Note: Descriptions are shown in the official language in which they were submitted.
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TYROSINE DERIVATIVES AND COMPOSITIONS COMPRISING THEM
TECHNICAL FIELD
[0001] The present inventions relate generally to compositions, kits and
methods for
the reduction of cellular proliferation as, for example, in the treatment of
cancer.
BACKGROUND
[0002] According to the U.S. National Cancer Institute's Surveillance
Epidemiology and End Results (SEER) database for the year 2008, the most
recent year for
which incidence data are available, 11,958,000 Americans have invasive
cancers. Cancer is
the second most common cause of death in the United States, behind only heart
disease, and
accounts for one in four deaths. It has been estimated that approximately 1600
Americans die
of cancer each day. In addition to the medical, emotional and psychological
costs of cancer,
cancer has significant financial costs to both the individual and society. It
is estimated by the
National Institutes of Health that the overall costs of cancer in 2010 was
$263.8 billion. In
addition, it is estimated that another $140.1 billion is lost in productivity
due to premature
death.
[0003] Cancer treatments today include surgery, hormone therapy, radiation,
chemotherapy, immunotherapy, targeted therapy, and combinations thereof
Surgical
removal of cancer has advanced significantly; however, there remains a high
chance of
recurrence of the disease. Hormone therapy using drugs such as aromatase
inhibitors and
luteinizing hormone-releasing hormone analogs and inhibitors has been
relatively effective in
treating prostate and breast cancers. Radiation and the related techniques of
conformal
proton beam radiation therapy, stereotactic radiosurgery, stereotactic
radiation therapy,
intraoperative radiation therapy, chemical modifiers, and radio sensitizers
are effective at
killing cancerous cells, but can also kill and alter surrounding normal
tissue. Chemotherapy
drugs such as aminopterin, cisplatin, methotrexate, doxorubicin, daunorubicin
and others
alone and in combinations are effective at killing cancer cells, often by
altering the DNA
replication process. Biological response modifier (BRM) therapy, biologic
therapy,
biotherapy, or immunotherapy alter cancer cell growth or influence the natural
immune
response, and involve administering biologic agents to a patient such as an
interferons,
interleukins, and other cytokines and antibodies such as rituximab and
trastuzumab and even
cancer vaccines such as Sipuleucel-T.
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[0004] Cancer treatment using chemotherapy is often hindered by dose-limiting
side
effects. Such side effects often result from the action of the
chemotherapeutic agent on non-
cancerous cells. This limitation of chemotherapy has led to development of
targeted
therapies and site-directed chemotherapy.
[0005] Recently, new targeted therapies have been developed to fight cancer.
These
targeted therapies differ from chemotherapy because chemotherapy works by
killing both
cancerous and normal cells, with greater effects on the cancerous cells.
Targeted therapies
work by influencing the processes that control growth, division, and the
spread of cancer cells
and signals that cause cancer cells to die naturally. One type of targeted
therapy includes
growth signal inhibitors such as trastuzumab, gefitinib, imatinib, centuximab,
dasatinib and
nilotinib. Another type of targeted therapy includes angiogenesis inhibitors
such as
bevacizumab that inhibit cancers from increasing surrounding vasculature and
blood supply.
A final type of targeted therapy includes apoptosis-inducing drugs that are
able to induce
direct cancer cell death.
[0006] Site-directed chemotherapy directs anticancer agents preferentially to
cancer
cells by means of a targeting molecule. The targeting molecule has a specific
affinity for the
cancer being treated. Antibodies are examples of targeting molecules that can
be used to
direct anticancer agents to specific cancer types. An antibody may recognize
an antigen that
is expressed on the surface of a specific type of cancer cell. By attaching
anticancer agents to
the antibody, the anticancer agents can be brought specifically to the cancer
cells that are
being targeted.
[0007] Although all of these treatments have been effective to one degree or
another, they all have drawbacks and limitations. In addition to many of the
treatments being
expensive, they also are often too imprecise or the cancers are able to adapt
to them and
become resistant.
[0008] Thus, there is a great need for additional cancer treatments. In
particular,
there is a need for treatments for cancers that have become resistant to other
forms of
treatment.
SUMMARY
[0009] The present invention provides compositions, kits, and methods for
reducing
undue cellular proliferation, including that associated with the treatment of
cancer, and
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combination therapies. In certain embodiments, the invention provides
compositions
comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is
chemically
bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
Other
embodiments provide methods of reducing cell proliferation and/or methods of
treating
cancer comprising administering an effective amount of such compositions. Some
embodiments also provide combination therapies that are administered in
conjunction with
other therapeutic agents. In other embodiments, the invention provides kits
that comprise
such compositions together with suitable packaging.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0010] The present subject matter may be understood more readily by reference
to
the following detailed description which forms a part of this disclosure. It
is to be understood
that this invention is not limited to the specific products, methods,
conditions or parameters
described and/or shown herein, and that the terminology used herein is for the
purpose of
describing particular embodiments by way of example only and is not intended
to be limiting
of the claimed invention.
[0011] Unless otherwise defined herein, scientific and technical terms used in
connection with the present application shall have the meanings that are
commonly
understood by those of ordinary skill in the art. Further, unless otherwise
required by
context, singular terms shall include pluralities and plural terms shall
include the singular.
[0012] As employed above and throughout the disclosure, the following terms
and
abbreviations, unless otherwise indicated, shall be understood to have the
following
meanings.
[0013] In the present disclosure the singular forms "a," "an," and "the"
include the
plural reference, and reference to a particular numerical value includes at
least that particular
value, unless the context clearly indicates otherwise. Thus, for example, a
reference to "a
compound" is a reference to one or more of such compounds and equivalents
thereof known
to those skilled in the art, and so forth. The term "plurality", as used
herein, means more than
one. When a range of values is expressed, another embodiment incudes from the
one
particular and/or to the other particular value. Similarly, when values are
expressed as
approximations, by use of the antecedent "about," it is understood that the
particular value
forms another embodiment. All ranges are inclusive and combinable.
