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`treatment
`
`The attending
`whether
`judging
`in
`clinician,
`
`well-being well as more
`general
`the
`consider
`administered, will
`
`inhibition tumor growth, of
`symptoms,
`
`
`
`relief as of disease-related
`definite signs
`such
`
`of metastasis. Size of the
`tumor
`can
`
`of tumor, or the
`inhibition
`actual shrinkage
`
`
`such studies, e.g., CAT as radiological or
`
`
`
`MRI
`measured by
`standard
`methods
`be
`to
`the
`used
`and successive measurements
`can
`tumor has been
`
`retarded
`even Relief of disease-related reversed.
`
`symptoms such as
`in
`pain, and
`improvement
`overall
`condition
`can
`effectiveness of
`treatment.
`
`or
`
`of
`
`be
`
`scan,
`judge
`
`also
`
`the
`treated
`methods
`
`useful
`can
`
`in
`be
`and
`
`Cardiovascular disease
`be
`may
`The disclosed methods
`that
`cardiovascular
`disease. Cardiovascular
`diseases
`compositions
`polymer-agent
`conjugates,
`particles,
`as
`include cardiomyopathy
`myocarditis; such
`cardiomyopathy,
`metabolic cardiomyopathy,
`alcoholic
`cardiomyopathy,
`ischemic cardiomyopathy,
`and
`hypertensive cardiomyopathy.
`preventable using
`polymer-agent
`conjugates,
`particles,
`vessels
`the
`described herein
`are
`atheromatous
`disorders
`of
`(macrovascular
`disease)
`such
`as
`the
`aorta, the carotid arteries, the
`
`
`the
`the cerebrovascular
`arteries,
`renal arteries,
`the
`Other
`and the popliteal
`arteries.
`vascular
`diseases
`platelet
`include
`those
`related
`to
`aggregation,
`the
`arterioles,
`the
`vasa
`nervorum,
`cardiac
`arterioles,
`the
`eye, the kidney,
`the
`heart,
`and
`central
`polymer-agent
`conjugates,
`particles,
`also be used
`for
`increasing
`HDL
`Yet other disorders
`that
`may
`particles, compositions
`and
`methods
`following coronary intervention,
`
`and disorders relating
`density and
`low
`density
`cholesterol.
`
`or
`
`1005052.1
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`
`idiopathic
`drug-induced
`Also
`compositions
`major
`coronary
`
`treatable
`
`and
`
`iliac
`that
`retinal
`
`associated
`
`and
`
`methods
`plasma
`
`and
`in
`
`with
`herein
`of
`high
`
`polymer-agent
`include
`
`the
`compositions
`levels
`be
`
`treated
`described
`
`
`an to abnormal
`
`level
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`has
`
`or
`
`a
`
`administered
`
`with
`
`or
`
`used
`as
`
`during
`coating
`
`term
`
`"stent"
`
`or
`
`or
`
`compositions
`refers
`conduit
`
`The polymer-agent
`
`or can be administered composition to
`
`particle
`
`conjugate,
`
`undergone In one embodiment,
`
`angioplasty. the
`who
`subject undergoing
`or
`composition
`is
`particle
`polymer-agent
`conjugate,
`a stent placement. In some
`angioplasty
`undergone
`undergoing or who
`has
`embodiments,
`the
`polymer-agent
`conjugate,
`particle
`a
`strut of a stent or
`
`coating a stent. for
`
`be
`or can
`particles compositions
`
`
`The polymer-agent
`conjugates,
`stent, separate e.g., intravenous
`as
`
`a administration,
`
`the implantation
`of
`a
`
`
`stent.
`of
`a
`for a stent or
`as
`the
`strut
`Stent
`particles
`conjugates,
`The polymer-agent
`the
`be used as or
`be
`part a stent. As used herein, of
`
`
`passage
`'tube'
`inserted
`into
`a
`natural
`coronary
`e.g.,
`include,
`localized
`flow
`constriction. Types of stents
`stent,
`vascular
`stent, urethral/prostatic
`stent,
`
`vascular (e.g., peripheral stent
`
`
`stent, pancreatic
`
`graft), esophageal
`stent,
`duodenal
`
`
`colonic stent, biliary stent, and
`include,
`stent. Types of stents that can be used
`in
`coronary
`arteries
`can
`stent (BMS)
`and
`drug-eluting
`
`stent A coronary
`
`(DES). stent
`be
`
`coronary artery
`during
`an
`angioplasty
`procedure.
`
`stent,
`
`or
`
`placed the
`
`conjugate,
`refers
`
`particle
`to a
`a
`
`combination
`
`| \/T
`
`| rv /T
`
`i \ /T
`
`(BMS)
`Bare-metal stent
`In one embodiment,
`the
`polymer-agent
`be used in
`combination
`
`
`
`
`BMS. a with As used herein, BMS
`coating that
`or
`is made
`or
`metal
`a
`e.g., stainless
`steel
`(e.g.,
`
`BxVelocity stent. Express! stent, R stent , and
`Matrix® coronary
`stent),
`cobalt-chromium
`alloy
`Vision® stent,
`and
`Coronnium®
`stent),
`or
`polymer-agent
`conjugate,
`particle
`or
`composition
`coating of a BMS,
`e.g.,
`to
`coat
`the
`luminal a BMS.
