetrahydrocurcumin is provided. In
some embodiments, the deuterated form of tetrahydrocurcumin has no more than fifteen
deuterated sites. In some embodiments, the deuterated form of tetrahydrocurcumin has at
least ten deuterated sites. In some embodiments, the deuterated form of tetrahydrocurcumin
has at least five deuterated sites. In some embodiments, the deuterated form of
tetrahydrocurcumin has at least one deuterated site. In some embodiments, the deuterated
form of tetrahydrocurcumin is deuterated at one or two alcohol sites. In some embodiments,
the deuterated form of tetrahydrocurcumin has at least 1 deuteron. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 5 deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 10 deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 20 deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 24 deuterons.
[0017] In a seventh aspect, a method of making a deuterated form of
tetrahydrocurcumin is provided. In some embodiments, the method includes contacting
tetrahydrocurcumin in the presence of a catalyst and deuterated water under a condition to
form the deuterated form of tetrahydrocurcumin. In some embodiments, the method further
includes hydrogenating curcumin to form the tetrahydrocurcumin. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least one deuterated site. In some
embodiments, the deuterated form of tetrahydrocurcumin has at least five deuterated sites. In
some embodiments, the deuterated form of tetrahydrocurcumin has at least ten deuterated
sites. In some embodiments, the deuterated form of tetrahydrocurcumin has no more than
fifteen deuterated sites. In some embodiments, the deuterated form of tetrahydrocurcumin is
deuterated at one or two alcohol sites. In some embodiments, the deuterated form of
tetrahydrocurcumin has no more than twenty-four deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 1 deuteron. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 5 deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 10 deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 20 deuterons. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least 24 deuterons.
[0018] In some embodiments, the catalyst is palladium on carbon. In some
embodiments, the catalyst is palladium barium carbonate. In some embodiments, the catalyst
is palladium barium sulphate. In some embodiments, the catalyst is palladium silica. In some
embodiments, the catalyst is platinum on carbon. In some embodiments, the catalyst is
platinum-palladium carbon. In some embodiments, the catalyst is platinum alumina. In some
embodiments, the catalyst is platinum calcium carbonate. In some embodiments, the catalyst
is platinum barium sulfate. In some embodiments, the catalyst is platinum silica. In some
embodiments, the catalyst is platinum graphite.
[0019] In some embodiments, the method further includes purifying the
deuterated form of tetrahydrocurcumin. In some embodiments, the purifying step includes
isolating the deuterated form of tetrahydrocurcumin with column chromatography. In some
embodiments, the deuterated water is at least 25% deuterated. In some embodiments, the
deuterated water is at least 50% deuterated. In some embodiments, the deuterated water is at
least 75% deuterated. In some embodiments, the deuterated water is 100% deuterated.
[0020] In an eighth aspect, a pharmaceutical formulation, for example a
pharmaceutical formulation, including a deuterated form of tetrahydrocurcumin is provided.
In some embodiments, the pharmaceutical formulation includes a deuterated form of
tetrahydrocurcumin and a pharmaceutical vehicle. In some embodiments, the deuterated form
of tetrahydrocurcumin has no more than fifteen deuterated sites. In some embodiments, the
deuterated form of tetrahydrocurcumin has at least ten deuterated sites. In some
embodiments, the deuterated form of tetrahydrocurcumin has at least five deuterated sites. In
some embodiments, the deuterated form of tetrahydrocurcumin has at least one deuterated
site. In some embodiments, the deuterated form of tetrahydrocurcumin is deuterated at one or
two alcohol sites. In some embodiments, the deuterated form of tetrahydrocurcumin has at
least 1 deuteron. In some embodiments, the deuterated form of tetrahydrocurcumin has at
least 5 deuterons. In some embodiments, the deuterated form of tetrahydrocurcumin has at
least 10 deuterons. In some embodiments, the deuterated form of tetrahydrocurcumin has at
least 20 deuterons. In some embodiments, the deuterated form of tetrahydrocurcumin has at
least 24 deuterons.
[0021] In some embodiments, the pharmaceutical formulation further includes a
first lipid. In some embodiments, the first lipid is a phospholipid. In some embodiments, the
first lipid is polyenylphosphatidylcholine. In some embodiments, the pharmaceutical
formulation includes at least 5% of the first lipid by weight. In some embodiments, the
pharmaceutical formulation includes no more than 95% of the first lipid by weight. In some
embodiments, the pharmaceutical formulation includes a second lipid. In some embodiments,
the pharmaceutical formulation includes at least 5% of the second lipid by weight. In some
embodiments, the pharmaceutical formulation includes no more than 95% of the second lipid
by weight. In some embodiments, the second lipid is omega-3. In some embodiments, the
second lipid is omega-3 from fish or flaxseed.
[0022] In some embodiments, the pharmaceutical formulation includes an
antioxidant. In some embodiments, the pharmaceutical formulation includes at least 5% of
antioxidant by weight. In some embodiments, the pharmaceutical formulation includes no
more than 95% of the antioxidant by weight. In some embodiments, the antioxidant is
Vitamin E. In some embodiments, the antioxidant is Vitamin C. In some embodiments, the
antioxidant is alpha lipoic acid.