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[0014] As used herein, the terms "component," "composition," "composition of
compounds," "compound," "drug," "pharmacologically active agent," "active
agent,"
"agent," "therapeutic," "therapy," "treatment," or "medicament" are used
interchangeably
herein to refer to a compound or compounds or composition of matter which,
when
administered to a subject (human or animal) induces a desired pharmacological
and/or
physiologic effect by local and/or systemic action.
[0015] As used herein, the terms "treatment" or "therapy" (as well as
different
forms thereof) include preventative (e.g., prophylactic), curative or
palliative treatment. As
used herein, the term "treating" includes alleviating or reducing at least one
adverse or
negative effect or symptom of a condition, disease or disorder. This
condition, disease or
disorder can be cancer.
[0016] As employed above and throughout the disclosure the term "effective
amount" refers to an amount effective, at dosages, and for periods of time
necessary, to
achieve the desired result with respect to the treatment of the relevant
disorder, condition, or
side effect. It will be appreciated that the effective amount of components of
the present
invention will vary from patient to patient not only with the particular
compound, component
or composition selected, the route of administration, and the ability of the
components to
elicit a desired result in the individual, but also with factors such as the
disease state or
severity of the condition to be alleviated, hormone levels, age, sex, weight
of the individual,
the state of being of the patient, and the severity of the pathological
condition being treated,
concurrent medication or special diets then being followed by the particular
patient, and other
factors which those skilled in the art will recognize, with the appropriate
dosage being at the
discretion of the attending physician. Dosage regimes may be adjusted to
provide the
improved therapeutic response. An effective amount is also one in which any
toxic or
detrimental effects of the components are outweighed by the therapeutically
beneficial
effects.
[0017] "Pharmaceutically acceptable" refers to those compounds, materials,
compositions, and/or dosage forms which are, within the scope of sound medical
judgment,
suitable for contact with the tissues of human beings and animals without
excessive toxicity,
irritation, allergic response, or other problem complications commensurate
with a reasonable
benefit/risk ratio.
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[0018] Within the present invention, the disclosed compounds may be prepared
in
the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable
salts" refer to
derivatives of the disclosed compounds wherein the parent compound is modified
by making
acid or base salts thereof Examples of pharmaceutically acceptable salts
include, but are not
limited to, mineral or organic acid salts of basic residues such as amines;
alkali or organic
salts of acidic residues such as carboxylic acids; and the like. The
pharmaceutically
acceptable salts include the conventional non-toxic salts or the quaternary
ammonium salts of
the parent compound formed, for example, from non-toxic inorganic or organic
acids. For
example, such conventional non-toxic salts include those derived from
inorganic acids such
as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the
like; and the salts
prepared from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic,
malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic,
benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic,
ethane disulfonic, oxalic, isethionic, and the like. These pharmaceutically
acceptable salts are
prepared by methods known in the art, e.g., by dissolving the free amine bases
with an excess
of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an
alkali metal base
such as a hydroxide, or with an amine.
[0019] Compounds described herein can be prepared in alternate forms. For
example, many amino-containing compounds can be used or prepared as an acid
addition
salt. Often such salts improve isolation and handling properties of the
compound. For
example, depending on the reagents, reaction conditions and the like,
compounds as
described herein can be used or prepared, for example, as their hydrochloride
or tosylate
salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide,
hydrates, solvates,
and acid salt hydrates, are also contemplated to be within the scope of the
present invention.
[0020] Certain acidic or basic compounds of the present invention may exist as
zwitterions. All forms of the compounds, including free acid, free base and
zwitterions, are
contemplated to be within the scope of the present invention. It is well known
in the art that
compounds containing both amino and carboxy groups often exist in equilibrium
with their
zwitterionic forms. Thus, any of the compounds described herein that contain,
for example,
both amino and carboxy groups, also include reference to their corresponding
zwitterions.
[0021] The term "stereoisomers" refers to compounds that have identical
chemical
constitution, but differ as regards the arrangement of the atoms or groups in
space.
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[0022] The term "administering" means either directly administering a compound
or
composition of the present invention, or administering a prodrug, derivative
or analog which
will form an equivalent amount of the active compound or substance within the
body.
[0023] The terms "subject," "individual," and "patient" are used
interchangeably
herein, and refer to an animal, for example a human, to whom treatment,
including
prophylactic treatment, with the pharmaceutical composition according to the
present
invention, is provided. The term "subject" as used herein refers to human and
non-human
animals. The terms "non-human animals" and "non-human mammals" are used
interchangeably herein and include all vertebrates, e.g., mammals, such as non-
human
primates, (particularly higher primates), sheep, dog, rodent, (e.g. mouse or
rat), guinea pig,
goat, pig, cat, rabbits, cows, horses and non-mammals such as reptiles,
amphibians, chickens,
and turkeys.
[0024] The term "inhibitor" as used herein includes compounds that inhibit the
expression or activity of a protein, polypeptide or enzyme and does not
necessarily mean
complete inhibition of expression and/or activity. Rather, the inhibition
includes inhibition of
the expression and/or activity of a protein, polypeptide or enzyme to an
extent, and for a time,
sufficient to produce the desired effect.
[0025] The term "promoter" as used herein includes compounds that promote the
expression or activity of a protein, polypeptide or enzyme and does not
necessarily mean
complete promotion of expression and/or activity. Rather, the promotion
includes promotion
of the expression and/or activity of a protein, polypeptide or enzyme to an
extent, and for a
time, sufficient to produce the desired effect.
[0026] "Chemically bonded" refers to the connection of two atoms by a chemical
bond. A chemical bond is a bond resulting from the electronic interaction of
one atom
(which may be part of a molecule) with another atom (which may be part of a
molecule).
Chemical bonds may be covalent bonds or non-covalent bonds.