`
`(e.g.,
`nickel
`
`A
`
`described
`
`
`
`Drug-eluting stent (DES)
`
`1005052.1
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`
`stent
`
`within
`
`stent
`
`Driver®
`titanium
`
`and/or
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`
`conjugate,
`
`refers stent placed to
`body
`agents
`
`
`
`into
`(e.g.,
`
`or
`
`particle
`a
`a
`
`to
`
`a
`treat
`conduit
`
`example,
`muscle
`and/or proliferation
`epithelialization,
`inhibits inflammation,
`of
`restenosis,
`
`the
`
`of
`
`that
`
`an
`
`agent
`conjugate,
`
`with
`conjugate,
`be e.g.,
`on
`
`polymeric
`conjugates,
`used
`
`as
`
`coated
`
`particles
`
`to
`
`the
`
`
`
`can
`
`at
`
`or
`
`vessel
`
`cardiac
`
`or
`polymer-agent
`least 10,
`
`having
`
`conjugate,
`
`or
`polymer-agent
`least 10,
`
`In one embodiment,
`polymer-agent
`the
`
`be a DES or
`can
`
`of be part a DES. As used herein, DES
`natural passage
`or
`conduit
`of
`the
`(e.g., slowly
`releases)
`one
`or
`more
`with the constricted
`flow
`passage
`the
`by or associated with
`the
`For
`stent.
`that reduces or
`inhibits
`migration
`or
`cells (SMCs),
`that
`promotes
`increases
`reduces
`hypersensitivity reaction,
`that
`or
`risk
`the
`reduces
`inhibits
`thrombosis,
`that
`stent.
`the
`to
`due
`other unwanted
`effects
`which
`includes strut and a polymer, a stent
`on
`
`
`One type of DES
`embodiment,
`a
`
`
`polymer-agent particle or composition
`loaded. Thus,
`in
`one
`in
`used
`combination
`be
`described herein
`can
`polymers).
`biocompatible
`or
`bioasorbable
`a
`For example,
`polymer-agent
`
`herein on a polymeric can
`
`strut,
`particle or
`composition
`described
`a
`of
`the luminal and/or
`abluminal
`surface
`In another embodiment,
`the
`polymer-agent
`compositions described
`herein
`be
`additional polymer
`and/or
`agent.
`In one embodiment,
`the
`rate
`subject having
`a
`stent made of a polymer-agent
`
`described herein
`or
`a
`strut
`coated
`is
`composition described
`herein
`reduced
`95% or more,
`as
`
`compared to the rate of MACE
`of
`different material
`(e.g.,
`a
`metal
`or
`polymer and/or
`agent
`other
`than
`In another embodiment,
`the
`need
`subject having
`a
`stent made of a polymer-agent
`
`described herein
`or
`a
`strut
`coated
`composition described
`herein
`reduced
`
`major
`of
`conjugate,
`with
`
`the
`for
`conjugate,
`with
`
`adverse a
`
`particle
`a
`80, 90,
`by
`subject
`a
`a
`polymer)
`a
`polymer-agent
`a
`target
`particle
`a
`80, 90,
`
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`
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`at
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`
`TYR a stent made
`or
`
`
`
`of of
`
`95% or more,
`a
`the
`to
`compared
`a
`polymer)
`or
`a metal
`material (e.g.,
`conjugate,
`polymer-agent
`the
`and/or agent other
`than
`In yet
`
`(TLR) subject
`lesion
`revascularization
`
`another embodiment,
`
`the for target rate
`or
`conjugate,
`particle
`
`
`of having a stent made polymer-agent a
`
`herein or a
`strut
`coated
`with
`a
`polymer-agent
`described herein
`reduced
`least
`is
`at
`by
`compared
`to
`the
`
`TLR a subject having of
`
`different
`a stent made of a
`
`metal or polymer)
`or
`a
`stent
`not
`coated
`than the polymer-agent
`conjugate,
`particle
`or
`
`
`a subject different
`stent
`particle
`a
`
`of
`composition
`conjugate,
`
`10,
`more,
`material
`or
`
`20,
`(e.g.,
`coated
`
`composition.
`
`Agents
`Agents that can
`loaded
`be
`(e.g.,
`agents
`agents, e.g.,
`anticancer
`(e.g.,
`anthracycline
`cabazitaxel)
`and
`an
`agents;
`restenotic agents;
`anti-inflammatory
`immunosuppresants
`(e.g.,
`mycophenolic
`angiopeptin);
`and
`dimethyl
`sulfoxide.
`e.g.,
`Exemplary anti-proliferative
`agents
`cabazitaxel)
`taxane (e.g., docetaxel, paclitaxel,
`larotaxel
`agent,
`(e.g., doxorubicin);
`and
`an
`immunosuppressive
`(e.g., everolimus,
`zotarolimus,
`biolimus),
`pimecrolimus,
`One or more
`of
`the
`pro-endothelial
`agents
`promote, accelerate
`or
`increase
`
`endothelial Exemplary pro-endothelial healing.
`
`include, e.g.,
`agents
`diminish
`platelet
`adhesion
`that
`titanium-nitride-oxide
`titanium-nitride),
`agents
`that
`or
`cells (EPCs)
`(e.g.,
`antibodies
`(e.g.,
`anti-CD34
`antibody)
`estradiol.
`binding cyclic Arg-Gly-Asp
`peptide)),
`or
`can
`One or more
`of
`anti-restenotic
`agent
`e.g., anti-inflammatory
`agents
`(e.g.,
`dexamethasone),
`mycophenolic
`acid),
`antisense
`agents
`(e.g., an advanced
`six-ring morpholino
`
`a
`
`onto
`
`1005052.1
`
`354
`
`a
`
`DES
`taxane
`doxorubicin);
`(e.g.,
`statins
`somatostatin
`acid);
`(e.g.,
`receptor agonists
`
`include,
`(e.g.,
`pro-endothelial
`simovastatin);
`
`include,
`and
`
`can
`
`or
`
`agents
`
`an
`
`e.g.,
`
`be
`
`and/or
`capture
`or
`
`loaded
`also be
`immunosuppressive
`
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`
`
`vascular
`
`simvastatin,
`agents
`is
`
`the
`the
`
`abluminal
`agents)
`(or
`and
`an
`(e.g.,
`different
`elution,
`same
`elution.