[0023] In some embodiments, the pharmaceutical formulation further includes
curcumin. In some embodiments, the curcumin is deuterated. In some embodiments, the
pharmaceutical formulation includes a terpenoid. In some embodiments, the pharmaceutical
formulation includes cysteamine. In some embodiments, the pharmaceutical formulation
includes pantethine. In some embodiments, the pharmaceutical formulation includes baicalin.
In some embodiments, the vehicle is a lipophilic solvent, fatty oil, organic oil, or liposome.
In some embodiments, the pharmaceutical formulation further includes an excipient. In
some embodiments, the excipient is a sugar, lactose, sucrose, mannitol, sorbitol, cellulose
preparations of maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth,
methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or
polyvinylpyrrolidone (PVP).
[0024] In a ninth aspect, a method of treating, inhibiting, or ameliorating a
disorder in a subject is provided. In some embodiments, the method includes administering a
pharmaceutical formulation includes a deuterated form of tetrahydrocurcumin according to
any of the embodiments described herein to the subject. In some embodiments, the disorder
is a liver disorder. In some embodiments, the disorder is a fatty liver disease. In some
embodiments, the disorder is alcoholic liver disease. In some embodiments, the disorder is a
kidney disease. In some embodiments, the disorder is diabetic kidney disease. In some
embodiments, the disorder is polycystic kidney disease.
[0025] In some embodiments, the disorder is hypertension. In some embodiments,
the disorder is hypertension with left ventricular hypertrophy. In some embodiments, the
disorder is diabetes. In some embodiments, the disorder is diabetes with hyperlipidemia. In
some embodiments, the disorder is heart failure.
[0026] In some embodiments, the subject has elevated Galectin- 3 levels in the
blood. In some embodiments, the subject has elevated levels of fibrotic markers. In some
embodiments, the fibrotic markers are in blood. In some embodiments, the fibrotic markers
are in urine. In some embodiments, the subject has an elevated level of a marker of oxidative
stress. In some embodiments, the marker of oxidative stress is in blood. In some
embodiments, the marker of oxidative stress is in urine. In some embodiments, the subject
has an elevated level of a marker of inflammation. In some embodiments, the marker of
inflammation is in blood. In some embodiments, the marker of inflammation is in urine.
[0027] In some embodiments, the pharmaceutical formulation is administered to
the subject by oral administration. In some embodiments, the administering is performed by
intravenous administration. In some embodiments, the subject is human. In some
embodiments, the administering is performed by intravenous administration. In some
embodiments, the subject is under treatment with one or more anti-malarial drugs.
[0028] In a tenth aspect a method of protecting an organ is provided. In some
embodiments, the method includes identifying a subject in need of protection of an organ and
administering the pharmaceutical formulation including a deuterated form of
tetrahydrocurcumin according to any of the embodiments described herein to the subject in
need. In some embodiments, the organ is kidney. In some embodiments, the organ is liver. In
some embodiments, the organ is heart. In some embodiments, the subject is human.
[0029] In some embodiments, the administering is performed by oral
administration. In some embodiments, the administering is performed by intravenous
administration. In some embodiments, the subject has a liver disorder. In some embodiments,
the subject has a fatty liver disease. In some embodiments, the subject has alcoholic liver
disease. In some embodiments, the subject has a kidney disease. In some embodiments, the
subject has diabetic kidney disease. In some embodiments, the subject has polycystic kidney
disease. In some embodiments, the subject has heart failure.
[0030] In some embodiments, the subject has hypertension. In some
embodiments, the subject has hypertension with left ventricular hypertrophy. In some
embodiments, the subject has diabetes. In some embodiments, the subject has diabetes with
hyperlipidemia.
[0031] In some embodiments, the subject has an elevated level of Galectin- 3 in
the blood. In some embodiments, the subject has an elevated level of one or more fibrotic
markers. In some embodiments, the one or more fibrotic markers are in blood. In some
embodiments, at least one of the one or more fibrotic markers is in urine. In some
embodiments, the subject has an elevated level of one or more markers of oxidative stress. In
some embodiments, at least one of the markers of oxidative stress is in blood. In some
embodiments, at least one of the markers of oxidative stress is in urine. In some
embodiments, the subject has an elevated level of one or more markers of inflammation. In
some embodiments, at least one of the elevated markers of inflammation is in blood. In some
embodiments, at least one of the elevated markers is in urine.
[0032] In an eleventh aspect, a method of treating or preventing heart failure in a
subject in need is provided. In some embodiments, the method includes identifying a subject
in need of prevention of heart failure administering the pharmaceutical formulation including
a deuterated form of tetrahydrocurcumin of any one of any one of the embodiments described
herein to a subject in need. In some embodiments, the subject has chronic kidney disease
and/or hypertension. In some embodiments, the subject is human. In some embodiments, the
administering is performed by oral administration. In some embodiments, the administering
is performed by intravenous administration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Figure 1 shows a schematic illustration of tetrahydrocurcumin. Sites are
numbered on the schematic illustration of tetrahydrocurcumin to indicate non-limiting
exemplary deuteration sites. In one or more of these deuteration sites, there can be one, two,
or three deuterons.