[0027] "Physically associated" refers to two molecules that are maintained in
close
proximity by means other than a chemical bond. One example of physically
associated
molecules is the impregnation of one molecule into a sample of the other
molecule. Another
example when one molecule is encapsulated by another molecule.
[0028] The term "linker" refers to a chemical moiety that allows two molecules
to
be indirectly chemically bonded, or indirectly physically associated. A linker
that indirectly
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chemically bonds two molecules forms separate chemical bonds with each of the
two
molecules such that the two molecules are connected through the linker. A
linker that
indirectly physically associates two molecules forms separate physically
associations with
each of the two molecules such that the two molecules are physically
associated through the
linker. A linker can also connect two molecules by chemically bonding to one
of the two
molecules and physically associating with the other of the two molecule.
[0029] In one embodiment, the present invention provides a chemotherapy that
specifically directs anticancer agents to cancer cells. While not intending to
be bound by any
particular mechanism of operation, the compositions of the present invention
specifically
target cancer cells and thereby provide a site-directed chemotherapy. It is
believed that the
tyrosine hydroxylase portion of the compositions of the present invention is
absorbed by
cancer cells. By chemically bonding, or physically associating, the tyrosine
hydroxylase
inhibitor and an anticancer agent, the anticancer agent accompanies the
tyrosine hydroxylase
inhibitor to, and/or into, the cancer cells. In this manner, the anticancer
agent is directed to
cancer cells in preference to non-cancerous cells.
[0030] The present invention provides compositions comprising a tyrosine
hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or
physically
associated with, the tyrosine hydroxylase inhibitor.
[0031] Representative tyrosine hydroxylase inhibitors that may be used in the
compositions of the present invention include tyrosine derivatives, which
typically are rapidly
absorbed by most cancers and inflamed tissues. Thus, in some embodiments, the
tyrosine
hydroxylase inhibitor is a tyrosine derivative. Representative tyrosine
derivatives that may
be used in compositions of the present invention include one or more of methyl
(2R)-2-
amino-3-(2-chloro-4-hydroxyphenyl) propanoate, D-tyrosine ethyl ester
hydrochloride,
methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate, H-D-
Tyr(TBU)-
ally' ester HC1, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-
amino-3-
(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2-
amino-3-(2-
chloro-3,4-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-5-
fluoro-4-
hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-
fluorobenzyl) oxy]
benzyl malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propanoate,
methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-
amino-3-
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(2,6- dichloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-
chloro-4-
hydroxyphenyl) propanoate, H-DL-tyr-OMe HC1, H-3,5-diiodo-tyr-OME HC1, H-D-3,5-
diiodo-tyr-OME HC1, D-tyrosine methyl ester hydrochloride, D-tyrosine-OMe HC1,
methyl
D-tyrosinate hydrochloride, D-tyrosine methyl ester HC1, H-D-Tyr-OMe-HC1, (2R)-
2-amino-
3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl) methyl
ester
hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate
hydrochloride, methyl
(2R)-2-azany1-3-(4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-
tyrosine, 3-nitro-
L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-
tyrosine, Boc-
Tyr (3,5-12)-0Su, Fmoc-tyr(3-NO2)-0H, a-methyl-L-tyrosine, a-methyl-D-
tyrosine, and a-
methyl-DL-tyrosine (also known as DL-2-Methyl-3-(4-Hydroxyphenyl) alanine).
These
tyrosine derivatives are referred to herein as the "representative tyrosine
derivatives." In
some embodiments, the tyrosine derivative is a-methyl-DL-tyrosine.
[0032] Anticancer agents that may be used in compositions of the present
invention
include any agents that are active against cancer, and include alkylating
agents,
antimetabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic
antibiotics,
selective estrogen receptor modulators, aromatase inhibitors, signal
transduction inhibitors,
agents that modify the function of proteins that regulate gene expression and
other cellular
functions, drugs that induce cancer cells to undergo apoptosis, and drugs that
interfere with
angiogenesis.
[0033] Representative anticancer agents that may be used in the present
invention
include 5-fluorouracil, abiraterone acetate, acetylcholine, ado-trastuzumab
emtansine,
afatinib, aldesleukin, alectinib, alemtuzumab, alitretinoin, aminolevulinic
acid, anastrozole,
anastrozole, aprepitant, arsenic trioxide, asparaginase erwinia chrysanthemi,
atezolizumab,
axitinib, azacitidine, belinostat, bendamustine, benzyl isothiocyanate,
bevacizumab,
bexarotene, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib,
brentircimab
vedotin, busulfan, cabazitaxel, cabozantinib, capecitabine, carboplatin,
carfilzomib,
carmustine, ceritinib, cetircimab, chlorambucil, cisplatin, clofarabine,
cobimetinib, crizotinib,
cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacarbazine,
dactinomycin,
daratumumab, dasatinib, daunorubicin, decitabine, defibrotide sodium,
degarelix, denileukin
diftitox, denosumab, dexamethasone, dexrazoxane, dihydrotestosterone (DHT),
dinutuximab,
docetaxel, doxorubicin, elotuzumab, eltrombopag, enzalutamide, epirubicin,
eribulin
mesylate, erlotinib, etoposide, everolimus, exemestane, exemestane,
filgrastim, fludarabine
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phosphate, flutamide, fulvestrant, fulvestrant, gefitinib, gemcitabine,
gemtuzumab,
gemtuzumab ozogamicin, glucarpidase, goserelin acetate, hydroxyurea,
ibritumomab
tiuxetan, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, imiquimod,
interferon alfa-2b,
ipilimumab, irinotecan, ixabepilone, ixazomib, lanreotide, lapatinib,
lenalidomide, lenvatinib,
letrozole, leucovorin, leuprolide, lomustine, mechlorethamine, megestrol
acetate, melphalan,
mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, necitumumab,
nelarabine,
netupitant, nilotinib, nilutamide, nivolumab, obinutuzumab, ofatumumab,
olaparib,
omacetaxine mepesuccinate, osimertinib, oxaliplatin, ozogamicin, paclitaxel,
palbociclib,
palifermin, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase,
peginterferon
alfa-2b, pembrolizumab, pemetrexed, pertuzumab, plerixafor, pomalidomide,
ponatinib,
pralatrexate, prednisone, procarbazine, propranolol, radium 223 dichloride,
raloxifene,
ramucirumab, rasburicase, regorafenib, ritircimab, rolapitant, romidepsin,
romiplostim,
ruxolitinib, siltuximab, sipuleucel-t, sonidegib, sorafenib, sunitinib,
talimogene
laherparepvec, tamoxifen, temozolomide, temsirolimus, thalidomide,
thioguanine, thiotepa,
tipiracil, topotecan, toremifene, toremifene, tositumomab, trabectedin,
trametinib,
trastuzumab, tretinoin, trifluridine, uridine triacetate, vandetanib,
vemurafenib, venetoclax,
vinblastine, vincristine, vinorelbine, vismodegib, vorinostat, ziv-
aflibercept, zoledronic acid,
and pharmaceutically acceptable salts thereof These anticancer agents are
referred to herein
as the "representative anticancer agents."