`at
`than
`over
`(e.g.,
`release
`
`backbone c-myc
`inhibitors muscle cell of
`
`(AVI-4126)),
`antisense
`
`
`expression factor (e.g., 3-hydroxy-3-methylglutaryl
`tissue
`proliferation
`and/or
`coenzyme A
`(HMG-CoA)-reductase-inhibitors
`(statins),
`dimethyl sulfoxide
`(DMSO)),
`or
`anti-hyperlipidemic
`In one embodiment,
`the
`agent
`(or
`agents)
`loaded
`
`stent. In another embodiment,
`the (or agents) agent
`
`is
`on
`agent
`the stent. In yet another
`embodiment,
`the
`
`(or the
`luminal and
`abluminal
`
`of sides the stent. In another embodiment,
`an
`
`is loaded on
`the
`luminal
`side
`of
`the
`stent
`agents) is
`loaded
`
`
`the on abluminal side
`
`the Thus, different stent.
`
`agents
`of
`anti-proliferation
`agent
`and
`
`pro-endothelial agent) can be
`loaded
`on
`a
`(luminal or
`abluminal)
`of
`
`
`the to allow for stent,
`e.g., differential
`
`agent
`different agents
`can
`be
`loaded
`on
`the
`stent, e.g.,
`to
`allow
`for
`dual
`local
`agent
`the
`In one embodiment,
`agent
`is
`present
`
`2, 3, 4, 5, 6,
`
`7, 10, 20, 50, or 8, 9,
`
`100
`|_ig/mm. In one embodiment,
`
`more
`50, 60, 70,
`
`80, 90, 95, 99%
`of
`the
`agent
`is
`released
`one embodiment,
`the
`the
`release
`of
`agent
`4,
`5,
`at least about
`1,
`2,
`3,
`6,
`days. In one embodiment,
`agent sustains
`for
`at
`
`
`least 28, 35, or 42 7, days.
`
`14,
`
`agent
`
`In
`
`7,
`
`the
`21,
`
`loaded
`
`sides
`or
`side
`
`a
`
`a
`a
`
`about
`
`8,
`of
`
`Polymeric Stents
`be
`can
`herein
`Stents described
`particle
`polymers. A polymer-agent
`conjugate,
`poly-agent
`be the stent,
`the
`
`of strut a stent or
`
`the
`can coat a
`
`strut made a polymeric material. of
`
`is
`stent
`An example
`of
`a
`biocompatible
`system is composed
`one
`of
`three
`elements:
`polymer
`drug and control
`drug
`release,
`another
`
`biocompatibility,
`and
`finally
`the of the stent) a polyvinyl outer-most side
`
`(on
`pyrrolidinone
`(PVP)
`hydrophilic
`which
`increases
`polymer
`
`Endeavor
`
`This
`
`the
`hydrophobic
`('CI9')
`
`made
`or
`conjugate,
`
`of
`composition
`particle
`
`biocompatible
`described
`
`or
`
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`
`embodiment,
`be
`conjugate,
`of
`
`polymer-agent
`on
`
`or
`elements
`polymer)
`and/or
`
`further enhances
`the
`biocompatibility. Thus, in one
`In
`coated
`or
`composition can
`conjugate, particle
`particle
`a
`polymer-agent
`other embodiments,
`the
`more
`one
`or
`herein can
`replace
`bioabsorbable
`inert
`(e.g.,
`polymers
`Bioabsorbable
`potential
`prothrombogenic
`reduce
`in a DES, e.g.,
`to
`imaging. In some embodiments,
`the
`bioabsorbable polymer
`35, 63, 70 days.
`
`42, 49,
`at least about
`14,
`21,
`28,
`a
`include,
`stents
`Exemplary bioasorbable
`ethyl ester)
`poly(desaminotyrosyl-tyrosine
`lactide stent,
`a
`tyrosine
`stent).
`salicyclic
`acid
`and a poly(anhydride
`ester)
`Igaki-Tamai
`stent
`For example,
`a
`
`polymer either the tyrosine
`constructed
`from
`poly-L-lactic
`
`acid
`
`and kinase
`or
`antagonist ST638
`
`paclitaxel. REV A® stent
`is a tyrosine poly(desaminotyrosyl-
`and
`tyrosine ethyl
`ester)
`
`carbonate It is radio-opaque stent.
`
`and
`has
`slide
`reductions
`mechanism designed
`to
`allow
`for
`substantial
`TIVI
`is
`acid stent
`
`IDEAL
`stent is a poly(anhydride
`ester)
`
`salicyclic Infinnium®
`
`different kinetics.
`composed of
`two
`biodegradable
`polymers
`with paclitaxel-release
`
`BYS®,
`e.g.,
`Other exemplary
`bioasorbable
`stents
`include,
`BioMATRIX®, Champion®,
`and
`Infinnium®.
`polymer-agent
`a
`In one embodiment,
`
`conjugate, particle
`or
`composition
`described
`herein onto any of these
`bioabsorbable
`stents. In other embodiments,
`polymer-agent
`conjugate,
`composition described
`herein
`can
`replace
`bioabsorbable
`stents.