[0034] Figures 2A-2G show the measurements between the four groups of rats: 1)
control rats 2) rats with chronic kidney disease (CKD), 3) rats treated with
tetrahydrocurcumin after CDK, and 4) rats treated with tetrahydrocurcumin/curcumin after
CDK. Figure 2A shows the average blood urea nitrogen (BUN) in the four groups of rats.
Figure 2B shows the change in BUN, or delta-BUN. Figure 2C shows the Body Weight in
the four groups of rats Figure 2D shows the amount of Hemoglobin (Hgb) in the four groups
of rats. Figure 2E shows the Heart wt to Body wt (g/kg) ratio of the four groups of rats.
Figure 2F shows the systolic blood pressure in the four groups of rats. Figure 2G shows the
diastolic blood pressure in the four groups of rats.
DETAILED DESCRIPTION
[0035] Many drugs can be administered through the oral route as liquids, capsules
or tablets. As oral administration is a safe, convenient and cost effective route, it is the route
taken for most therapeutics. However oral administration has several limitations. Orally
administered drugs bypass the mouth and the stomach in order to be absorbed into the system
for use. Drug absorption can begin in the mouth and stomach, and can be finally absorbed by
the small intestine, passing the intestinal walls, passing through the liver for processing, and
then finally be transported through the bloodstream to reach its target site. As such, the drugs
can be metabolized before the blood and plasma are reached.
[0036] “Bioavailability” as described herein, refers to the absorption of a drug or
drugs and is a subcategory of absorption as is the fraction of an administered dose of
unchanged drug that reaches the systemic circulation and is one of the principal
pharmacokinetic properties of drugs. Bioavailability thereby can refer to the extent and rate
at which the active drug or metabolite enters the systemic circulation to reach the site for
action. Low bioavailability is the most common problem of orally administered drugs, as
many are poorly water soluble and slowly absorbed drugs. The bioavailability of a drug is
affected by the function of the intestinal walls and the liver, in which enzymatic reactions can
metabolize the drug, thus decreasing the amount of the drug that eventually reaches the blood
stream for delivery. This in effect decreases the bioavailability of a drug, or its extent and
rate at which the active drug enters the systemic circulation.
[0037] Drugs can be metabolized by oxidation, reduction, hydrolysis,
conjugation, condensation and other additional processes that can make the drug easier for a
subject to excrete. Some drugs can be metabolized so rapidly that a therapeutically effective
concentration in the blood is not reached.
[0038] A property of orally administered drugs that can affect its ability to reach
its destined tissue or site of treatment can be its absorption and solubility. Solubility behavior
is a challenge for many drugs, which can require pharmaceutical formulations with solubility
enhancers in order to improve its ability to become absorbed by a system for use. Solubility
is a phenomenon of dissolution of solute into a solvent to give a homogenous system and is
important for achieving a desired concentration of drug in a systemic circulation for a desired
pharmacological response. The solubility of a drug is intrinsically related to its size and its
properties. Low aqueous solubility is a problem for many drugs, as a drug will need to be in a
form of a solution at the site of absorption, such as within the gastro-intestinal tract. To date,
more than 40% of chemical entities developed for the pharmaceutical industry are poorly
soluble in water. Solubility however can be increased by the drug solutions of oil in water
emulsion, addition of a hydrophilic carrier, cellulosic derivatives, lipids, phospholipids and
antioxidants. In some embodiments, a pharmaceutical formulation is provided. In some
embodiments, the pharmaceutical formulation is administered to a subject by oral
administration. In some embodiments, the subject is human. In some embodiments, the
administering is performed by intravenous administration.
[0039] Drug solutions of oil and surfactants can form oil in water emulsions upon
mixing with aqueous media in the gastro-intestinal tract, which can lead to an increase in
drug absorption of a drug with poor solubility. Pharmaceutical formulations comprising
lipids can also be used to increase the bioavailability of a drug by increasing its absorption.
Lipids, as described herein refers to fatty acids, or fatty acid residues that are hydrophobic or
amphiphilic small molecules that can form structures, liposomes, or membranes when
exposed to an aqueous environment such as liquids in a gastro-intestinal tract. Lipids can be
categorized into fatty acids, glycerolipids, glycerophospholipids, phospholipids,
sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides. In some
embodiments, a pharmaceutical formulation comprising one or more lipids is provided. In
some embodiments, the pharmaceutical formulation comprises a lipid. In some embodiments,
the pharmaceutical formulation comprises a phospholipid.