[0034] In some embodiments, the anticancer agent is one or more of 5-
fluorouracil,
capecitabine, cisplatin, erlotinib, everolimus, gemcitabine, irinotecan,
lanreotide acetate,
leucovorin, mitomycin C, oxaliplatin, paclitaxel, taxotere, and sunitinib
malate.
[0035] In some embodiments of the present invention, the anticancer agent is
chemically bonded to the tyrosine hydroxylase inhibitor. The anticancer agent
can be
chemically bonded to the tyrosine hydroxylase inhibitor by a covalent bond. A
covalent bond
between the tyrosine hydroxylase inhibitor and the anticancer agent may be
formed by
chemical reaction of reactive functional groups on the tyrosine hydroxylase
inhibitor with
reactive functional groups on the anticancer agent. Reactive function groups
on the tyrosine
hydroxylase inhibitor may include esters, carboxylic acids, amides, amino
groups, hydroxyl
groups, and activated aromatic or aliphatic carbon atoms. Reactive function
groups on the
anticancer agent may include esters, carboxylic acids, amides, amino groups,
hydroxyl
groups, activated aromatic or aliphatic carbon atoms, sulfides, and cyano
groups. Thus,
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reaction of functional groups on the tyrosine hydroxylase inhibitor with
functional groups on
the anticancer agent can result in ethers, amines, esters, amides, thioesters,
thioethers,
carbamates, and ureas. Methods for making the types of covalent bonds required
by
embodiments of the present invention are generally known in the art. See,
e.g., Michael B.
Smith and Jerry March, March's Advanced Organic Chemistry, Reactions,
Mechanism, and
Structure (John Wiley & Sons 2001).
[0036] An exemplary embodiment of the present invention wherein an anticancer
agent is chemically bonded to a tyrosine hydroxylase inhibitor by a covalent
bond is the ester
that would result from condensing a hydroxyl group of capecitabine with the
carboxylic acid
group of a-methyl tyrosine:
OH
0
HO NH2
111100.,0
0 N F 0
ONNO
[0037] In other embodiments the anticancer agent is chemically bonded to the
tyrosine hydroxylase inhibitor by a non-covalent bond. In some embodiments,
the non-
covalent bond is an ionic bond. An ionic bond between the tyrosine hydroxylase
inhibitor
and the anticancer agent may be formed by chemical reaction of salt-forming
functional
groups on the tyrosine hydroxylase inhibitor with salt-forming functional
groups on the
anticancer agent. Salt-forming functional groups on the tyrosine hydroxylase
inhibitor may
include carboxylic acids, amino groups, and acidic hydroxyl groups. Salt-
forming functional
groups on the anticancer agent may include carboxylic acids, amino groups,
acidic hydroxyl
groups, and acidic thiols. Methods for making the types of non-covalent bonds
required by
embodiments of the present invention are generally known in the art. See,
e.g., Michael B.
Smith and Jerry March, March's Advanced Organic Chemistry, Reactions,
Mechanism, and
Structure (John Wiley & Sons 2001).
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[0038] An exemplary embodiment of the present invention wherein an anticancer
agent is chemically bonded to a tyrosine hydroxylase inhibitor by a non-
covalent, ionic bond
is the salt that would result from reacting D-tyrosine ethyl ester with
leucovorin:
HO
0 NH3
OH 0
0
0
0
NH
NH
0 C)N
NH
H2N
[0039] In other embodiments of the present invention, the anticancer agent is
chemically bonded to the tyrosine hydroxylase inhibitor through a linker. In
some
embodiments, the linker is a chemical moiety that forms chemical bonds to both
the tyrosine
hydroxylase inhibitor and the anticancer agent and thus separates the tyrosine
hydroxylase
inhibitor and the anticancer agent. Thus, in some embodiments, the present
invention
provides a tyrosine hydroxylase inhibitor-anticancer agent conjugate. Covalent
bonds
between the tyrosine hydroxylase inhibitor and the linker may include, for
example,
carbamate bonds, amide bonds, ester bonds, amino bonds, and ether bonds formed
by
reaction of reactive functional groups on the tyrosine hydroxylase inhibitor
with reactive
functional groups on the linker. Covalent bonds between the anticancer agent
and the linker
may include, for example, disulfide bonds, carbamate bonds, amide bonds, ester
bonds,
amino bonds, and ether bonds formed by reaction of reactive functional groups
on the
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anticancer agent with reactive functional groups on the linker. Thus, in some
embodiments,
the linker is a chemical moiety having reactive functional groups that react
with the tyrosine
hydroxylase inhibitor, and reactive functional groups that react with the
anticancer agent. In
some embodiments, the linker is a molecule with two functional groups, one of
which is
capable of forming a covalent bond with a functional group on the tyrosine
hydroxylase
inhibitor, and the other of which is capable of forming a covalent bond with a
functional
group on the anticancer agent. In some embodiments, the linker is selected
from aliphatic
compounds having two or more reactive functional groups, aromatic compounds
having two
or more reactive functional groups, carbohydrates, amino acids, peptides,
diamino
compounds, polyamino compounds, diols, polyols, amino-alcohols, ethanolamine,
diamides,
polyamides, lipids, and polyethylene glycols. Methods for making the chemical
bonds
required for embodiments of the present invention are generally known in the
art. See, e.g.,
Michael B. Smith and Jerry March, March's Advanced Organic Chemistry,
Reactions,
Mechanism, and Structure (John Wiley & Sons 2001).
