U.S. patent application number 14/862923 was filed with the patent office on 2016-02-18 for systems and methods to image intercellular and intercompartmental defects with magnetic resonance imaging (mri).
The applicant listed for this patent is LIPELLA PHARMACEUTICALS, INC.. Invention is credited to Ari GOLDBERG, Jonathan KAUFMAN.
Application Number | 20160045623 14/862923 |
Document ID | / |
Family ID | 55301337 |
Filed Date | 2016-02-18 |
United States Patent
Application |
20160045623 |
Kind Code |
A1 |
KAUFMAN; Jonathan ; et
al. |
February 18, 2016 |
Systems and Methods to Image Intercellular and Intercompartmental
Defects with Magnetic Resonance Imaging (MRI)
Abstract
The invention provides systems and methods for providing a
diagnostic examination to a patient, including, but not limited to
a determination of the permeability of a patients' body cavity.
Inventors: |
KAUFMAN; Jonathan;
(Pittsburgh, PA) ; GOLDBERG; Ari; (Chicago,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LIPELLA PHARMACEUTICALS, INC. |
PITTSBURGH |
PA |
US |
|
|
Family ID: |
55301337 |
Appl. No.: |
14/862923 |
Filed: |
September 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2015/024309 |
Apr 3, 2015 |
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14862923 |
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14678638 |
Apr 3, 2015 |
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PCT/US2015/024309 |
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61974964 |
Apr 3, 2014 |
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62062339 |
Oct 10, 2014 |
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61974964 |
Apr 3, 2014 |
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62062339 |
Oct 10, 2014 |
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Current U.S.
Class: |
424/9.32 ;
424/9.364; 424/9.365 |
Current CPC
Class: |
A61K 49/105 20130101;
G01R 33/5601 20130101; A61K 49/103 20130101; A61B 5/0044 20130101;
A61B 5/055 20130101; A61K 49/0004 20130101; A61K 49/1827
20130101 |
International
Class: |
A61K 49/06 20060101
A61K049/06; A61K 49/10 20060101 A61K049/10; G01R 33/56 20060101
G01R033/56; A61B 5/055 20060101 A61B005/055; A61B 5/00 20060101
A61B005/00 |
Claims
1. A method for detecting patent foramen ovale in a patient
comprising: administering a T1-reducing contrast agent and a
T2-reducing contrast agent to the patient; and imaging the
patient's heart; wherein diffusion of the T2 reducing contrast
agent from the right atrium to the left atrium is indicative of
patent foramen ovale.
2. The method of claim 1, wherein the particle size of the
T2-reducing contrast agent is larger than the particle size of the
T1-reducing contrast agent
3. The method of claim 1, wherein the T1-reducing contrast agent
and the T2-reducing contrast agent are administered to the patient
as a single composition.
4. The method of claim 1, wherein the T1-reducing agent and the
T2-reducing contrast agent are administered to the patient as two
separate compositions.
5. The method of claim 1, wherein administering T1-reducing
contrast agent and the T2-reducing contrast agent are completed
simultaneously.
6. The method of claim 1, wherein imaging the patient's heart
comprises imaging via magnetic resonance imaging.
7. The method of claim 1, wherein imaging the patient's heart is
performed within about 10 minutes of administration of the
T1-reducing contrast agent and the T2-reducing contrast agent.
8. The method of claim 1, wherein the first T1-reducing contrast
agent comprises a gadolinium compound.
9. The method of claim 8, wherein the gadolinium compound is
selected from gadopentetate dimeglumine (Gd-DTPA), gadoterate
meglumine, gadoversetamide, gadoteridol, gadodiamide, gadobenate
dimeglumine, gadobutrol, gadoxetate disodium, gadofosveset
trisodium and combinations thereof.
10. The method of claim 1, wherein the T2-reducing contrast agent
comprises an iron oxide.
11. The method of claim 10, wherein the iron oxide is selected from
iron (II) oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin
XS, Feraspin S, Feraspin M, Feraspin R, Feraspin L, Feraspin XL,
iron nickel oxide nanopowder, iron oxide (II,III) magnetic
nanoparticles, iron-nickel alloy nanopowder, magnetic iron oxide
nanoparticles, carbon coated iron nanopowder, and combinations
thereof.
12. The method of claim 1, wherein administration of the
T1-reducing contrast agent and the T2-reducing contrast agent is
achieved by administration to the patient's cardiovascular
system.
13. A method for detecting patent foramen ovale in a patient
comprising: imaging the patient after administering a T1-reducing
contrast agent and a T2-reducing contrast agent to the patient;
wherein diffusion of the T2 reducing contrast agent from the right
atrium to the left atrium is indicative of patent foramen
ovale.
14. The method of claim 13, wherein the particle size of the
T2-reducing contrast agent is larger than the particle size of the
T1-reducing contrast agent.
15. The method of claim 13, wherein the T1-reducing contrast agent
and the T2-reducing contrast agent are administered to the patient
as a single composition.
16. The method of claim 13, wherein the T1-reducing contrast agent
and the T2-reducing contrast agent are administered to the patient
as two separate compositions.
17. The method of claim 13, wherein administering T1-reducing
contrast agent and the T2-reducing contrast agent are completed
simultaneously.
18. The method of claim 13, wherein imaging the patient comprises
imaging via magnetic resonance imaging.
19. The method of claim 13, wherein imaging the patient is
performed within about 10 minutes of administration of the
T1-reducing contrast agent and the T2-reducing contrast agent.
20. The method of claim 13, wherein the first T1-reducing contrast
agent comprises a gadolinium compound.
21. The method of claim 20, wherein the gadolinium compound is
selected from gadopentetate dimeglumine (Gd-DTPA), gadoterate
meglumine, gadoversetamide, gadoteridol, gadodiamide, gadobenate
dimeglumine, gadobutrol, gadoxetate disodium, gadofosveset
trisodium and combinations thereof.
22. The method of claim 13, wherein the T2-reducing contrast agent
comprises an iron oxide.
23. The method of claim 22, wherein the iron oxide is selected from
iron (II) oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin
XS, Feraspin S, Feraspin M, Feraspin R, Feraspin L, Feraspin XL,
iron nickel oxide nanopowder, iron oxide (II,III) magnetic
nanoparticles, iron-nickel alloy nanopowder, magnetic iron oxide
nanoparticles, carbon coated iron nanopowder, and combinations
thereof.
24. The method of claim 13, wherein administration of the
T1-reducing contrast agent and the T2-reducing contrast agent is
achieved by administration to the patient's cardiovascular
system.
25.-48. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of PCT
Application PCT/US2015/024309 entitled "Systems and Methods for
detecting Interstitial cystitis" filed Apr. 3, 2015, which claims
the benefit of U.S. Provisional Application Ser. No. 61/974,964
entitled "Systems and Methods of Detecting Interstitial Cystitis"
filed Apr. 3, 2014, and U.S. Provisional Application Ser. No.
62/062,339 entitled "Systems and Methods of Detecting Interstitial
Cystitis" filed Oct. 10, 2014; and a continuation-in-part of U.S.
application Ser. No. 14/678,638 entitled "Systems and Methods for
detecting Interstitial cystitis" filed Apr. 3, 2015, which claims
the benefit of U.S. Provisional Application Ser. No. 61/974,964
entitled "Systems and Methods of Detecting Interstitial Cystitis"
filed Apr. 3, 2014, and U.S. Provisional Application Ser. No.
62/062,339 entitled "Systems and Methods of Detecting Interstitial
Cystitis" filed Oct. 10, 2014, each of which are hereby
incorporated herein by reference in their entirety.
GOVERNMENT INTERESTS
[0002] Not Applicable
PARTIES TO A JOINT RESEARCH AGREEMENT
[0003] The presently claimed invention was made by or on behalf of
the below listed parties to a joint research agreement. The joint
research agreement was in effect on or before the date the claimed
invention was made and the claimed invention was made as a result
of activities undertaken within the scope of the joint research
agreement. The parties to the joint research agreement are Lipella
Pharmaceuticals Inc. and Ari Goldberg.
BRIEF SUMMARY OF THE INVENTION
[0004] Embodiments herein are directed to methods for detecting
patent foramen ovale in a patient comprising: administering a
T1-reducing contrast agent and a T2-reducing contrast agent to the
patient; and imaging the patient's heart; wherein diffusion of the
T2 reducing contrast agent from the right atrium to the left atrium
is indicative of patent foramen ovale.
[0005] In some embodiments, the particle size of the T2-reducing
contrast agent is larger than the particle size of the T1-reducing
contrast agent. In some embodiments, the T1-reducing agent, the
T2-reducing agent, or a combination thereof further comprises an
aqueous solvent. In some embodiments, the T1-reducing contrast
agent and the T2-reducing contrast agent are administered to the
patient as a single composition; wherein the single composition
comprises the T1-reducing contrast agent and the T2-reducing
contrast agent. In some embodiments, the single composition further
comprises an aqueous solvent. In some embodiments, the T1-reducing
agent and the T2-reducing contrast agent are administered to the
patient as two separate compositions; wherein a first composition
comprises the T1-reducing contrast agent; and wherein a second
composition comprises the T2-reducing contrast agent. In some
embodiments, the two separate compositions each further comprise an
aqueous solvent. In some embodiments, administering T1-reducing
contrast agent and the T2-reducing contrast agent are completed
simultaneously.
[0006] In some embodiments, imaging the patient's heart comprises
imaging via magnetic resonance imaging. In some embodiments,
imaging the patient's heart is performed within about 10 minutes of
administration of the T1-reducing contrast agent and the
T2-reducing contrast agent.
[0007] In some embodiments, the first T1-reducing contrast agent
comprises a gadolinium compound. In some embodiments, the
gadolinium compound is selected from gadopentetate dimeglumine
(Gd-DTPA), gadoterate meglumine, gadoversetamide, gadoteridol,
gadodiamide, gadobenate dimeglumine, gadobutrol, gadoxetate
disodium, gadofosveset trisodium and combinations thereof. In some
embodiments, the gadolinium compound is encapsulated in
liposomes.
[0008] In some embodiments, the T2-reducing contrast agent
comprises an iron oxide. In some embodiments, the iron oxide is
selected from iron (II) oxide, iron (III) oxide, ferumoxytol
(Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,
Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide
(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder,
magnetic iron oxide nanoparticles, carbon coated iron nanopowder,
and combinations thereof.
[0009] In some embodiments, the iron oxide is encapsulated in
liposomes. In some embodiments, administration of the T1-reducing
contrast agent and the T2-reducing contrast agent is achieved by
administration to the patient's cardiovascular system.
[0010] Some embodiments are directed to methods detecting patent
foramen ovale in a patient comprising: imaging the patient after
administering a T1-reducing contrast agent and a T2-reducing
contrast agent to the patient; wherein diffusion of the T2 reducing
contrast agent from the right atrium to the left atrium is
indicative of patent foramen ovale.
[0011] In some embodiments, the particle size of the T2-reducing
contrast agent is larger than the particle size of the T1-reducing
contrast agent. In some embodiments, the T1-reducing agent, the
T2-reducing agent, or a combination thereof further comprises an
aqueous solvent.