[0040] Examples of phospholipids include, but are not limited to, phosphatidic
acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,
phosphatidylinositol, phosphatidylinositol phosphate, phosphatidylinositol bisphosphate,
phosphatidylinositol triphosphate, ceramide phosphorylcholine, ceramide
phosphorylethanolamine, ceramide phosphorylipid, phosphatidylcholine and
polyenylphosphatidylcholine. Polyenylphosphatidyl choline can have the added benefit of
increasing the bioavailability by allowing absorption of a drug in the gut; additionally
polyenylphosphatidyl choline has added benefits to hepatic health. For example,
polyenylphosphatidyl choline has been shown to reduce free phenol and ammonia
concentrations in subjects suffering from liver cirrhosis, this indicating that oxidative
processes were ameliorated and detoxification processing in the liver was improved. In some
embodiments, the pharmaceutical formulation disclosed herein comprises a non-deuterated
form of tetrahydrocurcumin. In some embodiments, the pharmaceutical formulation
comprises deuterated forms of tetrahydrocurcumin, as described in several embodiments
herein. In some embodiments, the pharmaceutical formulation disclosed herein comprises a
non-deuterated form of tetrahydrocurcumin and a deuterated form of tetrahydrocurcumin, as
described in several embodiments herein. In some embodiments, pharmaceutical
formulations disclosed herein comprise a lipid. In some embodiments, pharmaceutical
formulations disclosed herein comprise a phospholipid. In some embodiments,
pharmaceutical formulations disclosed herein comprise polyenylphosphatidylcholine. In
some embodiments, pharmaceutical formulations disclosed herein comprise a
phosphatidylcholine. The pharmaceutical formulation disclosed herein can comprise a first
lipid. The first lipid can be any of the lipids disclose herein or a mixture thereof. In some
embodiments, the pharmaceutical formulation comprises at least 5% of the first lipid by
weight. In some embodiments, the pharmaceutical formulation comprises no more than 95%
of the first lipid by weight. In some embodiments, the pharmaceutical formulation comprises
a second lipid. In some embodiments, the pharmaceutical formulation comprises at least 5%
of the second lipid by weight. In some embodiments, the pharmaceutical formulation
comprises no more than 95% of the second lipid by weight. In some embodiments, the
second lipid is omega-3. The second lipid can be any of the lipids disclose herein or a
mixture thereof.
[0041] Pharmaceutical formulations comprising drugs or molecules of interest
can also comprise elements that can have beneficial effects on organs that are being treated.
For example lipids and anti-oxidants can be used, which can have beneficial effects for
preventing or treating oxidative stress, fibrosis and scarring. Examples of lipids that can be
included in the pharmaceutical formulations disclosed herein can include, but are not limited
to, oils, emulsions, and omega-3 from fish oil, omega-3 from flaxseed, and omega-3 from
walnuts. In some embodiments, the pharmaceutical formulation disclosed herein comprises a
non-deuterated form of tetrahydrocurcumin. In some embodiments, the pharmaceutical
formulation comprises deuterated forms of tetrahydrocurcumin, as described in several
embodiments herein. In some embodiments, the pharmaceutical formulation disclosed herein
comprises a non-deuterated form of tetrahydrocurcumin and a deuterated form of
tetrahydrocurcumin, as described in several embodiments herein. In some embodiments,
pharmaceutical formulations are provided comprising lipids. In some embodiments, the
lipids are phospholipids. In some embodiments, the lipids are omega-3. In some
embodiments, the lipids are polyenylphosphatidylcholine.

WHATIS CLAIMED IS:
1. A pharmaceutical formulation, comprising:
a non-deuterated form of tetrahydrocurcumin; and
a pharmaceutical vehicle.
2. The pharmaceutical formulation of claim 1 further comprising a first lipid.
3. The pharmaceutical formulation of claim 2, wherein the first lipid is a
phospholipid.
4. The pharmaceutical formulation of claim 2 or 3, wherein the first lipid is
polyenylphosphatidylcholine.
5. The pharmaceutical formulation of any one of claims 2-4, wherein the
pharmaceutical formulation comprises at least 5% of the first lipid by weight.
6. The pharmaceutical formulation of any one of claims 2-5, wherein the
pharmaceutical formulation comprises no more than 95% of the first lipid by weight.
7. The pharmaceutical formulation of any one of claims 1-6, further comprising a
second lipid.
8. The pharmaceutical formulation of claim 7, wherein the pharmaceutical
formulation comprises at least 5% of the second lipid by weight.
9. The pharmaceutical formulation of claim 7 or 8, wherein the pharmaceutical
formulation comprises no more than 95% of the second lipid by weight.
10. The pharmaceutical formulation of any one of claims 7-9, wherein the second
lipid is omega-3.
11. The pharmaceutical formulation of any one of claims 10, wherein the second lipid
is omega-3 from fish or flaxseed.
12. The pharmaceutical formulation of any one of claims 1-11, further comprising an
antioxidant.
13. The pharmaceutical formulation of claim 12, wherein the pharmaceutical
formulation comprises at least 5% of antioxidant by weight.
14. The pharmaceutical formulation of claim 12 or 13, wherein the pharmaceutical
formulation comprises no more than 95% of the antioxidant by weight.
15. The pharmaceutical formulation of any one of claims 12-14, wherein the
antioxidant is Vitamin E.
16. The pharmaceutical formulation of any one of claims 12-14, wherein the
antioxidant is Vitamin C.
17. The pharmaceutical formulation of any one of claims 12-14, wherein the
antioxidant is alpha lipoic acid.