[0040] In some embodiments, the linker can be cleaved under physiological
conditions, thereby disjoining the tyrosine hydroxylase inhibitor and the
anticancer agent. In
some embodiments, the linker is cleaved when the conjugate has been taken into
the cancer
cell. In some embodiments, the linker is cleaved by enzymes located within, or
on the
surface of, the cancer cell.
[0041] In some embodiments, a single linker may be chemically bound to
multiple
anticancer agents and to a single tyrosine hydroxylase inhibitor.
[0042] In other embodiments of the present invention, the anticancer agent is
physically associated with the tyrosine hydroxylase inhibitor. In some
embodiments, the
anticancer agent is physically associated with the tyrosine hydroxylase
inhibitor by
impregnation. Impregnation may be achieved by and applying force to a tyrosine
hydroxylase inhibitor and a solid anticancer agent for a time and under
conditions effective to
impregnate at least one of the tyrosine hydroxylase inhibitor and the
anticancer agent with the
other of said tyrosine hydroxylase inhibitor and said anticancer agent.
Compositions formed
by impregnation and methods of impregnation are set forth in U.S. Patent
Application
Publication No. 2015/0112116-Al, published on April 23, 2015, the contents of
which are
incorporated in their entirety herein.
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[0043] In other embodiments, the anticancer agent is physically associated
with the
tyrosine hydroxylase inhibitor by encapsulation.
[0044] In other embodiments, the linker joins the tyrosine hydroxylase
inhibitor to
the anticancer agent through physical association, or through a combination of
physical
association and chemical bonding. In some embodiments, the anticancer agent is
encapsulated within a liposome that has one or more tyrosine hydroxylase
inhibitors
covalently bonded to its outer surface. In this embodiment, the liposome is a
linker that
bonds to the tyrosine hydroxylase inhibitor by chemical (covalent) bonds, and
binds to the
anticancer agent by physical association (encapsulation).
[0045] In some embodiments of the present invention, the compositions of the
present invention further comprise one or more pharmaceutically acceptable
excipients.
Pharmaceutically acceptable excipients are known in the art. See, e.g.,
Remington's
Pharmaceutical Sciences, 18th Edition, Mack Publishing Company (1990).
[0046] Methods of treating cancer in a subject also are provided, as are
methods of
reducing undue cellular proliferation. Such methods can include administering
an effective
amount of a composition that targets cancer cells. Suitable embodiments are
methods that
include administering an effective amount of the above-noted composition
comprising a
tyrosine hydroxylase inhibitor and an anticancer agent that is chemically
bonded to, or
physically associated with, the tyrosine hydroxylase inhibitor. Other suitable
methods
include administering an effective amount of the above-noted composition
comprising a
tyrosine hydroxylase inhibitor and an anticancer agent that is chemically
bonded to, or
physically associated with, the tyrosine hydroxylase inhibitor, in conjunction
with one or
more additional therapeutic agents.
[0047] The compositions, with or without additional therapeutic agents, may be
provided in a single dosage form or any number of desired dosage forms,
including in
individual dosage forms. Representative dosage forms include tablets,
capsules, caplets,
sterile aqueous or organic solutions, reconstitutable powders, elixirs,
liquids, colloidal or
other types of suspensions, emulsions, beads, beadlets, granules,
microparticles,
nanoparticles, and combinations thereof The amount of composition administered
will, of
course, be dependent on the subject being treated, the subject's weight, the
severity of the
condition being treated, the manner of administration, and the judgment of the
prescribing
physician.
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[0048] Administration of the compositions, with or without additional
therapeutic
agents, can be through various routes, including orally, nasally,
subcutaneously,
intravenously, intramuscularly, transdermally, vaginally, rectally or in any
combination
thereof Transdermal administration can be effected using, for example, oleic
acid, 1-methyl-
2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether.
[0049] The subject to which the instant compositions, with or without
additional
therapeutic agents, are administered can be a mammal, preferably a human.
[0050] Representative methods include those in which the cancer is non-small
cell
lung cancer. In certain embodiments, the non-small cell lung cancer is stage
IV non-small
cell lung cancer. In yet other embodiments, the cancer is ovarian cancer,
breast cancer,
cervical cancer, pancreatic cancer, stomach cancer, brain cancer, liver
cancer, testicular
cancer, leukemia, lymphoma, appendix cancer, biliary cancer,
choleangiocarcinoma, colon
cancer, colorectal cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung
cancer,
neuroblastoma, prostate cancer, renal cancer, sarcoma, thyroid cancer, tongue
cancer, tonsil
squamous cell carcinoma, or urothelial cancer. In some embodiments, the cancer
is
pancreatic cancer.
[0051] The present methods can include not only the disclosed administration
step
but also the step of assessing progression of said cancer in said subject
and/or the extent of
cellular proliferation. The assessing step can be performed before or after
the administering
step.
[0052] Suitable embodiments can include administering the above-noted
compositions comprising a tyrosine hydroxylase inhibitor and an anticancer
agent that is
chemically bonded to, or physically associated with, the tyrosine hydroxylase
inhibitor. The
tyrosine hydroxylase inhibitor in the composition can be a tyrosine
derivative. The tyrosine
derivative may be one or more of the representative tyrosine derivatives noted
above.