[0012] In some embodiments, the T1-reducing contrast agent and the
T2-reducing contrast agent are administered to the patient as a
single composition. In some embodiments, the single composition
further comprises an aqueous solvent. In some embodiments, the
T1-reducing contrast agent and the T2-reducing contrast agent are
administered to the patient as two separate compositions; wherein a
first composition comprises the T1-reducing contrast agent and a
second composition comprises the T2-reducing agent. In some
embodiments, the two separate compositions each further comprise an
aqueous solvent. In some embodiments, administering T1-reducing
contrast agent and the T2-reducing contrast agent are completed
simultaneously. In some embodiments, imaging the patient comprises
imaging via magnetic resonance imaging. In some embodiments,
imaging the patient is performed within about 10 minutes of
administration of the T1-reducing contrast agent and the
T2-reducing contrast agent.
[0013] In some embodiments, the first T1-reducing contrast agent
comprises a gadolinium compound. In some embodiments, the
gadolinium compound is selected from gadopentetate dimeglumine
(Gd-DTPA), gadoterate meglumine, gadoversetamide, gadoteridol,
gadodiamide, gadobenate dimeglumine, gadobutrol, gadoxetate
disodium, gadofosveset trisodium and combinations thereof. In some
embodiments, the gadolinium compound is encapsulated in
liposomes.
[0014] In some embodiments, the T2-reducing contrast agent
comprises an iron oxide. In some embodiments, the iron oxide is
selected from iron (II) oxide, iron (III) oxide, ferumoxytol
(Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,
Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide
(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder,
magnetic iron oxide nanoparticles, carbon coated iron nanopowder,
and combinations thereof. In some embodiments, the iron oxide is
encapsulated in liposomes.
[0015] In some embodiments, administration of the T1-reducing
contrast agent and the T2-reducing contrast agent is achieved by
administration to the patient's cardiovascular system.
[0016] Some embodiments are directed to methods for detecting
ischemic endocardium in a patient comprising: administering a
T1-reducing contrast agent and a T2-reducing contrast agent to the
patient; and imaging the patient's heart; wherein diffusion of the
T1 reducing contrast agent across the endocardium is indicative of
ischemic endocardium.
[0017] In some embodiments, the particle size of the T2-reducing
contrast agent is larger than the particle size of the T1-reducing
contrast agent. In some embodiments, the T1-reducing agent, the
T2-reducing agent, or a combination thereof further comprises an
aqueous solvent. In some embodiments, the T1-reducing contrast
agent and the T2-reducing contrast agent are administered to the
patient as a single composition; wherein the single composition
comprises the T1-reducing contrast agent and the T2-reducing
contrast agent. In some embodiments, the single composition further
comprises an aqueous solvent. In some embodiments, the T1-reducing
agent and the T2-reducing contrast agent are administered to the
patient as two separate compositions; wherein a first composition
comprises the T1-reducing contrast agent; and wherein a second
composition comprises the T2-reducing contrast agent. In some
embodiments, the two separate compositions each further comprise an
aqueous solvent. In some embodiments, administering T1-reducing
contrast agent and the T2-reducing contrast agent are completed
simultaneously.
[0018] In some embodiments, imaging the patient's heart comprises
imaging via magnetic resonance imaging. In some embodiments,
imaging the patient's heart is performed within about 10 minutes of
administration of the T1-reducing contrast agent and the
T2-reducing contrast agent.
[0019] In some embodiments, the first T1-reducing contrast agent
comprises a gadolinium compound. In some embodiments, the
gadolinium compound is selected from gadopentetate dimeglumine
(Gd-DTPA), gadoterate meglumine, gadoversetamide, gadoteridol,
gadodiamide, gadobenate dimeglumine, gadobutrol, gadoxetate
disodium, gadofosveset trisodium and combinations thereof. In some
embodiments, the gadolinium compound is encapsulated in
liposomes.
[0020] In some embodiments, the T2-reducing contrast agent
comprises an iron oxide. In some embodiments, the iron oxide is
selected from iron (II) oxide, iron (III) oxide, ferumoxytol
(Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,
Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide
(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder,
magnetic iron oxide nanoparticles, carbon coated iron nanopowder,
and combinations thereof. In some embodiments, the iron oxide is
encapsulated in liposomes.
[0021] In some embodiments, administration of the T1-reducing
contrast agent and the T2-reducing contrast agent is achieved by
administration to the patient's cardiovascular system.
[0022] Some embodiments are directed to methods for detecting
ischemic endocardium in a patient comprising: imaging the patient
after administering a T1-reducing contrast agent and a T2-reducing
contrast agent to the patient; wherein diffusion of the T1 reducing
contrast agent across the endocardium is indicative of ischemic
endocardium.
[0023] In some embodiments, the particle size of the T2-reducing
contrast agent is larger than the particle size of the T1-reducing
contrast agent. In some embodiments, the T1-reducing agent, the
T2-reducing agent, or a combination thereof further comprises an
aqueous solvent. In some embodiments, the T1-reducing contrast
agent and the T2-reducing contrast agent are administered to the
patient as a single composition. In some embodiments, the single
composition further comprises an aqueous solvent. In some
embodiments, the T1-reducing contrast agent and the T2-reducing
contrast agent are administered to the patient as two separate
compositions; wherein a first composition comprises the T1-reducing
contrast agent and a second composition comprises the T2-reducing
agent. In some embodiments, the two separate compositions each
further comprise an aqueous solvent. In some embodiments,
administering T1-reducing contrast agent and the T2-reducing
contrast agent are completed simultaneously.
[0024] In some embodiments, imaging the patient comprises imaging
via magnetic resonance imaging. In some embodiments, imaging the
patient is performed within about 10 minutes of administration of
the T1-reducing contrast agent and the T2-reducing contrast
agent.
[0025] In some embodiments, the first T1-reducing contrast agent
comprises a gadolinium compound. In some embodiments, the
gadolinium compound is selected from gadopentetate dimeglumine
(Gd-DTPA), gadoterate meglumine, gadoversetamide, gadoteridol,
gadodiamide, gadobenate dimeglumine, gadobutrol, gadoxetate
disodium, gadofosveset trisodium and combinations thereof. In some
embodiments, the gadolinium compound is encapsulated in
liposomes.
[0026] In some embodiments, the T2-reducing contrast agent
comprises an iron oxide. In some embodiments, the iron oxide is
selected from iron (II) oxide, iron (III) oxide, ferumoxytol
(Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,
Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide
(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder,
magnetic iron oxide nanoparticles, carbon coated iron nanopowder,
and combinations thereof. In some embodiments, the iron oxide is
encapsulated in liposomes.
[0027] In some embodiments, administration of the T1-reducing
contrast agent and the T2-reducing contrast agent is achieved by
administration to the patient's cardiovascular system.
BRIEF DESCRIPTION OF THE FIGURES
[0028] Not Applicable
DETAILED DESCRIPTION
[0029] Before the present compositions and methods are described,
it is to be understood that this invention is not limited to the
particular processes, compositions, or methodologies described, as
these may vary. It is also to be understood that the terminology
used in the description is for the purpose of describing the
particular versions or embodiments only, and is not intended to
limit the scope of the present invention which will be limited only
by the appended claims. Unless defined otherwise, all technical and
scientific terms used herein have the same meanings as commonly
understood by one of ordinary skill in the art. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of embodiments of the
present invention, the preferred methods, devices, and materials
are now described. All publications mentioned herein are
incorporated by reference in their entirety. Nothing herein is to
be construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention.
[0030] Optical Isomers, Diastereomers, Geometric Isomers, and
Tautomers. Compounds described herein may contain an asymmetric
center and may thus exist as enantiomers. Where the compounds
according to the invention possess two or more asymmetric centers,
they may additionally exist as diastereomers. The present invention
includes all such possible stereoisomers as substantially pure
resolved enantiomers, racemic mixtures thereof, as well as mixtures
of diastereomers. The formulas are shown without a definitive
stereochemistry at certain positions. The present invention
includes all stereoisomers of such formulas and pharmaceutically
acceptable salts thereof. Diastereoisomeric pairs of enantiomers
may be separated by, for example, fractional crystallization from a
suitable solvent, and the pair of enantiomers thus obtained may be
separated into individual stereoisomers by conventional means, for
example by the use of an optically active acid or base as a
resolving agent or on a chiral HPLC column. Further, any enantiomer
or diastereomer of a compound of the general formula may be
obtained by stereospecific synthesis using optically pure starting
materials or reagents of known configuration.
[0031] It must also be noted that as used herein and in the
appended claims, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "fibroblast" is a reference to
one or more fibroblasts and equivalents thereof known to those
skilled in the art, and so forth.
[0032] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
Therefore, about 50% means in the range of 45%-55%.
[0033] "Administering" when used in conjunction with the imaging
compositions containing the T1-reducing contrast agents,
T2-reducing contrast agents, or combinations thereof, described
herein means to administer the agent, agents or compositions
directly into, or onto a target body cavity or to administer the
agent, agents or compositions to a patient whereby the agent or
agents impacts the body cavity to which it is targeted. Thus, as
used herein, the term "administering", when used in conjunction
with any agent, agents, or compositions described herein, can
include, but is not limited to, providing an agent, agents, or
compositions into or onto the target body cavity; providing an
agent, agents, or composition systemically to a patient by, e.g.,
intravenous injection whereby the agent or agents reaches the
target tissue; administering the agent, agents or compositions
described herein to the lumen of a body cavity. "Administering" a
composition may be accomplished by injection, instillation,
catheterization, or by either method in combination with other
known techniques. "Administering" agent, agents or compositions
described herein to the lumen of a body cavity can also be achieved
through a natural opening to the body cavity. For example, the
agent, agents or compositions described herein can be administered
to the lumen of a blood vessel via intravenous injection. In yet
another example the agent, agents or compositions described herein
can be administered to the lumen of the gastrointestinal tract via
oral administration.
[0034] The term "animal" as used herein includes, but is not
limited to, humans and non-human vertebrates such as wild, domestic
and farm animals.
[0035] By "pharmaceutically acceptable", it is meant the carrier,
diluent or excipient must be compatible with the other ingredients
of the formulation and not deleterious to the recipient
thereof.
[0036] The term "liposome" generally refers to spherical or roughly
spherical particles containing an internal cavity. The walls of
liposomes can include a bilayer of lipids. These lipids can be
phospholipids. Numerous lipids and/or phospholipids may be used to
make liposomes. One example are amphipathic lipids having
hydrophobic and polar head group moieties which may form
spontaneously into bilayer vesicles in water, as exemplified by
phospholipids, or which may be stably incorporated into lipid
bilayers, with their hydrophobic moiety in contact with the
interior, hydrophobic region of the bilayer membrane, and their
polar head group moiety oriented toward the exterior, polar surface
of the membrane.
[0037] The term "body cavity" refers to any fluid filled space in a
multicellular organism including but not limited the cardiovascular
system, the heart, blood vessels, lymph vessels, coelom,
pericardial cavity, pericardium, intraembryonic coelom,
extraembryonic coelom, chorionic cavity, dorsal cavity, ventral
cavity, thoracic cavity, abdominopelvic cavity, cranial cavity,
spinal cavity (or vertebral cavity), a pleural cavity, superior
mediastinum, thoracic cavity, abdominal cavity, pelvic cavity.
abdominopelvic cavity, urinary bladder, kidneys, ureters,
gastrointestinal tract, stomach, intestines, liver, gallbladder,
pancreas, anus, reproductive system or any combination thereof. In
some embodiments, the body cavity is naturally fluid filled. In
some embodiments, the body cavity is artificially fluid filled.
[0038] The term "cardiovascular system" refers to a closed organ
system made up of the heart and blood vessels (including arteries,
veins and capillaries, coronary vessels, portal veins) of a
vertebrate organism such as a mammal, and more preferably a
human.