`
`has a
`
`degradation
`
`56,
`
`e.g.,
`
`polymeric
`
`is
`
`stent.
`
`can
`
`lock
`
`particle
`
`a
`
`one
`
`or
`
`Biosorbable Metallic Stents
`compositions
`and
`particles
`The polymer-agent
`conjugates,
`
`bioabsorbable stent. An exemplary metallic bioabsorbable
`stent
`can be used
`to
`coat
`a
`
`
`is the Absorbable Metal
`Stent
`
`(AMS®) alloy stent made which
`
`of
`is 93%
`magnesium and
`7%
`rare-earth
`metals.
`
`
`
`an
`
`Reservoir stents
`
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`stents
`reduce
`drug
`e.g.,
`
`polymer-agent
`in
`the
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`PCT/US2010/028770
`
`T2021-7000W O
`
`can
`the
`
`be
`
`can
`more
`
`be
`unwanted
`loaded
`
`used,
`
`in
`
`or
`
`less
`
`conjugate,
`reservoirs
`composition
`the
`
`abluminal the stent. In
`conjugate,
`reservoirs
`
`particle
`or
`described
`side
`
`of
`
`particle
`
`or
`
`As described herein,
`reservoir
`or
`"thickness"
`of
`the
`stent
`the polymer and/or
`the
`agent. For example, the
`reservoirs or wells
`
`in stent, compared the
`
`to,
`the stent.
`a
`In one embodiment,
`described herein
`is
`loaded
`or
`polymer-agent
`conjugate,
`particle
`or
`side
`the luminal
`reservoirs or wells
`located
`on
`yet another embodiment,
`the
`polymer-agent
`described herein
`is
`loaded
`in
`the
`abluminal sides
`of
`the
`stent.
`In one embodiment, different
`pro-endothelial
`agent)
`can
`(luminal or
`abluminal)
`of
`another embodiment,
`different
`of the same
`side
`(luminal
`drug elution.
`
`an
`agents
`into the
`loaded
`be
`e.g.,
`stent,
`the
`agent In
`to allow for
`differential
`
`agents
`can into adjacent
`be reservoirs
`
`
`
`abluminal the stent, e.g.,
`
`side) allow
`to
`
`(e.g.,
`
`anti-proliferation
`reservoirs
`elution.
`
`loaded wells
`dual
`
`or
`of for
`
`
`
`or
`
`is
`number is at least of
`
`
`zig
`art
`
`coil,
`zag
`
`
`and be employed can
`in
`
`a
`
`the
`
`stents
`
`Strut
`is
`thickness
`strut
`the
`In one embodiment,
`strut
`wideness
`the
`250 (im. In another embodiment,
`0.006, 0.008,
`or
`0.01 inch. In yet another embodiment,
`
`the
`
`about 4, 8, 12,
`
`or 16, 18 in its cross-section.
`
`Various shapes
`
`of struts such as a
`circumferential
`loops,
`
`
`
`are etc. known in the
`described herein.
`In one embodiment,
`particle or
`composition
`
`strut
`
`the
`described
`
`can
`herein.
`
`be
`
`made
`
`Combination
`
`therapy
`
`1005052.1
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`357
`
`at
`
`least
`
`at
`
`struts
`
`ratchet
`
`of
`
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`
`conjugate,
`as
`part with
`
`anti-arrhythmic
`blocker,
`a
`
`a
`
`agent,
`a
`sclerosing
`potassium
`
`In one embodiment,
`polymer-agent
`a
`administered
`be
`described herein may
`
`including, for example,
`agent
`another cardiovascular
`calcium channel
`a
`antihypertensive
`agent,
`fibrinolytic
`agent,
`cardiotonic agent,
`a
`nitric
`oxide
`donor,
`vasodilator agent,
`a
`a
`naturiuretic
`agent.
`or
`blocker, statins,
`conjugate,
`In one embodiment,
`a
`polymer-agent
`particle
`be administered
`as
`part
`of
`a
`combination with an anti-arrhythmia
`
`
`therapeutic agent.
`are
`Anti-arrhythmia
`agents
`often
`
`organized main groups
`
`into according
`to
`
`mechanism of action: type I, sodium
`channel
`blockade;
`type
`type
`blockade;
`type
`III,
`repolarization
`prolongation;
`and
`moricizine, mexiletine,
`
`
`I blockade. Type anti-arrhythmic
`agents
`include
`lidocaine,
`tocainide, procainamide,
`encainide,
`flecanide,
`tocainide, phenytoin,
`Type
`quinidine, disopyramide,
`and
`flecainide.
`II
`Type
`propranolol and
`esmolol.
`III
`includes agents that act by prolonging
`the
`of the action potential, such
`amiodarone,
`as
`artilide, bretylium,
`sotalol, azimilide,
`dofetilide,
`dronedarone,
`ersentilide,
`trecetilide. Type
`IV
`anti-
`arrhythmic
`agents
`verapamil, diltiazem,
`adenosine, nickel
`chloride,
`and
`magnesium
`ions.