[0053] The anticancer agents in the above-noted compositions include any
agents
that are active against cancer, and include alkylating agents,
antimetabolites, anti-microtubule
agents, topoisomerase inhibitors, cytotoxic antibiotics, selective estrogen
receptor modulators,
aromatase inhibitors, signal transduction inhibitors, agents that modify the
function of proteins
that regulate gene expression and other cellular functions, drugs that induce
cancer cells to
undergo apoptosis, and drugs that interfere with angiogenesis. The anticancer
agent may be one
or more of the representative anticancer agents noted above.
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[0054] Methods of treating cancer in a subject are also provided comprising
administering to the subject in need thereof an effective amount of the above-
noted
composition comprising a tyrosine hydroxylase inhibitor and an anticancer
agent that is
chemically bonded to, or physically associated with, the tyrosine hydroxylase
inhibitor. In
suitable embodiments, the composition is administered orally, subcutaneously,
intravenously,
transdermally, vaginally, rectally or in any combination thereof The
transdermal
administration can be done with oleic acid, 1-methyl-2-pyrrolidone, or
dodecylnonaoxyethylene glycol monoether. In other embodiments, the composition
is
administered during a cycle consisting of five to seven days of administering
the composition
and one to two days of not administering the composition. The composition can
be
administered over the course of at least six of said cycles. The tyrosine
hydroxylase inhibitor
in the composition for treating cancer can be a tyrosine derivative. The
tyrosine derivative
may be one or more of the representative tyrosine derivatives noted above.
[0055] The anticancer agents that may be used in compositions for treating
cancer
include any agents that are active against cancer, and include alkylating
agents,
antimetabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic
antibiotics,
selective estrogen receptor modulators, aromatase inhibitors, signal
transduction inhibitors,
agents that modify the function of proteins that regulate gene expression and
other cellular
functions, drugs that induce cancer cells to undergo apoptosis, and drugs that
interfere with
angiogenesis. The anticancer agent may be one or more of the representative
anticancer agents
noted above.
[0056] The subject in methods of treating cancer can be a mammal and that
mammal can be a human. In some embodiments, the subject is a human.
[0057] Representative methods of treating cancer include those in which the
cancer
is non-small cell lung cancer. In certain embodiments, the non-small cell lung
cancer is stage
IV non-small cell lung cancer. In other embodiments, the cancer is ovarian
cancer, breast
cancer, cervical cancer, pancreatic cancer, stomach cancer, brain cancer,
liver cancer,
testicular cancer, leukemia, lymphoma, appendix cancer, biliary cancer,
choleangiocarcinoma, colon cancer, colorectal cancer, germ cell tumor, glioma,
Hodgkin's
lymphoma, lung cancer, neuroblastoma, prostate cancer, renal cancer, sarcoma,
thyroid
cancer, tongue cancer, tonsil squamous cell carcinoma, or urothelial cancer.
In some
embodiments, the cancer is pancreatic cancer.
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[0058] Another suitable embodiment further comprises assessing progression of
said cancer in said subject. The assessing step can be performed before said
administering
step or the assessing step can be performed after said administering step.
[0059] In some embodiments, the methods of treating cancer further comprise
administering one or more additional therapeutic agents. Such additional
therapeutic agents
may include anticancer agents which are the same as, or different than, the
anticancer agents
that are components of the above-noted compositions. In some embodiments, the
additional
therapeutic agents are one or more of the representative anticancer agents
noted above.
[0060] In other embodiments, the additional therapeutic agents may include one
or
more additional tyrosine hydroxylase inhibitors, melanin and/or a melanin
promoter, a p450
3A4 promoter, a leucine aminopeptidase inhibitor, and a growth hormone
inhibitor. In some
embodiments, at least two of the additional therapeutic agents (i.e., melanin,
promoters
and/or inhibitors) are administered simultaneously. In other embodiments, at
least three of
the additional therapeutic agents are administered simultaneously. Each of the
additional
therapeutic agents can be administered simultaneously.
[0061] In some embodiments, the additional therapeutic agent is one or more
tyrosine hydroxylase inhibitors. Representative tyrosine hydroxylase
inhibitors include
tyrosine derivatives. The tyrosine derivative may be one or more of the
representative
tyrosine derivatives noted above.
[0062] In some embodiments, the additional therapeutic agents include at least
one
of melanin, a melanin promoter, or a combination thereof Thus, melanin can be
used, one or
more melanin promoters can be used, and both melanin and one or more melanin
promoters
can be used (either in separate dosage forms or in the same dosage form).
Melanin promoters
according to the present invention are chemical compounds that increase the
production
and/or the activity of melanin. Increased melanin levels are believed to
reduce inflammation
(through, for example, suppression of TNF) and exclude the sequestered lymph
system.
Melanin is a photo catalyst, and can therefore promote chemical reactions that
generate free
radicals which, in turn, can become accessible to cancer cells. Representative
melanin
promoters are methoxsalen and melanotan II.
[0063] In some embodiments, the additional therapeutic agents include a p450
3A4
promoter. "Cytochrome p450 3A4" (which can be abbreviated as "p450 3A4") is a
member
of the cytochrome p450 superfamily of enzymes, and is a mixed-function oxidase
that is
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involved in the metabolism of xenobiotics in the body. It has the widest range
of substrates
of all of the cytochromes. Representative p450 3A4 promoters are 5,5-
diphenylhydantoin
(sold commercially as, for example, Dilantin), valproic acid, and
carbamazepine, which are
believed to induce expression of the p450 3A4 enzyme.
[0064] In some embodiments, the additional therapeutic agents include leucine
aminopeptidase inhibitors (alternatively known as leucyl aminopeptidase
inhibitors). Leucine
aminopeptidases are enzymes that preferentially catalyze the hydrolysis of
leucine residues at
the N-terminus of peptides and/or proteins. Representative leucine
aminopeptidase inhibitors
are N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryll-L-leucine, and rapamycin.