[0039] The term "gastrointestinal tract" refers to a an organ
system made up of the stomach and intestines (including the small
and large intestines, appendix) of a vertebrate organism such as a
mammal, and more preferably a human. The gastrointestinal tract may
also include all structures between the mouth and the anus
(including the esophagus, stomach, small and large intestines,
appendix, and rectum) of a vertebrate organism such as a mammal,
and more preferably a human.
[0040] As used herein, the term "lumen" refers to the interior
space of a body cavity. In some embodiment, the lumen of a body
cavity is enclosed by a luminal wall, the porosity of which can be
measured using the methods and compositions described herein.
[0041] As used herein, the term "contrast agent" refers to a
compound or molecule that can be used in the imaging of body cavity
and which affects and/or enhances the contrast of structures and/or
fluids in the body. In some embodiments, the term "contrast agent"
refers to a paramagnetic and/or superparamagnetic compound or
molecule that can be used in the imaging of body cavity. In some
embodiments, a particular contrast agent may have a T1-reducing
contrast effect (spin-spin relaxation), a T2-contrast reducing
effect (spin-lattice relaxation) or a combination thereof. As used
herein, one or more contrast agents may be incorporated into a
composition which may then be administered to a patient to image a
body cavity.
[0042] The present disclosure generally relates to systems and
methods for providing a diagnostic examination to a patient,
including, but not limited to a determination of the permeability
of a patients' body cavity. In some embodiments, such diagnostic
examination may generally include measurement of patency and/or
porosity of the body cavity by observing the diffusion of a
non-invasively detectable molecular agent across the luminal
surface of the body cavity. In some embodiments, such diagnostic
examination may generally include measurement of permeability,
patency and/or porosity of the body cavity by observing the
diffusion of a non-invasively detectable molecular agent out the
lumen of the body cavity. In some embodiments, the systems and
methods described herein may be used for determining altered
permeability of the lining of other body cavities, such as, for
example, cardiovascular system, blood vessels, the heart, the
vagina, gut, sinus and oral cavities or a combination thereof. Some
embodiments are directed to a method for measuring the permeability
of a body cavity in a patient.
[0043] In some embodiments, present disclosure generally relates to
systems and methods for providing a diagnostic examination to a
patient, including, but not limited to detection of patent foramen
ovale (PFO). In some embodiments, such diagnostic examination may
generally include measurement of patency and/or porosity of the
body cavity by observing the diffusion of a non-invasively
detectable molecular agent across the luminal surface of the body
cavity. In some embodiments, such diagnostic examination may
generally include measurement of patency and/or porosity of the
body cavity by observing the diffusion of a non-invasively
detectable molecular agent out the lumen of the body cavity. In
some embodiments, the systems and methods described herein may also
be used for determining altered permeability of the lining of other
body cavities, such as, for example, the vagina, gut, sinus and
oral cavities. Some embodiments are directed to a diagnostic
examination of a patient's heart. In particular embodiments, such
diagnostic examination may generally include detection of PFO,
ischemic endocardium or a combination thereof. In some embodiments,
the systems and methods described herein may be used for diagnosing
PFO. In some embodiments, the systems and methods described herein
may be used for diagnosing ischemic endocardium.
[0044] The methods and contrast agents described herein may also be
utilized in the detection and diagnosis of diseases caused by, or
associated with, pathologic breakdown of the inner layers of
arterial walls, such as, but not limited to: post-embolic or
pre-hemorrhagic stroke breakdown of the blood-brain-barrier (BBB),
vasculitis, ruptured atherosclerotic plaque, diabetic vasculopathy,
inflammation, vasculitis, autoimmune diseases, infection, cancer,
septic shock, or a combination thereof.
[0045] PFO is characterized by a hole located in the septum of the
heart between the right and left atria, typically about 1 mm in
size. PFO is a known cause of embolic stroke where small blood
clots may bypass the filter of the lung capillary bed and become
ejected out the heart into the aorta and through the systemic and
cerebral circulation. The PFO works like a flap valve, only opening
during certain conditions when there is more pressure inside the
chest. This increased pressure occurs when a subjects strain while
having, for example, a bowel movement, cough, or sneeze. If the
resulting pressure is great enough, blood may travel from the right
atrium to the left atrium. If there is a clot or particles in the
blood traveling in the right side of the heart, it can cross the
PFO, enter the left atrium, and travel out of the heart and to the
brain (causing a stroke) or into a coronary artery (causing a heart
attack).
[0046] Embodiments herein are directed to methods for detecting PFO
in a patient comprising: administering a T1-reducing contrast agent
and a T2-reducing contrast agent to the patient; and imaging the
patient's heart; wherein diffusion of the T2 reducing contrast
agent into the left heart is indicative of PFO.
[0047] In some embodiments, the T1 reducing agent is able to pass
freely through the circulatory system and enter the left heart
cavity, whereas the T2 reducing agent is filtered by the lung
capillaries such that in a subject without PFO, only the T1
reducing agent is able to enter the left heart cavity. Conversely,
in a subject with PFO, the T2 reducing agent will be able to enter
the left heart cavity via the hole(s) in the heart between the
right and left atria. The result is that, in a healthy subject,
only the T1 reducing agent will be present in the left heart
whereas with a subject with PFO both the T1 reducing agent and T2
reducing agent will be present in the left heart.
[0048] Some embodiments are directed to methods for detecting PFO
in a patient comprising: imaging the patient's heart after
administering a T1-reducing contrast agent and a T2-reducing
contrast agent to the patient; wherein diffusion of the T2 reducing
contrast agent from the right atrium to the left atrium is
indicative of PFO. In some embodiments, diffusion of the T2
reducing contrast agent from the right atrium to the left atrium is
indicative of PFO. In some embodiments, the absence of the PFO
prevents the T2 reducing contrast agent from diffusing from the
right atrium to the left atrium. In some embodiments, the T1
reducing contrast agent is able to circulate freely through the
vasculature due to its small size. In some embodiments, the
particle size of the T2-reducing contrast agent is larger than the
particle size of the T1-reducing contrast agent. In some
embodiments, the average particle size of the T2-reducing contrast
agent is larger than the average particle size of the T1-reducing
contrast agent. In some embodiments, the particle size of the
majority of the particles comprising the T2-reducing contrast agent
is larger than the particle size of the majority of the particles
comprising the T1-reducing contrast agent. In some embodiments, the
particle size of about 90% to about 99% of the particles comprising
the T2-reducing contrast agent is larger than the particle size of
about 90% to about 99% of the particles comprising the T1-reducing
contrast agent. In some embodiments, the particle size of about 90%
of the particles comprising the T2-reducing contrast agent is
larger than the particle size of about 90% of the particles
comprising the T1-reducing contrast agent. In some embodiments, the
particle size of about 95% of the particles comprising the
T2-reducing contrast agent is larger than the particle size of
about 95% of the particles comprising the T1-reducing contrast
agent. In some embodiments, the particle size of about 99% of the
particles comprising the T2-reducing contrast agent is larger than
the particle size of about 99% of the particles comprising the
T1-reducing contrast agent.
[0049] Some embodiments are directed to the use of imaging
compositions comprising a T1-reducing contrast agent and
T2-reducing contrast agent, which may be administered to
cardiovascular system of a subject, where each of the contrast
agents have different size particles and have different contrast
effects. For example, relatively large iron oxide particles (having
approximate diameters from about 3.5 and about 80 microns) will
reduce local T2 (spin-spin relaxation) times, and relatively small
gadolinium chelate particles (having approximate diameters from
about 7 to about 11 angstroms) will reduce local T1 (spin-lattice
relaxation) times. Without wishing to be bound by theory, the use
of particles with differing particle size and contrast effect
results in a differential distribution in the subjects'
cardiovascular system due to filtration by lung capillaries that
prevent larger particles from entering the right side of the heart
and to the rest of the body via the systemic arteries. In a subject
without PFO, the smaller particles (i.e. gadolinium particles) can
diffuse throughout the cardiovascular system, whereas the larger
particles (i.e. iron oxide particles) are restricted to the right
side of the heart and pulmonary arteries and are prevented from
diffusing past the lungs due to their larger size. In yet other
embodiments, in a permeable body cavity, the smaller particles
(i.e. gadolinium particles) can diffuse out of the lumen of the
body cavity into the luminal wall and surrounding tissue, whereas
the larger particles (i.e. iron oxide particles) remain in the
lumen. Because iron and gadolinium have opposite effects on
magnetic resonance imaging signal intensity, once the smaller
particles have diffused across the luminal surface of the body
cavity, or out of the lumen of the body cavity, they can now be
visualized without interference or masking by the contrast effect
of the larger particles. For example, iron oxide particles reduce
image signal intensity within their immediate vicinity, whereas the
gadolinium particles increase signal intensity within their
immediate vicinity and the result of both particles being present
in the lumen of a body cavity is an overall decrease in signal
intensity masking the contrast effect of the gadolinium particle.
Therefore, when the lumen of a body cavity is intact and
impermeable, the contrast effect of the smaller gadolinium particle
is masked by the contrast effect of the larger iron particles.
[0050] In some embodiments, the relative concentrations of the
T1-reducing contrast agent and T2-reducing contrast agent used may
be optimized so that the concentration of the T2-reducing contrast
agent (i.e. iron oxide particles) is strong enough to completely
mask the effect of the T1-reducing contrast agent (i.e. gadolinium)
within the lumen of a blood vessel. Thus, when the blood vessel is
impermeable, there is virtually no signal, or image intensity,
present within the lumen of the blood vessel. However, when
administered to a permeable blood vessel, the T1-reducing contrast
agent, (i.e. gadolinium chelate) is able to diffuse across the
luminal surface of the blood vessel, or out of the lumen of the
blood vessel, and escape the vicinity of the T2-reducing contrast
agent (i.e. iron oxide particles), which are too large to diffuse
across the luminal surface of the blood vessel, or out of the lumen
of the blood vessel. In some embodiments, the result is that the
wall of a permeable blood vessel will appear as a bright ring on an
MRI image, including a slice selective MRI image that includes the
blood vessel and surrounding tissue, whereas in the case of an
impermeable blood vessel, the wall of said blood vessel will not be
visible on an MRI image, including a slice selective MRI image that
includes the blood vessel and surrounding tissue. In other
embodiments, in the case of an impermeable blood vessel, the wall
of said blood vessel will be visible on an MRI image, including a
slice selective MRI image that includes the blood vessel and
surrounding tissue, but will not have the bright ring enhancement
of the T1-reducing contrast agent.
[0051] In some embodiments, the methods of detecting PFO described
herein may additionally, or alternatively, be utilized to measure
the permeability of the luminal lining of a body cavity, the
permeability of the luminal surface of a body cavity or a
combination thereof. In some embodiments, detecting PFO described
herein may include measuring the permeability of the luminal lining
of a body cavity, the permeability of the luminal surface of a body
cavity or a combination thereof.
[0052] Embodiments herein are directed to methods for detecting
ischemic endocardium in a patient comprising: administering a
T1-reducing contrast agent and a T2-reducing contrast agent to the
patient; and imaging the patient's heart; wherein diffusion of the
T1 reducing contrast agent into the left heart is indicative of
ischemic endocardium.
[0053] The endocardium is the thin inner cellular lining of the
heart cavities, including the left ventricle. Sufficient ischemia
to a segment of the left ventricle results in a breakdown of the
cells and cell-cell junctions in the endocardium.