`In another embodiment,
`a
`polymer-agent
`conjugate,
`may be administered
`
`of as part a combination
`
`therapeutic
`another cardiovascular
`
`with
`agent. Examples
`of
`
`cardiovascular include vasodilators, agents
`
`example,
`for
`hydralazine;
`angiotensin converting
`
`enzyme inhibitors,
`for
`
`example, captopril; anti­
`anginal agents,
`for
`example,
`isosorbide
`nitrate,
`quinidine,
`tetranitrate; antiarrhythmic
`agents,
`for example,
`and
`lignocaine; cardioglycosides,
`for
`example, digoxin
`and related
`for example,
`verapamil
`and
`nifedipine;
`diuretics,
`compounds,
`for
`example, bendrofluazide,
`chlorothiazide,
`hydrochlorothiazide
`and
`other
`
`diuretics, fursemide and for
`
`sedatives,
`for
`example,
`nitrazepam,
`flurazepam
`
`an
`
`1005052.1
`
`358
`
`particle
`
`of
`an
`
`cardioplegic
`solution,
`
`
`
`four their
`
`II,
`
`beta-adrenergic
`
`anti-arrhythmic
`duration
`clofilium,
`ibutilide,
`include
`digitalis,
`
`particle
`
`glyceryl
`
`procainaltide
`digitoxin;
`as
`
`such
`chlorothalidone,
`
`
`example, triamterene, and
`and
`
`diazepam.
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`include,
`or
`
`for
`
`aspirin,
`
`indomethacin,
`
`example,
`
`fibrinogen
`
`trichloromethiazide,
`acid
`and
`inhibitors
`
`such
`
`such
`
`prourokinase,
`
`or
`
`such
`such
`
`Such
`
`approved
`
`for
`
`ebumamonine,
`naphlole, nikamate,
`
`or
`
`the
`
`Other exemplary
`agents
`cardiovascular
`aspirin
`as
`such
`cyclooxygenase
`inhibitor
`or
`ticlopidene
`inhibitor such
`as
`clopidogrel,
`hydrochlorothiazide, flumethiazide,
`diuretic such
`as
`chlorothiazide,
`hydroflumethiazide,
`bendroflumethiazide,
`methylchlorthiazide,
`ethacrynic
`polythiazide or
`benzthiazide
`as
`well
`as
`amiloride
`furosemide, musolimine,
`bumetanide,
`triamterene,
`salts of such compounds,
`enzyme
`angiotensin
`converting
`quinapril,
`
`zofenopril,
`fosinopril,
`enalapril,
`
`ceranopril, delapril, pentopril, cilazopril,
`
`antagonists as
`ramipril,
`lisinopril,
`and
`
`salts such compounds, of
`
`angiotensin
`II
`
`losartan,
`irbesartan
`or
`valsartan,
`
`thrombolytic tissue plasminogen agents
`activator (tPA),
`recombinant
`tPA,
`streptokinase,
`urokinase,
`complex,
`anisoylated plasminogen streptokinase
`activator
`agents
`plasminogen
`activators,
`calcium channel
`blocking
`antagonists
`nifedipine or
`diltiazem,
`thromboxane
`receptor
`ifetroban,
`prostacyclin mimetics,
`inhibitors.
`phosphodiesterase
`
`this invention within the dose
`formulated as a
`fixed
`dose
`employ
`the
`compounds
`range described
`above
`and
`
`other ally active agent within pharmaceutic
`
`its
`dose range.
`agents example, vasodilators, include,
`
`cardiovascular
`
`Yet other exemplary
`citicoline, cyclandelate,
`cyclonicate,
`e.g., bencyclane,
`cinnarizine,
`phenoxezyl,
`fiunarizine,
`ibudilast,
`ifenprodil,
`lomerizine,
`nosergoline, nimodipine,
`papaverine,
`pentifylline,
`nofedoline, vincamin,
`vinpocetine,
`vichizyl, pentoxifylline,
`prostacyclin
`derivatives
`(such
`prostaglandin 12),
`an
`endothelin
`receptor
`blocking
`cerebral
`nicorandil, and
`nitroglycerin. Examples
`of
`protecting drugs
`include
`scavengers
`(such
`as
`edaravone,
`vitamin
`E,
`AMPA antagonists,
`kainate
`antagonists,
`NMDA
`factors, opioid
`antagonists, phosphatidylcholine
`precursors,
`Na+/Ca2+ channel
`inhibitory
`drugs,
`and channel opening K+
`
`drugs.
`metabolic stimulants
`include
`amantadine,
`tiapride,
`
`as
`drug
`
`radical
`
`and
`antagonists,
`serotonin
`Examples
`of
`and
`
`vitamin
`
`brain
`gamma-aminobutyric acid.
`
`
`
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`
`
`
`(such heparin
`
`heparin
`
`ticlopidine
`
`a
`
`warfarin,
`
`sarpogrelate
`anti-inflammatory
`
`tissue-type
`and
`
`Examples of anticoagulants
`heparins as heparin sodium,
`
`include
`dalteparin
`calcium,
`potassium, dalteparin
`sodium,
`danaparoid
`sodium),
`and
`sodium, reviparin
`sodium,
`Examples
`of
`citrate.
`batroxobin, and
`sodium
`antiplatelet drugs
`include
`ethyl
`icosapentate,
`hydrochloride,
`dipyridamole, cilostazol,
`trapidil,
`nonsteroidal
`hydrochloride, dilazep hydrochloride,
`iloprost,
`indobufene.
`and
`(such as aspirin),
`beraprostsodium,
`include
`
`urokinase, plasminogen
`drugs
`Examples of
`thrombolytic
`nateplase, pamiteplase,
`monteplase,
`activators
`(such
`
`as alteplase,
`tisokinase,
`rateplase), and
`nasaruplase.