18. The pharmaceutical formulation of any one of claims 1-17, wherein the
pharmaceutical formulation further comprises curcumin.
19. The pharmaceutical formulation of any one of claims 1-18, wherein the
pharmaceutical formulation further comprises a terpenoid.
20. The pharmaceutical formulation of any one of claims 1-19, wherein the
pharmaceutical formulation further comprises cysteamine.
21. The pharmaceutical formulation of any one of claims 1-20, wherein the
pharmaceutical formulation further comprises pantethine.
22. The pharmaceutical formulation of any one of claims 18-21, wherein the
curcumin is deuterated.
23. The pharmaceutical formulation of any one of claims 1-22, wherein the vehicle is
a lipophilic solvent, fatty oil, organic oil, or liposome.
24. The pharmaceutical formulation of any one of claims 1-23, wherein the
pharmaceutical formulation further comprises an excipient, wherein the excipient is a sugar,
lactose, sucrose, mannitol, sorbitol, cellulose preparations of maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
25. The pharmaceutical formulation of any one of claims 1-24, wherein the
pharmaceutical formulation further comprises baicalin.
26. A method of treating, inhibiting, or ameliorating a disorder in a subject
comprising
administering the pharmaceutical formulation of any one of claims 1-25 to the
subject.
27. The method of claim 26, wherein the disorder is a liver disorder.
28. The method of claim 26 or 27, wherein the disorder is a fatty liver disease.
29. The method of any one of claims 26-28, wherein the disorder is alcoholic liver
disease.
30. The method of claim 26, wherein the disorder is a kidney disease or chronic
kidney disease.
31. The method of claims 26 or 30, wherein the disorder is diabetic kidney disease.
32. The method of claim 26 or 30, wherein the disorder is polycystic kidney disease.
33. The method of claim 26, wherein the disorder is hypertension.
34. The method of claim 26 or 33, wherein the disorder is hypertension with left
ventricular hypertrophy.
35. The method of claim 26, wherein the disorder is diabetes.
36. The method of claim 26 or 35, wherein the disorder is diabetes with
hyperlipidemia.
37. The method of any one of claims 26-36, wherein the subject has elevated
Galectin- 3 levels in the blood and/or urine.
38. The method of any one of claims 26-37, wherein the subject has elevated levels of
fibrotic markers.
39. The method of claim 38, wherein the fibrotic markers are in blood.
40. The method of claim 38 or 39, wherein the fibrotic markers are in urine.
41. The method of any one of claims 26-40, wherein the subject has an elevated level
of a marker of oxidative stress.
42. The method of claim 41, wherein the marker of oxidative stress is in blood.
43. The method of claims 41 or 42, wherein the marker of oxidative stress is in urine.
44. The method of any one of claims 26-43, wherein the subject has an elevated level
of a marker of inflammation.
45. The method of claim 44, wherein the marker of inflammation is in blood.
46. The method of claim 44 or 45, wherein the marker of inflammation is in urine.
47. The method of any one of claims 26-46, wherein the pharmaceutical formulation
is administered to the subject by oral administration.
48. The method of any one of claims 26-46, wherein the administering is performed
by intravenous administration.
49. The method of any one of claims 26-48, wherein the subject is human.
50. The method of any one of claims 26-49, wherein the subject is taking analgesics.
51. The method of any one of claims 26-50, wherein the subject is under treatment
with one or more anti-malarial drugs.
52. The method of any one of claims 26 or 37-51, wherein the subject has heart
failure or heart disease.
53. A method of protecting an organ, comprising:
identifying a subject in need of protection of an organ; and
administering the pharmaceutical formulation of any one of claims 1-25 to a
subject in need.
54. The method of claim 53, wherein the organ is kidney.
55. The method of claim 53, wherein the organ is liver.
56. The method of claim 53, wherein the organ is heart.
57. The method of any one of claims 53-56, wherein the subject is human.
58. The method of any one of claims 53-57, wherein the administering is performed
by oral administration.
59. The method of any one of claims 53-57, wherein the administering is performed
by intravenous administration.
60. The method of any one of claims 53, 55, or 57-59, wherein the subject has a liver
disorder.
61. The method of any one of claims 53, 55 or 57-60 wherein the subject has a fatty
liver disease.
62. The method of any one of claims 53, 55, or 57-61, wherein the subject has
alcoholic liver disease.
63. The method of any one of claims 53, 54 or 57-59 wherein the subject has a kidney
disease or chronic kidney disease.
64. The method of any one of claims 53, 54, 57-59 or 63 wherein the subject has
diabetic kidney disease.
65. The method of claim 53, 54, 57-59 or 63, wherein the subject has polycystic
kidney disease.
66. The method of any one of claims 53-65, wherein the subject has hypertension.
67. The method of any one of claims 53-66, wherein the subject has hypertension
with left ventricular hypertrophy.
68. The method of any one of claims 53-67, wherein the subject has diabetes.
69. The method of any one of claims 53-68, wherein the subject has diabetes with
hyperlipidemia.
70. The method of any one of claims 53-69, wherein the subject has an elevated level
of Galectin- 3 in the blood or urine.