[0054] In some embodiments, ischemic endocardium can be detected by
measurement of the permeability of the endocardium in a patient
comprising: administering a T1-reducing contrast agent and a
T2-reducing contrast agent to the patient; and imaging the
patient's heart; wherein diffusion of the T1 reducing contrast
agent across the luminal surface of the endocardium is indicative
of permeability, which in turn may be indicative of ischemic
endocardium. In some embodiments, diffusion of the T1 reducing
contrast agent out of the lumen of the endocardium is indicative of
permeability, which in turn may be indicative of ischemic
endocardium.
[0055] Some embodiments are directed to methods for detecting
ischemic endocardium in a patient comprising: imaging the patient's
heart after administering a T1-reducing contrast agent and a
T2-reducing contrast agent to the patient; wherein diffusion of the
T1 reducing contrast agent across the luminal surface of the
endocardium is indicative of permeability, which in turn may be
indicative of ischemic endocardium. In some diffusion of the T1
reducing contrast agent out of the lumen of the endocardium is
indicative of permeability, which in turn may be indicative of
ischemic endocardium. In some embodiments, the particle size of the
T2-reducing contrast agent is larger than the particle size of the
T1-reducing contrast agent. In some embodiments, the average
particle size of the T2-reducing contrast agent is larger than the
average particle size of the T1-reducing contrast agent. In some
embodiments, the particle size of the majority of the particles
comprising the T2-reducing contrast agent is larger than the
particle size of the majority of the particles comprising the
T1-reducing contrast agent. In some embodiments, the particle size
of about 90% to about 99% of the particles comprising the
T2-reducing contrast agent is larger than the particle size of
about 90% to about 99% of the particles comprising the T1-reducing
contrast agent. In some embodiments, the particle size of about 90%
of the particles comprising the T2-reducing contrast agent is
larger than the particle size of about 90% of the particles
comprising the T1-reducing contrast agent. In some embodiments, the
particle size of about 95% of the particles comprising the
T2-reducing contrast agent is larger than the particle size of
about 95% of the particles comprising the T1-reducing contrast
agent. In some embodiments, the particle size of about 99% of the
particles comprising the T2-reducing contrast agent is larger than
the particle size of about 99% of the particles comprising the
T1-reducing contrast agent.
[0056] Some embodiments are directed to the use of imaging
compositions comprising a T1-reducing contrast agent and
T2-reducing contrast agent, which may be administered to the lumen
of a body cavity for detecting ischemic endocardium, where each of
the contrast agents have different size particles and have
different contrast effects. For example, relatively large iron
oxide particles (having approximate diameters from about 3.5 and
about 80 microns) will reduce local T2 (spin-spin relaxation)
times, and relatively small gadolinium chelate particles (having
approximate diameters from about 7 to about 11 angstroms) will
reduce local T1 (spin-lattice relaxation) times. Without wishing to
be bound by theory, the use of particles with differing particle
size and contrast effect results in a differential distribution in
lumen and luminal wall of the endocardium depending on whether the
endocardium is permeable. In a permeable body cavity, the smaller
particles (i.e. gadolinium particles) can diffuse across the
luminal surface of the endocardium into the luminal wall and
surrounding tissue, whereas the larger particles (i.e. iron oxide
particles) remain in the lumen. In yet other embodiments, in a
permeable endocardium, the smaller particles (i.e. gadolinium
particles) can diffuse out of the lumen of the endocardium into the
luminal wall and surrounding tissue, whereas the larger particles
(i.e. iron oxide particles) remain in the lumen. Because iron and
gadolinium have opposite effects on magnetic resonance imaging
signal intensity, once the smaller particles have diffused across
the luminal surface of the endocardium, or out of the lumen of the
endocardium, they can now be visualized without interference or
masking by the contrast effect of the larger particles. For
example, iron oxide particles reduce image signal intensity within
their immediate vicinity, whereas the gadolinium particles increase
signal intensity within their immediate vicinity and the result of
both particles being present in the lumen of the endocardium is an
overall decrease in signal intensity masking the contrast effect of
the gadolinium particle. Therefore, when the lumen of the
endocardium is intact and impermeable, the contrast effect of the
smaller gadolinium particle is masked by the contrast effect of the
larger iron particles.
[0057] In some embodiments, the relative concentrations of the
T1-reducing contrast agent and T2-reducing contrast agent used may
be optimized so that the concentration of the T2-reducing contrast
agent (i.e. iron oxide particles) is strong enough to completely
mask the effect of the T1-reducing contrast agent (i.e. gadolinium)
within the lumen of the endocardium. Thus, when the endocardium is
impermeable, there is virtually no signal, or image intensity,
present within the lumen of the endocardium. However, when
administered to a permeable endocardium, the T1-reducing contrast
agent, (i.e. gadolinium chelate) is able to diffuse across the
luminal surface of the endocardium, or out of the lumen of the
endocardium, and escape the vicinity of the T2-reducing contrast
agent (i.e. iron oxide particles), which are too large to diffuse
across the luminal surface of the endocardium, or out of the lumen
of the endocardium. In some embodiments, the result is that the
wall of a permeable endocardium will appear as a bright ring on an
MRI image, including a slice selective MRI image that includes the
endocardium and surrounding tissue, whereas in the case of an
impermeable endocardium, the wall of said endocardium will not be
visible on an MRI image, including a slice selective MRI image that
includes the endocardium and surrounding tissue. In other
embodiments, in the case of an impermeable endocardium, the wall of
said endocardium will be visible on an MRI image, including a slice
selective MRI image that includes the endocardium and surrounding
tissue, but will not have the bright ring enhancement of the
T1-reducing contrast agent.
[0058] Embodiments herein are directed to methods for detecting a
condition associated with the pathological breakdown of the layers
of epithelial cells and cell junctions that line the
gastrointestinal tract in a patient comprising: administering a
T1-reducing contrast agent and a T2-reducing contrast agent to the
patient; and imaging the patient's gastrointestinal tract; wherein
diffusion of the T1 reducing contrast agent into the left heart is
indicative of a condition associated with the pathological
breakdown of the layers of epithelial cells and cell junctions that
line the gastrointestinal tract. In some embodiments, the
T1-reducing contrast agent and the T2-reducing contrast agent are
administered orally. In some embodiments, conditions associated
with the pathological breakdown of the layers of epithelial cells
and cell junctions that line the gastrointestinal tract include but
are not limited to inflammatory bowel disease, gastric/duodenal
ulcer disease, celiac disease, or any combination thereof.
[0059] In some embodiments, a condition associated with the
pathological breakdown of the layers of epithelial cells and cell
junctions that line the gastrointestinal tract can be detected by
measurement of the permeability of the gastrointestinal tract lumen
in a patient comprising: administering a T1-reducing contrast agent
and a T2-reducing contrast agent to the patient; and imaging the
patient's gastrointestinal tract; wherein diffusion of the T1
reducing contrast agent across the luminal surface of the
gastrointestinal tract is indicative of permeability, which in turn
may be indicative of a condition associated with the pathological
breakdown of the layers of epithelial cells and cell junctions that
line the gastrointestinal tract. In some embodiments, diffusion of
the T1 reducing contrast agent out of the lumen of the
gastrointestinal tract is indicative of permeability, which in turn
may be indicative of a condition associated with the pathological
breakdown of the layers of epithelial cells and cell junctions that
line the gastrointestinal tract. In some embodiments, the
T1-reducing contrast agent and the T2-reducing contrast agent are
administered orally. In some embodiments conditions associated with
the pathological breakdown of the layers of epithelial cells and
cell junctions that line the gastrointestinal tract include but are
not limited to inflammatory bowel disease, gastric/duodenal ulcer
disease, celiac disease or combinations thereof.
[0060] Some embodiments are directed to methods for detecting a
condition associated with the pathological breakdown of the layers
of epithelial cells and cell junctions that line the
gastrointestinal tract in a patient comprising: imaging the
patient's gastrointestinal tract after administering a T1-reducing
contrast agent and a T2-reducing contrast agent to the patient;
wherein diffusion of the T1 reducing contrast agent across the
luminal surface of the gastrointestinal tract is indicative of
permeability, which in turn may be indicative of a condition
associated with the pathological breakdown of the layers of
epithelial cells and cell junctions that line the gastrointestinal
tract. In some diffusion of the T1 reducing contrast agent out of
the lumen of the gastrointestinal tract is indicative of
permeability, which in turn may be indicative of a condition
associated with the pathological breakdown of the layers of
epithelial cells and cell junctions that line the gastrointestinal
tract. In some embodiments, the particle size of the T2-reducing
contrast agent is larger than the particle size of the T1-reducing
contrast agent. In some embodiments, the average particle size of
the T2-reducing contrast agent is larger than the average particle
size of the T1-reducing contrast agent. In some embodiments, the
particle size of the majority of the particles comprising the
T2-reducing contrast agent is larger than the particle size of the
majority of the particles comprising the T1-reducing contrast
agent. In some embodiments, the particle size of about 90% to about
99% of the particles comprising the T2-reducing contrast agent is
larger than the particle size of about 90% to about 99% of the
particles comprising the T1-reducing contrast agent. In some
embodiments, the particle size of about 90% of the particles
comprising the T2-reducing contrast agent is larger than the
particle size of about 90% of the particles comprising the
T1-reducing contrast agent. In some embodiments, the particle size
of about 95% of the particles comprising the T2-reducing contrast
agent is larger than the particle size of about 95% of the
particles comprising the T1-reducing contrast agent. In some
embodiments, the particle size of about 99% of the particles
comprising the T2-reducing contrast agent is larger than the
particle size of about 99% of the particles comprising the
T1-reducing contrast agent. In some embodiments, the T1-reducing
contrast agent and the T2-reducing contrast agent are administered
orally. In some embodiments conditions associated with the
pathological breakdown of the layers of epithelial cells and cell
junctions that line the gastrointestinal tract include but are not
limited to inflammatory bowel disease, gastric/duodenal ulcer
disease, celiac disease, or combinations thereof.
[0061] Some embodiments are directed to the use of imaging
compositions comprising a T1-reducing contrast agent and
T2-reducing contrast agent, which may be administered to the lumen
of a body cavity for detecting a condition associated with the
pathological breakdown of the layers of epithelial cells and cell
junctions that line the gastrointestinal tract, where each of the
contrast agents have different size particles and have different
contrast effects. For example, relatively large iron oxide
particles (having approximate diameters from about 3.5 and about 80
microns) will reduce local T2 (spin-spin relaxation) times, and
relatively small gadolinium chelate particles (having approximate
diameters from about 7 to about 11 angstroms) will reduce local T1
(spin-lattice relaxation) times. Without wishing to be bound by
theory, the use of particles with differing particle size and
contrast effect results in a differential distribution in lumen and
luminal wall of the gastrointestinal tract depending on whether the
lumen is permeable. In a permeable body cavity, the smaller
particles (i.e. gadolinium particles) can diffuse across the
luminal surface of the gastrointestinal tract into the luminal wall
and surrounding tissue, whereas the larger particles (i.e. iron
oxide particles) remain in the lumen. In yet other embodiments, in
a permeable gastrointestinal tract, the smaller particles (i.e.
gadolinium particles) can diffuse out of the lumen of the
gastrointestinal tract into the luminal wall and surrounding
tissue, whereas the larger particles (i.e. iron oxide particles)
remain in the lumen. Because iron and gadolinium have opposite
effects on magnetic resonance imaging signal intensity, once the
smaller particles have diffused across the luminal surface of the
gastrointestinal tract, or out of the lumen of the endocardium,
they can now be visualized without interference or masking by the
contrast effect of the larger particles. For example, iron oxide
particles reduce image signal intensity within their immediate
vicinity, whereas the gadolinium particles increase signal
intensity within their immediate vicinity and the result of both
particles being present in the lumen of the gastrointestinal tract
is an overall decrease in signal intensity masking the contrast
effect of the gadolinium particle. Therefore, when the lumen of the
gastrointestinal tract is intact and impermeable, the contrast
effect of the smaller gadolinium particle is masked by the contrast
effect of the larger iron particles. In some embodiments, the
compositions comprising a T1-reducing contrast agent and
T2-reducing contrast agent are administered orally. In some
embodiments condition associated with the pathological breakdown of
the layers of epithelial cells and cell junctions that line the
gastrointestinal tract include but are not limited to inflammatory
bowel disease, gastric/duodenal ulcer disease, celiac disease, or
combinations thereof.