`
`Examples antihypertensive of
`
`drugs
`include
`angiotensin
`converting enzyme
`inhibitors
`(such
`as
`captopril,
`alacepril,
`quinapril,
`temocapril,
`delapril,
`benazepril,
`cilazapril,
`trandolapril,
`ceronapril,
`fosinopril,
`imadapril,
`mobertpril,
`perindopril,
`ramipril,
`randolapril),
`angiotensin
`II
`antagonists
`as
`losartan,
`drugs
`eprosartan, and
`irbesartan),
`calcium channel
`manidipine,
`efonidipine, nicardipine,
`bamidipine,
`benidipine,
`amlodipine,
`nitrendipine, nifedipine,
`nilvadipine,
`felodipine,
`prenylamine,
`clentiazem, phendilin,
`galopamil,
`mibefradil,
`lacidipine,
`verapamil, cilnidipine,
`elgodipine,
`isradipine,
`bencyclane,
`cinnarizine,
`flunarizine,
`lidoflazine,
`lomerizine,
`perhexiline), P-adrenaline
`(propranolol,
`receptor
`blocking
`drugs
`carteolol, bunitrolol,
`atenolol,
`acebutolol,
`metoprolol,
`nadolol,
`tilisolol,
`carvedilol,
`bisoprolol,
`betaxolol,
`labetalol, alprenolol,
`amosulalol,
`arotinolol,
`befunolol,
`buferalol, buprandolol,
`butylidine,
`butofilolol,
`carazolol,
`dilevalol, epanolol,
`levobunolol,
`mepindolol,
`metipranolol,
`sufinalol,
`nevibolol, oxprenolol,
`practol,
`pronetalol,
`sotalol,
`blocking
`toliprolol, xybenolol,
`and
`esmolol),
`a-receptor
`as amosulalol,
`prazosin,
`terazosin,
`doxazosin, bunazosin, urapidil,
`phentolamine,
`dapiprazole,
`fenspiride,
`
`indoramin, labetalol, naftopidil,
`nicergoline,
`tamsulosin,
`tolazoline,
`trimazosin,
`and
`yohimbine),
`sympathetic nerve inhibitors
`
`(such
`as
`
`(such
`blocking
`
`cilnidipine,
`diltiazem,
`semotiadil,
`lercanidipine,
`etafenone,
`pindolol,
`
`timolol,
`celiprolol,
`bucumolol,
`cetamolol,
`moprolol,
`
`drugs
`arotinolol,
`
`1005052.1
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`
`and
`
`reserpine),
`
`(such
`
`blocking
`atenolol,
`tilisolol, carvedilol,
`alprenolol,
`buprandolol,
`epanolol,
`oxprenolol,
`andxybenolol),
`
`aspirin.
`
`clonidine, guanfacine, guanabenz,
`methyldopa,
`cadralazine.
`todralazine, budralazine,
`and
`nitrate drugs as amyl nitrite,
`
`drugs
`include
`Examples of antianginal
`receptor
`as
`P-adrenaline
`nitroglycerin,
`and
`isosorbide),
`bunitrolol,
`carteolol,
`propranolol, pindolol,
`indenolol,
`nadolol,
`penbutolol,
`metoprolol,
`timolol,
`nipradilol,
`labetalol,
`bevantolol,
`betaxolol, celiprolol,
`bopindolol,
`buferalol,
`bufetolol,
`arotinolol, befunolol,
`bucumolol,
`dilevalol,
`cloranolol,
`butofilolol, carazolol,
`cetamolol,
`nevibolol,
`nadoxolol,
`mepindolol, metipranolol,
`moprolol,
`toliprolol,
`pronetalol,
`sotalol,
`sufinalol,
`talindolol,
`tertalol,
`efonidipine,
`channel blocking
`drugs
`(such
`as
`aranidipine,
`bamidipine,
`benidipine, manidipine,
`nifedipine,
`nitrendipine,
`cilnidipine,
`nisoldipine,
`phendiline,
`clentiazem,
`felodipine, amlodipine,
`diltiazem,
`bepridil,
`cilnidipine,
`verapamil,
`mibefradil, prenylamine,
`semotiadil,
`terodiline,
`flunarizine,
`cinnarizine,
`isradipine, lacidipine,
`lercanidipine,
`nimodipine,
`trimetazidine,
`perhexiline)
`lomerizine, bencyclane,
`etafenone,
`and
`and
`enoxaparin,
`etafenone, dilazep,
`trapidil,
`nicorandil,
`(such
`thiazide
`diuretics as hydrochlorothiazide,
`
`Examples of diuretics
`include
`and
`benzylhydrochlorothiazide,
`methyclothiazide,
`trichlormethiazide,
`acid, bumetanide,
`etacrynic
`loop diuretics
`(such
`as
`furosemide,
`and torasemide), K+ sparing diuretics
`(spironolactone,
`triamterene,
`andpotassiumcanrenoate),
`osmotic
`diuretics
`(such
`glycerin), nonthiazide
`diuretics
`(such
`meticrane,
`cardiotonics
`digitalis
`mefruside), and
`acetazolamide.
`Examples
`formulations
`(such
`as
`digitoxin,
`digoxin,
`methyldigoxin,
`lanatoside C,
`and
`proscillaridin),
`xanthine formulations
`(such
`choline
`theophylline,
`diprophylline,
`and
`proxyphylline),
`(such as dopamine,
`dobutamine,
`and
`docarpamine),
`amrinone, olprinone,
`and milrinone),
`denopamine,
`levosimendan,
`aminoethylsulfonic
`vesnarinone,
`
`as
`include
`of
`
`as
`
`isosorbide,
`tripamide,
`
`deslanoside,
`as
`catecholamine
`
`PDE
`ubidecarenone,
`carperitide,
`
`1005052.1
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`
`acid,
`
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`
`include
`
`ajmaline,
`
`aprindine,
`acebutolol,
`
`daropate. Examples
`drugs
`antiarrhythmic
`of
`quinidine,
`disopyramide,
`procainamide,
`cibenzoline,
`flecainide, atenolol,
`propafenone,
`phenyloin, pilsicainide,
`amiodarone,
`pindolol,
`propranolol, metoprolol,
`antihyperlipidemic
`of
`verapamil. Examples
`fluvastatin
`sodium,
`pravastatin sodium,
`bezafibrate, colestimide,
`and
`colestyramine.