71. The method of any one of claims 53-70, wherein the subject has an elevated level
of one or more fibrotic markers.
72. The method of claim 71, wherein at least one of the one or more fibrotic markers
are in blood.
73. The method of claim 71 or 72, wherein at least one of the one or more fibrotic
markers are in urine.
74. The method of any one of claims 53-73, wherein the subject has an elevated level
of one or more markers of oxidative stress.
75. The method of claim 74, wherein at least one of the markers of oxidative stress is
in blood.
76. The method of claims 74 or 75, wherein at least one of the markers of oxidative
stress is in urine.
77. The method of any one of claims 53-76, wherein the subject has an elevated level
of one or more markers of inflammation.
78. The method of claim 77, wherein at least one of the elevated markers of
inflammation is in blood.
79. The method of claim 77 or 78, wherein at least one of the elevated markers is in
urine.
80. The method of any one of claims 53, 56-59, 66, 67 or 70-79, wherein the subject
has heart failure or heart disease.
81. A method of treating for or preventing of heart failure in a subject in need,
comprising:
identifying a subject in need of treatment or prevention of heart failure; and
administering the pharmaceutical formulation of any one of claims 1-25 to a
subject in need.
82. The method of Claim 81, wherein the subject has chronic kidney disease and/or
hypertension.
83. The method of Claim 81 or 82, wherein the subject is human.
84. The method of any one of claims 81-83 wherein the administering is performed
by oral administration.
85. The method of any one of claims 81-83, wherein the administering is performed
by intravenous administration.
86. A non-deuterated form of tetrahydrocurcumin.
87. A deuterated form of tetrahydrocurcumin.
88. The deuterated form of tetrahydrocurcumin of claim 87, wherein the deuterated
form of tetrahydrocurcumin has at least one deuterated site.
89. The deuterated form of tetrahydrocurcumin of claim 87 or 88, wherein the
deuterated form of tetrahydrocurcumin has at least five deuterated sites.
90. The deuterated form of tetrahydrocurcumin any one of claims 87-89, wherein the
deuterated form of tetrahydrocurcumin has at least ten deuterated sites.
91. The deuterated form of tetrahydrocurcumin of any one of claims 87-90, wherein
the deuterated form of tetrahydrocurcumin has no more than fifteen deuterated sites.
92. The deuterated form of tetrahydrocurcumin of any one of claims 87-91, wherein
the deuterated form of tetrahydrocurcumin is deuterated at one or two alcohol sites.
93. The deuterated form of tetrahydrocurcumin of any one of claims 84-89, wherein
the deuterated form of tetrahydrocurcumin has at least 1 deuteron.
94. The deuterated form of tetrahydrocurcumin of any one of claims 84-89, wherein
the deuterated form of tetrahydrocurcumin has at least 5 deuterons.
95. The deuterated form of tetrahydrocurcumin of any one of claims 87-92, wherein
the deuterated form of tetrahydrocurcumin has at least 10 deuterons.
96. The deuterated form of tetrahydrocurcumin of any one of claims 87-90 or 92,
wherein the deuterated form of tetrahydrocurcumin has at least 20 deuterons.
97. The deuterated form of tetrahydrocurcumin of any one of claims 87-92, wherein
the deuterated form of tetrahydrocurcumin has at least 24 deuterons.
98. A method of making a deuterated form of tetrahydrocurcumin, comprising:
contacting tetrahydrocurcumin in the presence of a catalyst and deuterated
water under a condition to form the deuterated form of tetrahydrocurcumin.
99. The method of claim 98, further comprising hydrogenating curcumin to form the
tetrahydrocurcumin.
100. The method of claim 98, wherein the deuterated form of tetrahydrocurcumin
has at least one deuterated site.
101. The method of any one of claims 98-100, wherein the deuterated form of
tetrahydrocurcumin has at least five deuterated sites.
102. The method of any one of claims 98-101, wherein the deuterated form of
tetrahydrocurcumin has at least ten deuterated sites.
103. The method of any one of claims 98-102, wherein the deuterated form of
tetrahydrocurcumin has no more than fifteen deuterated sites.
104. The method of any one of claims 98-103, wherein the deuterated form of
tetrahydrocurcumin is deuterated at one or two alcohol sites.
105. The method of any one of claims 98-104, wherein the deuterated form of
tetrahydrocurcumin has no more than twenty-four deuterons.
106. The method of any one of claims 98-105, wherein the deuterated form of
tetrahydrocurcumin has at least 1 deuteron.
107. The method of any one of claims 98-105, wherein the deuterated form of
tetrahydrocurcumin has at least 5 deuterons.
108. The method of any one of claims 98-105, wherein the deuterated form of
tetrahydrocurcumin has at least 10 deuterons.
109. The method of any one of claims 98-102 or 104-105, wherein the deuterated
form of tetrahydrocurcumin has at least 20 deuterons.
110. The method of any one of claims 98-102 or 104-105, wherein the deuterated
form of tetrahydrocurcumin has at least 24 deuterons.
111. The method of any one of claims 98-110, wherein the catalyst is palladium on
carbon.