[0062] In some embodiments, the relative concentrations of the
T1-reducing contrast agent and T2-reducing contrast agent used may
be optimized so that the concentration of the T2-reducing contrast
agent (i.e. iron oxide particles) is strong enough to completely
mask the effect of the T1-reducing contrast agent (i.e. gadolinium)
within the lumen of the gastrointestinal tract. Thus, when the
endocardium is impermeable, there is virtually no signal, or image
intensity, present within the lumen of the gastrointestinal tract.
However, when administered to a permeable gastrointestinal tract,
the T1-reducing contrast agent, (i.e. gadolinium chelate) is able
to diffuse across the luminal surface of the gastrointestinal
tract, or out of the lumen of the gastrointestinal tract, and
escape the vicinity of the T2-reducing contrast agent (i.e. iron
oxide particles), which are too large to diffuse across the luminal
surface of the gastrointestinal tract, or out of the lumen of the
gastrointestinal tract. In some embodiments, the result is that the
wall of a permeable gastrointestinal tract will appear as a bright
ring on an MRI image, including a slice selective MRI image that
includes the gastrointestinal tract and surrounding tissue, whereas
in the case of an impermeable gastrointestinal tract, the wall of
said endocardium will not be visible on an MRI image, including a
slice selective MRI image that includes the gastrointestinal tract
and surrounding tissue. In other embodiments, in the case of an
impermeable gastrointestinal tract, the wall of said
gastrointestinal tract will be visible on an MRI image, including a
slice selective MRI image that includes the gastrointestinal tract
and surrounding tissue, but will not have the bright ring
enhancement of the T1-reducing contrast agent.
[0063] Embodiments herein are directed to methods for measuring the
permeability of a body cavity in a patient comprising:
administering a T1-reducing contrast agent and a T2-reducing
contrast agent to the patient; and imaging the patient; wherein
diffusion of the T1 reducing contrast agent across the luminal
surface of the body cavity is indicative of permeability. In some
embodiments, diffusion of the T1 reducing contrast agent out of the
lumen of the body cavity is indicative of permeability.
[0064] In some embodiments, the methods of measuring the
permeability of a body cavity described herein may additionally, or
alternatively, be utilized to measure the permeability of the
luminal lining of a body cavity, the permeability of the luminal
surface of a body cavity or a combination thereof. In some
embodiments, measuring the permeability of a body cavity described
herein may include measuring the permeability of the luminal lining
of a body cavity, the permeability of the luminal surface of a body
cavity or a combination thereof.
[0065] Some embodiments are directed to methods for measuring the
permeability of a body cavity in a patient comprising: imaging the
patient after administering a T1-reducing contrast agent and a
T2-reducing contrast agent to the patient; wherein diffusion of the
T1 reducing contrast agent across the luminal surface of the body
cavity is indicative of permeability. In some diffusion of the T1
reducing contrast agent out of the lumen of the body cavity is
indicative of permeability. In some embodiments, the particle size
of the T2-reducing contrast agent is larger than the particle size
of the T1-reducing contrast agent. In some embodiments, the average
particle size of the T2-reducing contrast agent is larger than the
average particle size of the T1-reducing contrast agent. In some
embodiments, the particle size of the majority of the particles
comprising the T2-reducing contrast agent is larger than the
particle size of the majority of the particles comprising the
T1-reducing contrast agent. In some embodiments, the particle size
of about 90% to about 99% of the particles comprising the
T2-reducing contrast agent is larger than the particle size of
about 90% to about 99% of the particles comprising the T1-reducing
contrast agent. In some embodiments, the particle size of about 90%
of the particles comprising the T2-reducing contrast agent is
larger than the particle size of about 90% of the particles
comprising the T1-reducing contrast agent. In some embodiments, the
particle size of about 95% of the particles comprising the
T2-reducing contrast agent is larger than the particle size of
about 95% of the particles comprising the T1-reducing contrast
agent. In some embodiments, the particle size of about 99% of the
particles comprising the T2-reducing contrast agent is larger than
the particle size of about 99% of the particles comprising the
T1-reducing contrast agent.
[0066] Some embodiments are directed to the use of imaging
compositions comprising a T1-reducing contrast agent and
T2-reducing contrast agent, which may be administered to the lumen
of a body cavity, where each of the contrast agents have different
size particles and have different contrast effects. For example,
relatively large iron oxide particles (having approximate diameters
from about 3.5 and about 80 microns) will reduce local T2
(spin-spin relaxation) times, and relatively small gadolinium
chelate particles (having approximate diameters from about 7 to
about 11 angstroms) will reduce local T1 (spin-lattice relaxation)
times. Without wishing to be bound by theory, the use of particles
with differing particle size and contrast effect results in a
differential distribution in lumen and luminal wall of a body
cavity depending on whether the body cavity is permeable. In a
permeable body cavity, the smaller particles (i.e. gadolinium
particles) can diffuse across the luminal surface of the body
cavity into the luminal wall and surrounding tissue, whereas the
larger particles (i.e. iron oxide particles) remain in the lumen.
In yet other embodiments, in a permeable body cavity, the smaller
particles (i.e. gadolinium particles) can diffuse out of the lumen
of the body cavity into the luminal wall and surrounding tissue,
whereas the larger particles (i.e. iron oxide particles) remain in
the lumen. Because iron and gadolinium have opposite effects on
magnetic resonance imaging signal intensity, once the smaller
particles have diffused across the luminal surface of the body
cavity, or out of the lumen of the body cavity, they can now be
visualized without interference or masking by the contrast effect
of the larger particles. For example, iron oxide particles reduce
image signal intensity within their immediate vicinity, whereas the
gadolinium particles increase signal intensity within their
immediate vicinity and the result of both particles being present
in the lumen of a body cavity is an overall decrease in signal
intensity masking the contrast effect of the gadolinium particle.
Therefore, when the lumen of a body cavity is intact and
impermeable, the contrast effect of the smaller gadolinium particle
is masked by the contrast effect of the larger iron particles.
[0067] In some embodiments, the relative concentrations of the
T1-reducing contrast agent and T2-reducing contrast agent used may
be optimized so that the concentration of the T2-reducing contrast
agent (i.e. iron oxide particles) is strong enough to completely
mask the effect of the T1-reducing contrast agent (i.e. gadolinium)
within the lumen of a body cavity. Thus, when the body cavity is
impermeable, there is virtually no signal, or image intensity,
present within the lumen of the body cavity. However, when
administered to a permeable body cavity, the T1-reducing contrast
agent, (i.e. gadolinium chelate) is able to diffuse across the
luminal surface of the body cavity, or out of the lumen of the body
cavity, and escape the vicinity of the T2-reducing contrast agent
(i.e. iron oxide particles), which are too large to diffuse across
the luminal surface of the body cavity, or out of the lumen of the
body cavity. In some embodiments, the result is that the wall of a
permeable body cavity will appear as a bright ring on an MRI image,
including a slice selective MRI image that includes the body cavity
and surrounding tissue, whereas in the case of an impermeable body
cavity, the wall of said cavity will not be visible on an MRI
image, including a slice selective MRI image that includes the body
cavity and surrounding tissue. In other embodiments, in the case of
an impermeable body cavity, the wall of said cavity will be visible
on an MRI image, including a slice selective MRI image that
includes the body cavity and surrounding tissue, but will not have
the bright ring enhancement of the T1-reducing contrast agent.
[0068] In various embodiments, the T1-reducing contrast agent and
T2-reducing contrast agent have differing contrast effects. For
example, in some embodiments, the effects of the T1-reducing
contrast agent may be disambiguated from the effects of the
T2-reducing contrast agent such that a person skilled in the art
can detect a difference between the effects of the T1-reducing
contrast agent and the T2-reducing contrast agent when viewing the
results of the diagnostic imaging described herein. Different
contrast effects may be visible, for example, when the T1-reducing
contrast agent contains a plurality of molecules that are smaller
in diameter relative to the diameter of the plurality of molecules
contained in the T2-reducing contrast agent. Different contrast
effects may be visible, for example, when the T1-reducing contrast
agent contains a plurality of molecules that are smaller in average
diameter relative to the average diameter of the plurality of
molecules contained in the T2-reducing contrast agent. Different
contrast effects may also be visible, for example, when the
T1-reducing contrast agent affects a T1-weighted MRI image and the
T2-reducing contrast agent affects a T2-weighted MRI image. In some
embodiments, the T1-reducing contrast agent and the T2-reducing
contrast agent have different particle sizes. In some embodiments,
the T1-reducing contrast agent has a smaller particle size than the
T2-reducing contrast agent. In some embodiments, the T1-reducing
contrast agent has a particle size that enables it to move out of
lumen of a permeable body cavity. In other embodiments, for
example, the T2-reducing contrast agent contains a plurality of
molecules that are smaller in diameter relative to the diameter of
the plurality of molecules contained in the T1-reducing contrast
agent. Different contrast effects may be visible, for example, when
the T2-reducing contrast agent contains a plurality of molecules
that are smaller in average diameter relative to the average
diameter of the plurality of molecules contained in the T1-reducing
contrast agent. In some embodiments, the T2-reducing contrast agent
has a smaller particle size than the T1-reducing contrast agent. In
some embodiments, the T2-reducing contrast agent has a particle
size that enables it to move out of lumen of a permeable body
cavity. In some embodiments, the T2-reducing contrast agent has a
particle size that enables it to move out of lumen of a permeable
blood vessel.
[0069] In some embodiments, the T1-reducing contrast agent exhibits
predominantly T1-reducing contrast effects. In some embodiments,
the T1-reducing contrast agent may also exhibit T2-reducing
contrast effects. In some embodiments, the T2-reducing contrast
effects of the T1-reducing contrast agent are concentration
dependent. In some embodiments, the T2-reducing contrast effects of
the T1-reducing contrast agent are concentration dependent. In some
embodiments, the T1-reducing contrast agent may exhibit T2-reducing
effects at high concentrations. In some embodiments, the
T2-reducing contrast agent exhibits predominantly T2-reducing
contrast effects. In some embodiments, the T2-reducing contrast
agent may also exhibit T1-reducing contrast effects. In some
embodiments, the T1-reducing contrast effects of the T2-reducing
contrast agent are concentration dependent. In some embodiments,
the T2-reducing contrast effects of the T2-reducing contrast agent
are concentration dependent. In some embodiments, the T2-reducing
contrast agent may exhibit T1-reducing effects at high
concentrations.