[0065] In some embodiments, the additional therapeutic agents include a growth
hormone inhibitor. Growth hormone (such as, for example, pancreatic growth
hormone)
induces cell replication. Representative growth hormone inhibitors are
octreotide,
somatostatin, and seglitide.
[0066] In some embodiments, the additional therapeutic agents include D-
leucine.
D-leucine is a stereoisomer of the naturally occurring L-leucine, the form of
leucine
incorporated into polypeptides and proteins.
[0067] Methods of reducing cell proliferation in a subject are also provided
comprising administering an effective amount of a composition comprising a
tyrosine
hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or
physically
associated with, the tyrosine hydroxylase inhibitor. In suitable embodiments,
components are
administered orally, subcutaneously, intravenously, transdermally, vaginally,
rectally or in
any combination thereof The transdermal administration can be done with oleic
acid, 1-
methy1-2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether. In other
embodiments,
the composition is administered during a cycle consisting of five to seven
days of
administering the composition and one to two days of not administering the
composition.
The composition can be administered over the course of at least six of said
cycles. The
tyrosine hydroxylase inhibitor in the composition for reducing cell
proliferation can be a
tyrosine derivative. The tyrosine derivative may be one or more of the
representative
tyrosine derivatives noted above.
[0068] The anticancer agents that may be used in compositions for reducing
cell
proliferation include any agents that are active against cancer, and include
alkylating agents,
antimetabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic
antibiotics,
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selective estrogen receptor modulators, aromatase inhibitors, signal
transduction inhibitors,
agents that modify the function of proteins that regulate gene expression and
other cellular
functions, drugs that induce cancer cells to undergo apoptosis, and drugs that
interfere with
angiogenesis. The anticancer agent may be one or more of the representative
anticancer agents
noted above.
[0069] The subject in methods of reducing cell proliferation can be a mammal
and
the mammal can be a human. In some embodiments, the subject is a human.
[0070] Representative methods of reducing cell proliferation include those in
which
the cell proliferation is cancer. In some embodiments, the cancer is non-small
cell lung
cancer. In certain embodiments, the non-small cell lung cancer is stage IV non-
small cell
lung cancer. In other embodiments, the cancer is ovarian cancer, breast
cancer, cervical
cancer, pancreatic cancer, stomach cancer, brain cancer, liver cancer,
testicular cancer,
leukemia, lymphoma, appendix cancer, biliary cancer, choleangiocarcinoma,
colon cancer,
colorectal cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer,
neuroblastoma, prostate cancer, renal cancer, sarcoma, thyroid cancer, tongue
cancer, tonsil
squamous cell carcinoma, or urothelial cancer. In some embodiments, the cancer
is
pancreatic cancer.
[0071] Another suitable embodiment further comprises assessing progression of
said cancer in said subject. The assessing step can be performed before said
administering
step or the assessing step can be performed after said administering step.
[0072] In some embodiments, the methods of reducing cell proliferation further
comprise administering one or more additional therapeutic agents. Such
additional
therapeutic agents may include anticancer agents which are the same as, or
different than, the
anticancer agents that are components of the above-noted compositions. In some
embodiments, the additional therapeutic agents are one or more of the
representative
anticancer agents noted above.
[0073] In other embodiments, the additional therapeutic agents may include one
or
more additional tyrosine hydroxylase inhibitors, melanin and/or a melanin
promoter, a p450
3A4 promoter, a leucine aminopeptidase inhibitor, and a growth hormone
inhibitor. In some
embodiments, at least two of the additional therapeutic agents (i.e., melanin,
promoters
and/or inhibitors) are administered simultaneously. In other embodiments, at
least three of
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the additional therapeutic agents are administered simultaneously. Each of the
additional
therapeutic agents can be administered simultaneously.
[0074] In some embodiments, the additional therapeutic agent is one or more
tyrosine hydroxylase inhibitors. Representative tyrosine hydroxylase
inhibitors include
tyrosine derivatives. The tyrosine derivative may be one or more of the
representative
tyrosine derivatives noted above.
[0075] In some embodiments, the additional therapeutic agents include at least
one
of melanin, a melanin promoter, or a combination thereof Thus, melanin can be
used, one or
more melanin promoters can be used, and both melanin and one or more melanin
promoters
can be used (either in separate dosage forms or in the same dosage form).
Melanin promoters
according to the present invention are chemical compounds that increase the
production
and/or the activity of melanin. Increased melanin levels are believed to
reduce inflammation
(through, for example, suppression of TNF) and exclude the sequestered lymph
system.
Melanin is a photo catalyst, and can therefore promote chemical reactions that
generate free
radicals which, in turn, can become accessible to cancer cells. Representative
melanin
promoters are methoxsalen and melanotan II.
[0076] In some embodiments, the additional therapeutic agents include a p450
3A4
promoter. "Cytochrome p450 3A4" (which can be abbreviated as "p450 3A4") is a
member
of the cytochrome p450 superfamily of enzymes, and is a mixed-function oxidase
that is
involved in the metabolism of xenobiotics in the body. It has the widest range
of substrates
of all of the cytochromes. Representative p450 3A4 promoters are 5,5-
diphenylhydantoin
(sold commercially as, for example, Dilantin), valproic acid, and
carbamazepine, which are
believed to induce expression of the p450 3A4 enzyme.
[0077] In some embodiments, the additional therapeutic agents include leucine
aminopeptidase inhibitors (alternatively known as leucyl aminopeptidase
inhibitors). Leucine
aminopeptidases are enzymes that preferentially catalyze the hydrolysis of
leucine residues at
the N-terminus of peptides and/or proteins. Representative leucine
aminopeptidase inhibitors
are N-R2S,3R)-3-amino-2-hydroxy-4-phenylbutyryll-L-leucine, and rapamycin.