112. The method of any one of claims 98-110, wherein the catalyst is palladium
barium carbonate.
113. The method of any one of claims 98-110, wherein the catalyst is palladium
barium sulphate.
114. The method of any one of claims 98-110, wherein the catalyst is palladium
silica.
115. The method of any one of claims 98-110, wherein the catalyst is palladium
alumina.
116. The method of any one of claims 98-110, wherein the catalyst is platinum on
carbon.
117. The method of any one of claims 98-110, wherein the catalyst is platinumpalladium
carbon.
118. The method of any one of claims 98-110, wherein the catalyst is platinum
alumina.
119. The method of any one of claims 98-110, wherein the catalyst is platinum
calcium carbonate.
120. The method of any one of claims 98-110, wherein the catalyst is platinum
barium sulfate.
121. The method of any one of claims 98-110, wherein the catalyst is platinum
silica.
122. The method of any one of claims 98-110, wherein the catalyst is platinum
graphite.
123. The method of any one of claims 98-110, further comprising purifying the
deuterated form of tetrahydrocurcumin.
124. The method of claim 123, wherein the purifying step comprises isolating the
deuterated form of tetrahydrocurcumin with column chromatography.
125. The method of any one of claims 98-123, wherein the deuterated water is at
least 25% deuterated.
126. The method of any one of claims 98-123, wherein the deuterated water is at
least 50% deuterated.
127. The method of any one of claims 98-123, wherein the deuterated water is at
least 75% deuterated.
128. The method of any one of claims 98-127, wherein the deuterated water is
100% deuterated.
129. A pharmaceutical formulation, comprising:
the deuterated form of tetrahydrocurcumin of any one of claims 87-97; and
a pharmaceutical vehicle.
130. The pharmaceutical formulation of claim 129, wherein the pharmaceutical
formulation further comprises a first lipid.
131. The pharmaceutical formulation of claim 130, wherein the first lipid is a
phospholipid.
132. The pharmaceutical formulation of claim 130 or 131, wherein the first lipid is
polyenylphosphatidylcholine.
133. The pharmaceutical formulation of any one of claims 130-132, wherein the
pharmaceutical formulation comprises at least 5% of the first lipid by weight.
134. The pharmaceutical formulation of any one of claims 130-132, wherein the
pharmaceutical formulation comprises no more than 95% of the first lipid by weight.
135. The pharmaceutical formulation of any one of claims 130-134, further
comprising a second lipid.
136. The pharmaceutical formulation of claim 135, wherein the pharmaceutical
formulation comprises at least 5% of the second lipid by weight.
137. The pharmaceutical formulation of claim 135 or 136, wherein the
pharmaceutical formulation comprises no more than 95% of the second lipid by weight.
138. The pharmaceutical formulation of any one of claims 135-137, wherein the
second lipid is omega-3.
139. The pharmaceutical formulation of any one of claims 138, wherein the second
lipid is omega-3 from fish or flaxseed.
140. The pharmaceutical formulation of any one of claims 129-139, further
comprising an antioxidant.
141. The pharmaceutical formulation of claim 140, wherein the pharmaceutical
formulation comprises at least 5% of antioxidant by weight.
142. The pharmaceutical formulation of claim 140 or 141, wherein the
pharmaceutical formulation comprises no more than 95% of the antioxidant by weight.
143. The pharmaceutical formulation of any one of claims 140-142, wherein the
antioxidant is Vitamin E.
144. The pharmaceutical formulation of any one of claims 140-142, wherein the
antioxidant is Vitamin C.
145. The pharmaceutical formulation of any one of claims 140-142, wherein the
antioxidant is alpha lipoic acid.
146. The pharmaceutical formulation of any one of claims 129-145, wherein the
pharmaceutical formulation further comprises curcumin.
147. The pharmaceutical formulation of any one of claims 129-146, wherein the
pharmaceutical formulation further comprises a terpenoid.
148. The pharmaceutical formulation of any one of claims 129-147, wherein the
pharmaceutical formulation further comprises cysteamine.
149. The pharmaceutical formulation of any one of claims 129-148, wherein the
pharmaceutical formulation further comprises pantethine.
150. The pharmaceutical formulation of any one of claims 146-149, wherein the
curcumin is deuterated.
151. The pharmaceutical formulation of any one of claims 129-150, wherein the
pharmaceutical formulation further comprises baicalin.
152. The pharmaceutical formulation of any one of claims 129-151, wherein the
vehicle is a lipophilic solvent, fatty oil, organic oil, or liposome.
153. The pharmaceutical formulation of any one of claims 129-152, wherein the
pharmaceutical formulation further comprises an excipient, wherein the excipient is a sugar,
lactose, sucrose, mannitol, sorbitol, cellulose preparations of maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
154. A method of treating, inhibiting, or ameliorating a disorder in a subject
comprising
administering the pharmaceutical formulation of any one of claims 129-153 to
the subject.
155. The method of claim 154, wherein the disorder is a liver disorder.
156. The method of claim 154 or 155, wherein the disorder is a fatty liver disease.
157. The method of any one of claims 154-156, wherein the disorder is alcoholic
liver disease.