[0070] In some embodiments, the T1-reducing agent, the T2-reducing
agent, or a combination thereof further comprises an aqueous
solvent. In some embodiments, the T1-reducing contrast agent and
the T2-reducing contrast agent are administered to the patient as a
single composition; wherein the single composition comprises the
T1-reducing contrast agent and the T2-reducing contrast agent. In
some embodiments, the single composition further comprises an
aqueous solvent. In some embodiments, the T1-reducing agent and the
T2-reducing contrast agent are administered to the patient as two
separate compositions; wherein a first composition comprises the
T1-reducing contrast agent; and wherein a second composition
comprises the T2-reducing contrast agent. In some embodiments, the
T1-reducing agent and the T2-reducing contrast agent are
administered to the patient as two separate compositions; wherein a
first composition comprises the T2-reducing contrast agent; and
wherein a second composition comprises the T-1 reducing contrast
agent. In some embodiments, the two separate compositions each
further comprise an aqueous solvent. In some embodiments, where the
T1-reducing agent and the T2-reducing contrast agent are
administered to the patient as two separate compositions, the
separate compositions can be administered in any order including
but not limited to administering the T1-reducing contrast agent
followed by the T2-reducing contrast agent, administering the
T2-reducing contrast agent followed by the T1-reducing contrast
agent or administering the T1-reducing contrast agent and the
T2-reducing contrast agent simultaneously. In some embodiments, the
two separate compositions each further comprise an aqueous
solvent.
[0071] In particular embodiments where the T1-reducing contrast
agent and the T2-reducing contrast agent may be administered
simultaneously, the T1-reducing contrast agent and the T2-reducing
contrast agent may be mixed together as a dual-component solution
before administration. The dual-component solution may be composed
of a mixture of two MRI contrast agents: a T2-reducing contrast
agent that may be a large-particle agent that reduces T2 (spin-spin
relaxation time), and a T1-reducing contrast agent that may be a
small-molecule agent that reduces T1 (spin-lattice relaxation
time). The sizes of these two MRI contrast agents may be such that
neither can pass through the lining of a healthy blood vessel, and
only the relatively small T1 or T2 agent can pass through the
lining of a diseased blood vessel. These two contrast agents may
have opposite effects on MRI image intensity. The presence of the
T2 contrast agent may reduce local image intensity by causing a
more rapid nuclear spin dispersion, whereas the presence of the T1
contrast agent may increase local image intensity by allowing
nuclear spins to more quickly equilibrate between phase encoding
repetitions. In some embodiments, administering the dual-component
solution to a healthy blood vessel may cause the blood vessel lumen
to go dark (the T2 effect may mask any possible T1 effect).
However, if a region of the blood vessel lining is selectively
permeable to the smaller-sized T1 contrast agent, a bright signal
intensity may surround the blood vessel lumen. In other
embodiments, the dual-component solution may be composed of a
mixture of two MRI contrast agents: a T1-reducing contrast agent
that may be a large-particle agent that reduces T1 (spin-lattice
relaxation time), and a T2-reducing contrast agent that may be a
small-molecule agent that reduces T2 (spin-spin relaxation time).
In some embodiments, administering the dual-component solution to a
healthy blood vessel may cause the blood vessel lumen to go dark
(the T2 effect may mask any possible T1 effect). However, if a
region of the blood vessel lining is selectively permeable to the
smaller-sized T2 contrast agent, a bright signal may be formed in
the lumen due to diffusion of the smaller T2-reducing contrast
agent into the luminal wall.
[0072] In some embodiments, the T1-reducing contrast agent reduces
local T1 (spin-lattice relaxation) time. In some embodiments, the
T2-reducing contrast agent reduces local T2 (Spin-Spin relaxation)
time. In some embodiments, the T1-reducing contrast agent increases
image signal intensity. In some embodiments, the T2-reducing
contrast agent reduces image signal intensity.
[0073] In some embodiments, the T2-reducing contrast agent is
administered in a concentration sufficient to mask the contrast
effect of the T1-reducing contrast agent within the lumen of the
body cavity. In some embodiments, the T2-reducing contrast agent is
administered in a concentration sufficient to mask the contrast
effect of the T1-reducing contrast agent within the lumen of the
blood vessel.
[0074] In some embodiments, administering T1-reducing contrast
agent and the T2-reducing contrast agent are completed
simultaneously. In some embodiments, the T1-reducing contrast agent
and the T2-reducing contrast agent may be combined into a single
formulation prior to administration. In yet other embodiments,
whether administered sequentially or simultaneously, the
T1-reducing contrast agent and T2-reducing contrast agent may be
administered as separate formulations. In some embodiments, the
T1-reducing contrast agent and T2-reducing contrast agent are
administered in a ratio of T1-reducing contrast agent to
T2-reducing contrast agent ranging from about 1 to 100 to about 100
to 1. In some embodiments, the T1-reducing contrast agent and
T2-reducing contrast agent are administered in a ratio of
T1-reducing contrast agent to T2-reducing contrast agent of about 1
to about 100, about 1 to about 50, about 1 to about 25, about 1 to
about 20, about 1 to about 15, about 1 to about 10, about 1 to
about 5, about 1 to about 1, about 1 to about 12, or about 1 to
about 11.76. In some embodiments, the ratio of the T1-reducing
contrast agent to the T2-reducing contrast agent is such that the
contrast effect of the T1-reducing contrast agent is masked by the
contrast effect of the T2-reducing contrast agent when administered
to the lumen of a body cavity. In some embodiments, the ratio of
the T1-reducing contrast agent to the T2-reducing contrast agent is
such that the contrast effect of the T1-reducing contrast agent is
masked by the contrast effect of the T2-reducing contrast agent
when administered to the lumen of a blood vessel.
[0075] In some embodiments, the T1-reducing contrast agent has a
particle size that enables it to move out of lumen of a permeable
body cavity. In some embodiments, the T1-reducing contrast agent
has a particle size that enables it to move out of lumen of a
permeable blood vessel. In some embodiments, the T1-reducing
contrast agent reduces local T1 (spin-lattice relaxation) time. In
some embodiments, the T2-reducing contrast agent reduces local T2
(Spin-Spin relaxation) time. In some embodiments, the T1-reducing
contrast agent increases image signal intensity. In some
embodiments, the T2-reducing contrast agent reduces image signal
intensity. In some embodiments, the T2-reducing contrast agent is
present in a concentration sufficient to mask the contrast effect
of the T1-reducing contrast agent within the lumen of a body
cavity. In some embodiments, the T2-reducing contrast agent is
present in a concentration sufficient to mask the contrast effect
of the T1-reducing contrast agent within the lumen of a blood
vessel. In some embodiments, the T2-reducing contrast agent has a
particle size that enables it to move out of lumen of a permeable
body cavity. In some embodiments, the T2-reducing contrast agent
has a particle size that enables it to move out of lumen of a
permeable blood vessel.
[0076] Embodiments herein are directed to methods for measuring the
permeability of a body cavity in a patient which may also be
utilized to map heterogeneity in the permeability of a body cavity.
In some embodiments, the body cavity is a blood vessel. In some
embodiments, where only a portion of the luminal wall of a body
cavity is permeable, the T1-reducing contrast agent will diffuse
into the permeable region of the luminal wall of the body cavity
and a signal will be generated which can then be detected and will
allow for identification of the permeable region of the luminal
wall. In some embodiments, the ability to map heterogeneity may
have utility in detecting lesions in a body cavity. In particular
embodiments, the ability to map heterogeneity may have utility in
detecting diseased blood vessels. In some embodiments, diseased
blood vessels may be characterized by a breakdown of the
intercellular junctions of the vessel making the diseased blood
vessel permeable and allowing the T1-reducing contrast agent to
diffuse into the permeable region of the luminal wall of the
diseased blood vessel. In some embodiments, the ability to map
heterogeneity may have utility in detecting PFO, ischemic
endocardium, post-embolic or pre-hemorrhagic stroke breakdown of
the blood-brain-barrier (BBB), vasculitis, ruptured atherosclerotic
plaque, diabetic vasculopathy, inflammation, vasculitis, autoimmune
disease, infection, cancer, septic shock, or a combination
thereof.
[0077] In some embodiments, imaging the patient comprises imaging
via magnetic resonance imaging. Imaging the patient may generally
include imaging the patient via a magnetic resonance process, such
as, for example, magnetic resonance processes now known or later
developed. In some embodiments, imaging the patient comprises
imaging via magnetic resonance imaging. In some embodiments,
imaging the patient comprises imaging via magnetic resonance
imaging. However, those having ordinary skill in the art will
recognize other imaging processes, such as, for example, x-ray
imaging, computed tomography, positron emission scanning, and/or
the like. In addition, those having ordinary skill in the art will
recognize that other contrast agents, imaging agents, and/or the
like, may be used alone or in combination with other contrast
agents, imaging agents and/or the like to measure the permeability
of a body cavity using MRI or other imaging techniques known in the
art. In some embodiments, one or more contrast agents, imaging
agents, and/or the like may be used if they possess a contrast
effect that allows for measurement of the permeability of a body
cavity. In some embodiments, imaging the patient may include
imaging the patient for a period of time after administration of
the T1-reducing contrast agent and the T2-reducing contrast agent.
In particular embodiments, the period of time may generally be a
period of time that allows for diffusion of the T1-reducing
contrast agent and/or the T2-reducing contrast agent administered
to the lumen of the body cavity. In some embodiments, imaging the
patient is performed within about 10 minutes of administration of
the T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof. In some embodiments, imaging the patient is
performed within about 20 minutes of administration of the
T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof. In some embodiments, imaging the patient is
performed within about 30 minutes of administration of the
T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof. In some embodiments, imaging the patient is
performed within about 30 minutes of administration of the
T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof. In some embodiments, imaging the patient is
performed within about 40 minutes of administration of the
T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof. In some embodiments, imaging the patient is
performed within about 50 minutes of administration of the
T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof. In some embodiments, imaging the patient is
performed within about 60 minutes of administration of the
T1-reducing contrast agent, T2-reducing contrast agent or
combination thereof.
[0078] In some embodiments, the T1-reducing contrast agent may be a
magnetic resonance imaging (MRI) contrast agent. In some
embodiments, the first T1-reducing contrast agent comprises a
gadolinium compound. In some embodiments, the gadolinium compound
is selected from gadopentetate dimeglumine (Gd-DTPA), gadoterate
meglumine, gadoversetamide, gadoteridol, gadodiamide, gadobenate
dimeglumine, gadobutrol, gadoxetate disodium, gadofosveset
trisodium and combinations thereof. Those having ordinary skill in
the art will recognize that other gadolinium-containing contrast
agents and/or gadolinium salts that are now known or later
developed may also be used without departing from the scope of the
present disclosure. In some embodiments the T1-reducing contrast
agent comprises Gadopentetate dimeglumine (Gd-DTPA). In some
embodiments, the Gadopentetate dimeglumine (Gd-DTPA) is present in
a concentration of about 0.000425 M. In some embodiments, the
gadolinium compound is encapsulated in liposomes.
[0079] In some embodiments, the T2-reducing contrast agent
comprises an iron oxide. In some embodiments, the iron oxide is
selected from iron (II) oxide, iron (III) oxide, ferumoxytol
(Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,
Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide
(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder,
magnetic iron oxide nanoparticles, carbon coated iron nanopowder,
and combinations thereof. In some embodiments, the iron oxide is
encapsulated in liposomes. In particular embodiments, the
T2-reducing contrast agent may contain a plurality of magnetite
particles. In some embodiments, the T2-reducing contrast agent
comprises ferumoxytol. In some embodiments, the ferumoxytol is
present in present at a concentration of about 0.005M. In some
embodiments, the iron oxide is encapsulated in liposomes.