`
`Yet other exemplary
`cardiovascular
`agents example, anti-include,
`angiogenic agents
`and
`vascular
`disrupting agents.
`
`
`nifekalant,
`include
`clofibrate,
`
`drugs
`clinofibrate,
`
`
`
`diltiazem,
`atorvastatin,
`
`for
`
`and
`disease
`
`composition
`
`particle
`response
`
`Inflammation and Autoimmune
`Disease
`compositions
`particles,
`conjugates,
`The polymer-agent
`
`or disorder associated prevent
`a
`with
`
`treat
`herein may be
`used
`to
`or
`conjugate,
`particle
`inflammation. A
`polymer-agent
`to
`may be administered
`prior
`inflammation.
`of
`the onset of,
`
`at, or after the
`initiation
`conjugate,
`When used prophylactically,
`the
`polymer-agent
`inflammatory
`preferably provided
`in
`advance
`of
`any
`or
`of the polymer-agent
`conjugate,
`particle
`Administration
`symptoms.
`or
`or attenuate
`inflammatory
`responses
`sclerosis,
`multiple
`conditions
`include,
`for
`example,
`arthritis, degenerative
`joint
`disease, spondouloarthropathies,
`lupus erythematosus,
`juvenile
`arthritis,
`rheumatoid
`osteoporosis, diabetes
`(e.g.,
`insulin
`dependent
`diabetes), menstrual
`cramps,
`cystic
`fibrosis,
`bowel syndrome, Crohn's
`disease,
`mucous
`esophagitis, pancreatitis,
`peritonitis,
`Alzheimer's
`spondylitis, gastritis,
`conjunctivitis,
`pancreatis
`injury syndrome
`(e.g.,
`secondary
`to
`septicemia
`atherosclerosis, stroke,
`reperfusion
`injury
`(e.g.,
`kidney dialysis),
`acute
`glomerulonephritis,
`vasculitis,
`necrotizing enterocolitis,
`granulocyte
`transfusion
`
`composition
`Exemplary
`rheumatoid
`
`gouty
`arthritis,
`diabetes
`inflammatory
`colitis,
`disease,
`(acute
`
`or
`
`ulcerative
`shock,
`
`mellitus
`bowel
`
`trauma),
`
`to
`
`syndrome,
`
`1005052.1
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`
`or
`
`due
`
`thermal
`
`associated
`
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`
`conditions
`dermatitis,
`
`of
`
`urticaria,
`
`particle,
`treat
`
`conjugate,
`to
`fibrosis,
`respiratory
`conjugate,
`treat
`
`allergic
`
`chronic
`
`Sjogren's syndrome.
`inflammatory
`Exemplary
`atopic
`dermatitis,
`contact
`example, eczema,
`psoriasis, and
`dermatosis
`with
`acute inflammatory
`components.
`In another embodiment,
`a
`polymer-agent
`method described
`herein
`may
`be
`used
`conditions,
`including
`asthma, bronchitis,
`pulmonary
`toxicity, emphysema,
`chronic
`bronchitis,
`acute
`chronic obstructive
`pulmonary
`disease (COPD).
`The
`polymer-agent
`particle or
`composition
`may
`be
`used
`to
`hepatitis B and
`hepatitis
`C.
`particle,
`conjugate,
`Additionally,
`a
`polymer-agent
`composition
`to
`treat and/or inflammation autoimmune
`described herein may
`be
`used
`
`
`
`associated with
`autoimmune
`
`
`diseases as organ-tissue such autoimmune
`diseases
`Raynaud's syndrome),
`scleroderma, myasthenia
`gravis,
`transplant
`shock, sepsis, psoriasis,
`eczema,
`dermatitis,
`Addison's
`thyroiditis, uveitis,
`systemic
`lupus
`erythematosis,
`polyglandular disease
`(also
`known
`as
`autoimmune
`Grave's disease.
`therapy
`Combination
`polymer-agent
`In certain embodiments,
`alone
`administered
`described herein may
`be
`useful for
`treating
`or
`preventing
`inflammation.
`(e.g.,
`include, for
`example,
`steroids
`Cortisol,
`fludrocortisone,
`6[alpha]-methylprednisone,
`triamcinolone,
`betamethasone
`nonsteroidal anti-inflammatory
`drugs
`(NSAIDS
`(e.g.,
`acid,
`tolmetin,
`ibuprofen,
`mefenamic
`piroxicam,
`another
`etodolac or
`nimesulide).
`In
`embodiment,
`penicillin,
`antibiotic
`(e.g.,
`vancomycin,
`amoxicillin,
`ampicillin, cefotaxime,
`ceftriaxone,
`cefixime,
`rifampinmetronidazole, doxycycline
`or
`another embodiment,
`the
`other
`therapeutic
`agent
`or rolipram).