[0078] In some embodiments, the additional therapeutic agents include a growth
hormone inhibitor. Growth hormone (such as, for example, pancreatic growth
hormone)
induces cell replication. Representative growth hormone inhibitors are
octreotide,
somatostatin, and seglitide.
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[0079] In some embodiments, the additional therapeutic agents include D-
leucine.
D-leucine is a stereoisomer of the naturally occurring L-leucine, the form of
leucine
incorporated into polypeptides and proteins.
[0080] Also provided herein are kits including a therapy that specifically
targets
cancer cells. Representative kits comprise a composition comprising a tyrosine
hydroxylase
inhibitor and an anticancer agent that is chemically bonded to, or physically
associated with,
said tyrosine hydroxylase inhibitor together with suitable packaging for same.
The kit can
include one or more separate containers, dividers or compartments and,
optionally,
informational material such as instructions for administration. For example,
each
composition can be contained in a bottle, vial, or syringe, and the
informational material can
be contained in a plastic sleeve or packet or provided in a label. In some
embodiments, the
kit includes a plurality (e.g., a pack) of individual containers, each
containing one or more
unit dosage forms of a composition described herein. For example, the kit can
include a
plurality of syringes, ampules, foil packets, or blister packs, each
containing a single unit
dose of a composition described herein or any of the various combinations
thereof The
containers of the kits can be airtight, waterproof (e.g., impermeable to
changes in moisture or
evaporation), and/or light-tight. The kit optionally includes a device
suitable for
administration of the composition, e.g., a syringe, inhalant, pipette,
forceps, measured spoon,
dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any
such delivery
device. In some embodiments, the kit further comprises one or more additional
therapeutic
agents. In some embodiments, the additional therapeutic agents are selected
from anticancer
agents which are the same as, or different than, the anticancer agents that
are components of
the above-noted compositions, additional tyrosine hydroxylase inhibitors,
melanin, a melanin
promoter, a p450 3A4 promoter, leucine aminopeptidase inhibitors, a growth
hormone
inhibitor, and D-leucine.
[0081] The following example is offered for illustrative purposes only, and is
not
intended to limit the scope of the present invention in any way.
EXAMPLE 1
[0082] The ability of the tyrosine hydroxylase portion of the above-noted
compositions to be taken into pancreas cells is demonstrated by the following
study.
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[0083] Background: SM88 is a novel combination of five therapies (sirolimus,
melanin, melanotan, phenytoin, and tyrosine isomers) that when administered
together, has
demonstrated anti-cancer activity with little to no toxicity in a preliminary
study of 30
patients [J Clin Oncol 31, 2013 (suppl; abstr e22095) and Hoffman et al.
GynOncol, 130(1),
e431. This study reports preclinical animal data related to toxicity of the
tyrosine agent, a-
methyl-DL-tyrosine, and possible mechanism of action.
[0084] Material and Methods: Preclinical animal model with 7 day escalating
dose
and 28 day repeat dosing toxicology studies in Sprague Dawley rats and beagle
dogs using a-
methyl-DL-tyrosine. Test and control/ vehicle items were administered daily or
three times
per week over a 4-week period at dose levels of 25, 75, 150, and 300mg/kg. The
study
included mortality, clinical observations, body weights, food consumption,
electrocardiography and ophthalmology. In addition, hematology, coagulation,
clinical
chemistry and urinalysis parameters were evaluated during pretreatment as well
as on Day 29
(Main and Recovery animals) and on Day 55 (Recovery animals). Blood samples
were
collected on Days 1 and 27 at 8 time points relative to treatment in order to
determine the
toxicokinetic profile.
[0085] Results: All test rats regardless of sex, demonstrated consistent organ
volume decrease in the pancreas (decreased cell volume, and reduced
concentration of
zymogenous vacuoles), ovaries and uterus. These changes were completely
reversible upon
the discontinuation of a-methyl-DL-tyrosine. Twenty eight (28) consecutive
days resulted in
a reduction in mean body weight gain in the 300 mg/kg/day males, which
correlated with a
decrease in food consumption and a dose-related increase in mean body weight
gain in the
females of all dose groups. Dogs had no such observations. There were no
deaths, no
clinical signs, no effects on ECGs, no ocular findings, no changes in
hematology,
coagulation, clinical chemistry and urinalysis parameters, no changes in other
organ weights
and no macroscopic and microscopic findings that could be attributed to the
administration of
the Isomers at doses up to 300 mg/kg. Consequently the No Observed Effect
Level (NOEL)
for the tyrosine agent when administered three times per week for 4 weeks was
determined to
be 150 (for dog) and 300 (for rat) mg/kg. Plasma Cmax values at 150 mg/kg
(dog) obtained
on Day 27 were 41.7 [tg/m1 and 41.36 [tg/m1 for males and females
respectively. AUCo-Tlast
values were 717.7 (males) and 724.8 (females) hr*I.tg/ml. The difference in
combined isomer
concentrations in plasma between Day 1 and 27, show that the systemic
exposures to the
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agent generally increased dose-dependently, and in a slightly less than dose-
proportional
manner. In general, the agent's maximum concentration levels (Cmax) were
reached at 2 to
6.7 hours post-dosing. After Tmax, the agent's plasma concentrations declined
gradually at a
mean estimated T1/2 value ranging from 7.9 to 9.3 hours on Day 1 and from 8.4
to 9.6 hours
on Day 27. There were no major or consistent sex-related differences as
evidence by the sex
ratios which ranged between 0.3 and 1.8 for all measured toxicokinetic
parameters. Over the
4-week treatment period, AUCo-Tlast and AUCINF (Cmax) accumulation ratios (Day
27/Day 1)
ranged from 0.6 to 1.8 (0.8 to 1.6) in the animals treated with 25, 75 and 150
mg/kg,
suggesting that the agent does not accumulate when administered three (3)
times per week
over a 27 day period at doses up to 150 mg/kg. For rats, the results were
similar.
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