[0080] In some embodiments, the T2-reducing contrast agent may
contain a plurality of molecules, where the average diameter of the
molecules is about 100 .ANG. to about 1000 .ANG.. For example, the
average diameter of the molecules in the T2-reducing contrast agent
may be about 100 .ANG., about 200 .ANG., about 300 .ANG., about 400
.ANG., about 500 .ANG., about 600 .ANG., about 700 .ANG., about 800
.ANG., about 900 .ANG., about 1000 .ANG., or any value or range
between any two of these values (including endpoints).
[0081] In other particular embodiments, the T1-reducing contrast
agents, T2-reducing contrast agents, or a combination thereof, may
include one or more of an iron oxide, iron platinum, manganese, and
protein. In various embodiments, the MRI contrast agent may have an
anionic neutral pH.
[0082] In some embodiments, the patient's body cavity is selected
from the urinary bladder, the cardiovascular system, blood vessels,
heart, lymph vessels, coelom, pericardial cavity, pericardium,
intraembryonic coelom, extraembryonic coelom, chorionic cavity,
dorsal cavity, ventral cavity, thoracic cavity, abdominopelvic
cavity, cranial cavity, spinal cavity (or vertebral cavity), a
pleural cavity, superior mediastinum, thoracic cavity, abdominal
cavity, pelvic cavity. abdominopelvic cavity, kidneys, ureters,
gastrointestinal tract, stomach, intestines, liver, gallbladder,
pancreas, anus, reproductive system and any combination
thereof.
[0083] In some embodiments, the patient's body cavity is the
cardiovascular system, blood vessels, heart, or combination
thereof. In some embodiments, the patient is suspected of having
PFO, ischemic endocardium, post-embolic or pre-hemorrhagic stroke
breakdown of the blood-brain-barrier (BBB), vasculitis, ruptured
atherosclerotic plaque, diabetic vasculopathy, inflammation,
vasculitis, autoimmune diseases, infection, cancer, septic shock,
or a combination thereof. In some embodiments, administration of
the T1-reducing contrast agent and the T2-reducing contrast agent
is achieved by administration into the lumen of the cardiovascular
system, blood vessels, heart, or combination thereof.
[0084] In some embodiments, the patient's body cavity is the
gastrointestinal tract. In some embodiments, the patient is
suspected of having a condition associated with the pathological
breakdown of the layers of epithelial cells and cell junctions that
line the gastrointestinal tract including but are not limited to:
inflammatory bowel disease, gastric/duodenal ulcer disease, celiac
disease, or a combination thereof. In some embodiments,
administration of the T1-reducing contrast agent and the
T2-reducing contrast agent is achieved by administration into the
lumen of the gastrointestinal tract.
[0085] In some embodiments, a molecule or particle of T1-reducing
contrast agents, T2-reducing contrast agents, or a combination
thereof, may have a molecular weight of about 500 atomic mass units
(amu) to about 1500 amu. For example, the molecule or particle may
have a molecular weight of about 500 amu, about 550 amu, about 600
amu, about 650 amu, about 700 amu, about 750 amu, about 800 amu,
about 850 amu, about 900 amu, about 950 amu, about 1000 amu, about
1050 amu, about 1100 amu, about 1150 amu, about 1200 amu, about
1250 amu, about 1300 amu, about 1350 amu, about 1400 amu, about
1450 amu, about 1500 amu, or any value or range between any two of
these values (including endpoints). In a particular embodiment, the
molecule or particle may have a molecular weight of about 938
amu.
[0086] In some embodiments, molecules or particles of the
T1-reducing contrast agents, T2-reducing contrast agents, or a
combination thereof, may have an average diameter of about 1
Angstrom (.ANG.) to about 20 .ANG.. For example the molecule may
have a diameter of about 1 .ANG., about 2 .ANG., about 3 .ANG.,
about 4 .ANG., about 5 .ANG., about 6 .ANG., about 7 .ANG., about 8
.ANG., about 9 .ANG., about 10 .ANG., about 11 .ANG., about 12
.ANG., about 13 .ANG., about 14 .ANG., about 15 .ANG., about 16
.ANG., about 17 .ANG., about 18 .ANG., about 19 .ANG., about 20
.ANG., or any value or range between any two of these values
(including endpoints).
[0087] Table 1 displays the physical characteristics of T1-reducing
contrast agents suitable for use in the present invention.
TABLE-US-00001 TABLE 1 Stock Molecular Average Brand Concentration
Weight Diameter Name Generic Name (M) (amu) (.ANG.) Magnevist
Gadopentetate 0.5 938.00 10 dimeglumine (Gd-DTPA) Dotarem
Gadoterate 0.5 753.86 9 meglumine OptiMARK Gadoversetamide 0.5
661.77 8 ProHance Gadoteridol 0.5 558.70 7 Omniscan Gadodiamide 0.5
573.66 8 MultiHance Gadobenate 0.5 1058.20 11 Dimeglumine Gadovist
Gadobutrol 1 604.70 8 Eovist Gadoxetate 0.25 725.72 9 Disodium
Ablavar Gadofosveset 0.25 975.88 10 trisodium
[0088] Table 2 displays the physical characteristics of T2-reducing
contrast agents suitable for use in the present invention.
TABLE-US-00002 TABLE 2 Stock Con- Molecular Average. centration
Weight Diameter. Brand Name Generic Name of Fe (M) (amu) (nm)
Feraheme Ferumoxytol 0.537 n/a 17-31 FeraSpin XS n/a 0.01 n/a 10-20
FeraSpin S n/a 0.01 n/a 20-30 FeraSpin M n/a 0.01 n/a 30-40
FeraSpin L n/a 0.01 n/a 40-50 FeraSpin XL n/a 0.01 n/a 50-60
FeraSpin n/a 0.01 n/a 60-70 XXL FeraSpin R n/a 0.005 n/a 10-90 n/a
Iron nickel oxide n/a n/a <50 nanoparticle nanopowder n/a Iron
oxide(II, III) 0.018 to 0.09 n/a 4-6, 9-11, magnetic or 28-32
nanoparticle dispersion/solution n/a Iron oxide(II, III) n/a n/a
4-6, 9-11, magnetic or 28-32 nanopowder nanopowder n/a Iron
nanopowder n/a n/a 25, 35-45, 40-60, or 60-80 n/a Magnetic iron n/a
n/a 3.5-9.5 oxide nanopowder
[0089] Some embodiments are directed to a method for measuring the
permeability of a body cavity in a patient, the method comprising:
administering a contrast agent with both T1-reducing and
T2-reducing effects to the patient; imaging the patient; and
wherein diffusion of the solution across the luminal surface of the
body cavity is indicative of permeability. In some embodiment, the
body cavity is the cardiovascular system, blood vessels, heart, or
a combination thereof. Some embodiments are directed to a method
for measuring the permeability of a body cavity in a patient, the
method comprising: imaging the patient after administering a
contrast agent with both T1-reducing and T2-reducing effects to the
patient; imaging the patient; and wherein diffusion of the contrast
agent across the luminal surface of the body cavity is indicative
of permeability. In some embodiment, the body cavity is the
cardiovascular system, blood vessels, heart, or a combination
thereof. In some embodiments, the contrast agent with both
T1-reducing and T2-reducing effects comprises a gadolinium
compound. In some embodiments, the contrast agent with both
T1-reducing and T2-reducing effects may be a magnetic resonance
imaging (MRI) contrast agent. In particular embodiments, the
contrast agent with both T1-reducing and T2-reducing effects may be
a gadolinium-containing contrast agent. In some embodiments, the
gadolinium compounds include but are not limited to gadopentetate
dimeglumine (Gd-DTPA), gadoterate, gadoterate meglumine,
gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,
gadobutrol, gadoxetate disodium, gadofosveset trisodium, gadoteric
acid, gadopentetate and combinations thereof. Those having ordinary
skill in the art will recognize that other gadolinium-containing
contrast agents and/or gadolinium salts that are now known or later
developed may also be used without departing from the scope of the
present disclosure. In some embodiments the solution comprises
Gadopentetate dimeglumine (Gd-DTPA). In some embodiments, the
Gadopentetate dimeglumine (Gd-DTPA) is present in a concentration
of about 0.5 M. In some embodiments, administration of high
concentrations of a contrast agent with both T1-reducing and
T2-reducing effects such as, but not limited to, a gadolinium
compound results in a reduction of local T1 (spin-lattice
relaxation) time as well as a reduction of local T2 (Spin-Spin
relaxation) time. In yet other embodiments, administration of high
concentrations of a contrast agent with both T1-reducing and
T2-reducing effects such as, but not limited to, a gadolinium
compound results in a reduction of image signal intensity. In some
embodiments, administration of high concentrations of a contrast
agent with both T1-reducing and T2-reducing effects such as, but
not limited to, a gadolinium compound, is sufficient to mask the
contrast effect of the contrast agent with both T1-reducing and
T2-reducing effects within the lumen of the body cavity. In some
embodiments, masking of the contrast effect of the contrast agent
with both T1-reducing and T2-reducing effects within the lumen of
the body cavity indicative of a non-permeable body cavity. In yet
other embodiments, diffusion of the contrast agent with both
T1-reducing and T2-reducing effects across the luminal surface of
the bladder, or out of the lumen of the bladder, can be visualized
because of the reduction of local T2 (Spin-Spin relaxation) time
and masking of the contrast effect in the lumen of the body cavity.
In some embodiments, if the luminal wall of the body cavity is
permeable, a bright ring will result due to diffusion of the
contrast agent with both T1-reducing and T2-reducing effects into
the tissue at a concentration that is lower than in the lumen of
the body cavity which allows the T1-reducing effect of the contrast
agent to dominate and create the bright ring image. In some
embodiments, this is due to a filtering process. The contrast agent
with both T1-reducing and T2-reducing effects remaining in the
lumen of the body cavity remains in a concentration that is
sufficiently high that the T2-reducing effect dominates and masks
the signal.
[0090] Some embodiments are directed to a method for detecting the
porosity of the luminal wall of a body cavity comprising:
administering to the the lumen of the body cavity a T1-reducing
contrast agent, a T2-reducing contrast agent, wherein the particle
size of the T2-reducing contrast agent are larger than the porosity
of the luminal wall of the body cavity; and wherein the particle
size of the T1-reducing contrast agent is smaller than the porosity
of the luminal wall of the body cavity, acquiring an MRI image of
the body cavity and surrounding tissue, wherein the image is
acquired such that tissues and fluids having low T2 appear dark,
tissues and fluids and fluids having low T1 appear bright, but
however tissues and fluids having both low T1 and low T2 appear
dark, and detecting if there is bright signal in said MRI image
corresponding to tissue surrounding said cavity. In some
embodiment, the body cavity is the cardiovascular system, blood
vessels, heart, or a combination thereof.
[0091] In various embodiments, a method of performing a diagnostic
examination of a patient's cardiovascular system, blood vessels,
heart, or a combination thereof may include, but is not limited to,
providing a T1-reducing contrast agent to the cardiovascular
system, blood vessels, heart, or a combination thereof of a
patient, providing a T2-reducing contrast agent to the
cardiovascular system, blood vessels, heart, or a combination
thereof of the patient, and imaging the patient. In some
embodiments, the patient is suspected of having PFO, ischemic
endocardium, post-embolic or pre-hemorrhagic stroke breakdown of
the blood-brain-barrier (BBB), vasculitis, ruptured atherosclerotic
plaque, diabetic vasculopathy, inflammation, vasculitis, autoimmune
disease, infection, cancer, septic shock, or a combination thereof
without wishing to be bound by theory, certain diseases, including,
but not limited to, the conditions described herein result in a
breakdown of the intercellular junctions of the blood vessel making
the diseased blood vessel permeable and allowing the T1-reducing
contrast agent to diffuse into the permeable region of the luminal
wall of the diseased blood vessel.