`In
`another
`embodiment,
`the
`other
`
`(e.g.,
`
`multiple
`
`sclerosis,
`
`a
`
`conjugate,
`
`or
`Exemplary
`cortisone,
`prednisone,
`or
`
`disease,
`polyglandular
`
`particle
`in
`
`dexamethasone),
`
`aspirin,
`nabumetone,
`the
`
`other
`
`streptomycin).
`
`is
`therapeutic
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`diphenhydramine).
`an
`
`anti-malarial
`hydrochloride,
`
`or
`
`alfa.
`
`for
`acetaminosalol,
`
`(e.g., cyclizine,
`or
`promethazine
`hydroxyzine,
`agent (e.g., artemisinin, is
`therapeutic
`
`other
`embodiment,
`the
`
`artemether, artsunate,
`chloroquine
`phosphate,
`mefloquine
`hyclate, proguanil
`hydrochloride,
`atovaquone
`halofantrine).
`the other
`therapeutic
`agent
`drotrecogin
`is
`include,
`agents
`Further examples
`of
`anti-inflammatory
`acetaminophen,
`aceclofenac,
`acemetacin,
`e-acetamidocaproic acid,
`acetanilide, acetylsalicylic
`acid,
`S-adenosylmethionine,
`alclofenac,
`alfentanil, algestone, allylprodine,
`alminoprofen,
`aloxiprin,
`alphaprodine,
`bis(acetylsalicylate),
`amcinonide,
`amfenac,
`aminochlorthenoxazin,
`3-amino-4-
`hydroxybutyric acid,
`2-amino-4-picoline,
`aminopropylon,
`aminopyrine,
`ammonium
`salicylate,
`ampiroxicam,
`amtolmetin
`anileridine,
`guacil,
`antrafenine, apazone,
`beclomethasone,
`bendazac,
`benorylate, benoxaprofen,
`benzpiperylon,
`benzydamine, benzylmorphine,
`bermoprofen,
`betamethasone,
`betamethasone-
`17-valerate,
`bezitramide,
`[alpha]-bisabolol,
`bromfenac,
`bromoacetanilide,
`5-bromosalicylic
`acid
`acetate,
`bromosaligenin,
`acid, bucolome,
`budesonide,
`bufexamac, bumadizon,
`buprenorphine,
`butibufen, butorphanol,
`carbamazepine, carbiphene,
`caiprofen,
`chlorobutanol,
`chloroprednisone,
`chlorthenoxazin,
`choline
`cinmetacin, ciramadol,
`clidanac,
`
`clobetasol, clometacin, clonitazene, clocortolone,
`
`clonixin, clopirac, cloprednol, clove,
`codeine,
`
`codeine bromide, codeine
`phosphate, codeine
`sulfate,
`cortisone,
`cortivazol,
`cyclazocine.
`include
`agents
`anti-inflammatory
`of
`Further examples
`desoximetasone, dexamethasone,
`
`dehydrotestosterone,
`desomorphine,
`desonide,
`dexamethasone-21-
`dextromoramide,
`isonicotinate,
`dexoxadrol,
`deoxycorticosterone,
`dezocine,
`diampromide, diamorphone,
`diclofenac,
`difenpiramide,
`diflorasone,
`diflucortolone,
`diflunisal,
`difluprednate,
`dihydrocodeine,
`dihydrocodeinone
`enol
`acetate,
`dihydromorphine,
`dihydroxyaluminum
`acetylsalicylate,
`dimenoxadol,
`dimepheptanol,
`
`dimethylthiambutene, dioxaphetyl
`butyrate, dipipanone,
`diprocetyl,
`
`dipyrone, droxicam, emorfazone, ditazol,
`
`enfenamic
`
`butacetin,
`
`carsalam,
`salicylate,
`
`methyl
`cropropamide,
`
`deflazacort,
`
`dextropropoxyphene,
`
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`acid, enoxolone,
`ethoheptazine,
`eptazocine, etersalate, ethenzamide,
`
`epirizole,
`ethoxazene,
`ethylmethylthiambutene,
`
`ethylmorphine, etodolac, etofenamate,
`eugenol,
`felbinac,
`
`fenbufen, fenclozic acid,
`fendosal,
`fenoprofen,
`etonitazene,
`fentanyl,
`fentiazac,
`fepradinol,
`feprazone,
`floctafenine, fluazacort, flucloronide,
`
`flufenamic acid,
`flumethasone,
`flunisolide, flunixin,
`flunoxaprofen,
`acetonide,
`fluocinonide,
`fluocinolone
`acetonide, fluocortin
`butyl,
`fluoresone,
`fluorometholone,
`fluperolone,
`flupirtine,
`fluprednidene,
`fluprednisolone,
`fluproquazone,
`flurandrenolide,
`flurbiprofen,
`fluticasone,
`formocortal
`gentisic
`include
`Further examples
`of
`anti-inflammatory
`agents
`halobetasol,
`glucametacin,
`glycol
`salicylate,
`guaiazulene,
`halcinonide,
`hydrocortisone,
`haloprednone,
`heroin,
`hydrocodone,
`hydro
`cortamate,
`hydrocortisone
`acetate, hydrocortisone
`succinate,
`hydrocortisone
`hemisuccinate,
`lysinate, hydrocortisone
`cypionate,
`hydromorphone,
`hydroxypethidine, ibufenac,
`ibuprofen,
`ibuproxam,
`imidazole
`salicylate,
`indomethacin,
`indoprofen,
`isoflupredone,
`isoflupredone
`acetate,
`isoladol,
`isomethadone,
`isonixin,
`isoxicam, ketobemidone,
`ketoprofen,
`ketorolac,
`p-
`lactophenetide,
`levallorphan,
`levorphanol,
`levophenac