158. The method of claim 154, wherein the disorder is heart failure.
159. The method of claim 154, wherein the disorder is a kidney disease or chronic
kidney disease.
160. The method of claims 154 or 159, wherein the disorder is diabetic kidney
disease.
161. The method of claim 154 or 159, wherein the disorder is polycystic kidney
disease.
162. The method of claim 154, wherein the disorder is hypertension.
163. The method of claim 154 or 162, wherein the disorder is hypertension with
left ventricular hypertrophy.
164. The method of claim 154, wherein the disorder is diabetes.
165. The method of claim 154 or 164, wherein the disorder is diabetes with
hyperlipidemia.
166. The method of claim 154, wherein the subject has elevated Galectin- 3 levels
in the blood or urine.
167. The method of claim 154, wherein the subject has elevated levels of fibrotic
markers.
168. The method of claim 167, wherein the fibrotic markers are in blood.
169. The method of claim 167 or 168, wherein the fibrotic markers are in urine.
170. The method of claim 154, wherein the subject has an elevated level of a
marker of oxidative stress.
171. The method of claim 170, wherein the marker of oxidative stress is in blood.
172. The method of claims 170 or 171, wherein the marker of oxidative stress is in
urine.
173. The method of claim 154, wherein the subject has an elevated level of a
marker of inflammation.
174. The method of claim 173, wherein the marker of inflammation is in blood.
175. The method of claim 173 or 174, wherein the marker of inflammation is in
urine.
176. The method of any one of claims 154-175, wherein the pharmaceutical
formulation is administered to the subject by oral administration.
177. The method of any one of claims 154-175, wherein the administering is
performed by intravenous administration.
178. The method of any one of claims 154-177, wherein the subject is human.
179. The method of any one of claims 154-178, wherein the subject is taking
analgesics.
180. The method of any one of claims 154-178, wherein the subject is under
treatment with one or more anti-malarial drugs.
181. A method of protecting an organ, comprising:
identifying a subject in need of protection of an organ; and
administering the pharmaceutical formulation of any one of claims 129-153,
to a subject in need.
182. The method of claim 181, wherein the organ is kidney.
183. The method of claim 181, wherein the organ is liver.
184. The method of claim 181, wherein the organ is heart.
185. The method of any one of claims 181-184, wherein the subject is human.
186. The method of any one of claims 181-185, wherein the administering is
performed by oral administration.
187. The method of any one of claims 181-185, wherein the administering is
performed by intravenous administration.
188. The method of any one of claims 181, 183 or 185-187, wherein the subject
has a liver disorder.
189. The method of any one of claims 181, 183 or 185-188, wherein the subject
has a fatty liver disease.
190. The method of any one of claims 181, 183 or 185-189, wherein the subject
has alcoholic liver disease.
191. The method of any one of claims 181, 182 or 185-187, wherein the subject
has a kidney disease or chronic kidney disease.
192. The method of any one of claims 181, 182, 185-187 or 191, or 184, wherein
the subject has diabetic kidney disease.
193. The method of claim 181, 182, 185-187 or 191, wherein the subject has
polycystic kidney disease.
194. The method of any one of claims 181-193, wherein the subject has
hypertension.
195. The method of any one of claims 185-194, wherein the subject has
hypertension with left ventricular hypertrophy.
196. The method of any one of claims 181-195, wherein the subject has diabetes.
197. The method of any one of claims 181-196, wherein the subject has diabetes
with hyperlipidemia.
198. The method of any one of claims 181-197, wherein the subject has an elevated
level of Galectin- 3 in the blood or urine.
199. The method of any one of claims 181-198, wherein the subject has an elevated
level of one or more fibrotic markers.
200. The method of claim 199, wherein at least one of the one or more fibrotic
markers are in blood.
201. The method of claim 199 or 200, wherein at least one of the one or more
fibrotic markers are in urine.
202. The method of any one of claims 181-201, wherein the subject has an elevated
level of one or more markers of oxidative stress.
203. The method of claim 202, wherein at least one of the markers of oxidative
stress is in blood.
204. The method of claims 201 or 203, wherein at least one of the markers of
oxidative stress is in urine.
205. The method of any one of claims 181-204, wherein the subject has an elevated
level of one or more markers of inflammation.
206. The method of claim 205, wherein at least one of the elevated markers of
inflammation is in blood.
207. The method of claim 205 or 206, wherein at least one of the elevated markers
is in urine.
208. The method of any one of claims 181 or 184-187 or 194-207, wherein the
subject has heart failure.
209. A method of treating or preventing heart failure in a subject in need,
comprising:
identifying a subject in need of treatment for or prevention of heart failure;
and
administering the pharmaceutical formulation of any one of claims 129-153 to
a subject in need.
210. The method of Claim 209, wherein the subject has chronic kidney disease
and/or hypertension.
211. The method of Claim 209 or 210, wherein the subject is human.
212. The method of any one of claims 209-211, wherein the administering is
performed by oral administration.
213. The method of any one of claims 209-211, wherein the administering is
performed by intravenous administration.