[0092] In some embodiments, the solutions, compositions, and
methods disclosed herein can be utilized with or on a subject in
need of such treatment, which can also be referred to as "in need
thereof." As used herein, the phrase "in need thereof" means that
the subject has been identified as having a need for the particular
method or treatment and that the treatment has been given to the
subject for that particular purpose.
[0093] In some aspects, the invention is directed to an imaging
composition comprising one or more solutions, as defined herein,
and, in some embodiments, a pharmaceutically acceptable carrier or
diluent, or an effective amount of a pharmaceutical composition
comprising a solution as defined above.
[0094] Some embodiments are directed to imaging compositions
comprising: a T1-reducing contrast agent; and a T2-reducing
contrast agent, wherein the T2-reducing contrast agent. In some
embodiments, the imaging composition further comprises an aqueous
solution. In some embodiments, the particle size of the T2-reducing
contrast agent is larger than the particle size of the T1-reducing
contrast agent.
[0095] In some embodiments, the T1-reducing contrast agent
comprises a gadolinium compound. In some embodiments, the
gadolinium compound is selected from gadopentetate dimeglumine
(Gd-DTPA), gadoterate meglumine, gadoversetamide, gadoteridol,
gadodiamide, gadobenate dimeglumine, gadobutrol, gadoxetate
disodium, gadofosveset trisodium and combinations thereof. In some
embodiments, the gadolinium compound is encapsulated in
liposomes.
[0096] In some embodiments, the T2-reducing contrast agent
comprises an iron oxide. In some embodiments, the iron oxide is
selected from iron (II) oxide, iron (III) oxide, ferumoxytol
(Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,
Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide
(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder,
magnetic iron oxide nanoparticles, carbon coated iron nanopowder,
and combinations thereof. In some embodiments, the iron oxide is
encapsulated in liposomes.
[0097] In some embodiments, the methods and compositions described
herein may comprise other contrast agents that when administered
together, or alone, exhibit a contrast effect that allows
measurement of the permeability of a body cavity. In some
embodiments, these contrast agents may be useful for measuring body
cavity permeability using MRI as well as imaging techniques other
than MRI.
[0098] The contrast agents and compositions of the present
invention can be administered in the conventional manner by any
route where they are active. Administration can be systemic,
topical, or oral or via instillation. For example, administration
can be, but is not limited to, parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, oral,
buccal, or ocular routes, or intravaginally, by inhalation, by
depot injections, or by implants. Thus, modes of administration for
the compositions and solutions of the present invention (either
alone or in combination with other pharmaceuticals) can be, but are
not limited to, instillation, sublingual, injectable (including
short-acting, depot, implant and pellet forms injected
subcutaneously or intramuscularly), or by use of vaginal creams,
suppositories, pessaries, vaginal rings, rectal suppositories,
intrauterine devices, and transdermal forms such as patches and
creams.
[0099] Specific modes of administration will depend on the
indication or body cavity being imaged. The selection of the
specific route of administration and concentration of imaging
compositions containing the T1-reducing contrast agents,
T2-reducing contrast agents, or combinations thereof, is to be
adjusted or titrated by the clinician according to methods known to
the clinician in order to optimize the imaging process. The
concentration to be administered will depend on the characteristics
of the patient to which the contrast agent, contrast agents, or
compositions being administered, e.g., the particular patient
(human or animal) treated, age, weight, health, types of concurrent
treatment, if any, and frequency of treatments, and can be easily
determined by one of skill in the art (e.g., by the clinician).
[0100] Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof, of
the present invention and a suitable carrier can be solid dosage
forms which include, but are not limited to, tablets, capsules,
cachets, pellets, pills, powders and granules; topical dosage forms
which include, but are not limited to, solutions, powders, fluid
emulsions, fluid suspensions, semi-solids, ointments, pastes,
creams, gels and jellies, and foams; and parenteral dosage forms
which include, but are not limited to, solutions, suspensions,
emulsions, and dry powder; comprising an effective amount of a
polymer or copolymer of the present invention. It is also known in
the art that the active ingredients can be contained in such
formulations with pharmaceutically acceptable diluents, fillers,
disintegrants, binders, lubricants, surfactants, hydrophobic
vehicles, water soluble vehicles, emulsifiers, buffers, humectants,
moisturizers, solubilizers, preservatives and the like. The means
and methods for administration are known in the art and an artisan
can refer to various pharmacologic references for guidance. For
example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker,
Inc. (1979); and Goodman & Gilman's The Pharmaceutical Basis of
Therapeutics, 6th Edition, MacMillan Publishing Co., New York
(1980) can be consulted.
[0101] Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof, can
be formulated for instillation. The agents and compositions can be
administered by instillation over a period of about 15 minutes to
about 24 hours. Formulations for instillation can be presented in
unit dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The compositions can take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and can contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0102] Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof, can
be formulated for parenteral administration by injection, e.g., by
bolus injection or continuous infusion. The agents and compositions
can be administered by continuous infusion subcutaneously over a
period of about 15 minutes to about 24 hours. Formulations for
injection can be presented in unit dosage form, e.g., in ampoules
or in multi-dose containers, with an added preservative. The
compositions can take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and can contain formulatory
agents such as suspending, stabilizing and/or dispersing
agents.
[0103] For oral administration, the Imaging compositions containing
the T1-reducing contrast agents, T2-reducing contrast agents, or
combinations thereof, can be formulated readily by combining the
agents described herein with pharmaceutically acceptable carriers
well known in the art. Such carriers enable the agents of the
invention to be formulated as tablets, pills, dragees, capsules,
liquids, gels, syrups, slurries, suspensions and the like, for oral
ingestion by a patient to be treated. Imaging preparations for oral
use can be obtained by adding a solid excipient, optionally
grinding the resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients include, but are not
limited to, fillers such as sugars, including, but not limited to,
lactose, sucrose, mannitol, and sorbitol; cellulose preparations
such as, but not limited to, maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and
polyvinylpyrrolidone (PVP). If desired, disintegrating agents can
be added, such as, but not limited to, the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0104] Dragee cores can be provided with suitable coatings. For
this purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active doses.
[0105] Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof, which
can be used orally include, but are not limited to, push-fit
capsules made of gelatin, as well as soft, sealed capsules made of
gelatin and a plasticizer, such as glycerol or sorbitol. The
push-fit capsules can contain the agents in admixture with filler
such as, e.g., lactose, binders such as, e.g., starches, and/or
lubricants such as, e.g., talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the agents can be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers can be added. All formulations for oral administration
should be in dosages suitable for such administration. For buccal
administration, the solutions can take the form of, e.g., tablets
or lozenges formulated in a conventional manner.
[0106] For administration by inhalation, the Imaging compositions
containing the T1-reducing contrast agents, T2-reducing contrast
agents, or combinations thereof, for use according to the present
invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol the
dosage unit can be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, e.g., gelatin for use
in an inhaler or insufflator can be formulated containing a powder
mix of the compound and a suitable powder base such as lactose or
starch.
[0107] Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof, of
the present invention can also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0108] In some embodiments, the Imaging compositions containing the
T1-reducing contrast agents, T2-reducing contrast agents, or
combinations thereof, may be prepared as suspensions, solutions or
emulsions in oily or aqueous vehicles suitable for injection. In
such embodiments, such solutions may further include formulatory
agents such as suspending, stabilizing and or dispersing agents
formulated for parenteral administration. Such injectable solutions
may be administered by any route, for example, instillation,
subcutaneous, intravenous, intramuscular, intra-arterial or bolus
injection or continuous infusion, and in embodiments in which
injectable compositions are administered by continuous infusion,
such infusion may be carried out for a period of about 15 minutes
to about hours. In certain embodiments, compositions for injection
may be presented in unit dosage form, e.g., in ampoules or in
multi-dose containers, with an added preservative.
[0109] In some embodiments, the Imaging compositions containing the
T1-reducing contrast agents, T2-reducing contrast agents, or
combinations thereof, described herein may be encapsulated in
liposomes. The liposomes may be used to increase the size of the
agents. The liposomes may be prepared by a variety of methods. In
the process of making liposomes, the agents may be added at any
desired time. For example, agents may be associated with components
of liposomes before liposomes are formed. Agents may be combined
with liposome components at the time the liposomes are made. Agents
may also be added after the liposomes are formed. Other methods of
associating agents with liposomes may exist. Generally, agents
which are hydrophilic in nature may be located or associated with
the internal cavity of the liposome particles. Agents which are
lipophilic in nature may be located or associated with the lipid
bilayer of liposome particles. Generally, the agents herein are
located or associated with the internal cavity of the liposome.
[0110] There are a variety of methods for encapsulating the Imaging
compositions containing the T1-reducing contrast agents,
T2-reducing contrast agents, or combinations thereof, described
herein into the liposomes. The method may include selecting one or
more agents to be used. The method may also include forming
liposomes in the presence of the one or more agents. In some
embodiments, these methods may include hydration of dried lipids,
introduction of a volatile organic solution of lipids into an
aqueous solution causing evaporation of the organic solution,
dialysis of an aqueous solution of lipids and detergents or
surfactants to remove the detergents or surfactants, and others. In
some embodiments, the agents encapsulated in liposomes may be
manufactured by co-dissolving sphingomyelin with the agent in a 30%
tertiary butyl alcohol-water solvent then lyophilized. This
procedure will generate a pre-liposomal lyophilate of the agent
with particle sizes that range from about 1 .mu.m to about 50 .mu.m
diameters. Upon rehydration, a standard multiple dialysis technique
will be used to isolate specific size ranges of the agents
encapsulated in the liposomes.
[0111] In addition to the formulations described herein, the
Imaging compositions containing the T1-reducing contrast agents,
T2-reducing contrast agents, or combinations thereof, of the
present invention can also be formulated as a depot preparation.
Such long acting formulations can be administered by implantation
(for example subcutaneously or intramuscularly) or by intramuscular
injection.
[0112] Depot injections can be administered at about 1 to about 6
months or longer intervals. Thus, for example, the compounds can be
formulated with suitable polymeric or hydrophobic materials (for
example as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
[0113] In transdermal administration, the compounds of the present
invention, for example, can be applied to a plaster, or can be
applied by transdermal, therapeutic systems that are consequently
supplied to the organism.
[0114] Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof,
described herein also can comprise suitable solid or gel phase
carriers or excipients. Examples of such carriers or excipients
include but are not limited to calcium carbonate, calcium
phosphate, various sugars, starches, cellulose derivatives,
gelatin, and polymers such as, e.g., polyethylene glycols.
[0115] The Imaging compositions containing the T1-reducing contrast
agents, T2-reducing contrast agents, or combinations thereof, of
the present invention can also be formulated and/or administered in
combination with other active ingredients, such as, for example,
adjuvants, protease inhibitors, or other compatible drugs or
compounds where such combination is seen to be desirable or
advantageous in achieving the desired effects of the methods
described herein.
[0116] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Therefore the spirit and
scope of the appended claims should not be limited to the
description and the preferred versions contained within this
specification.
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