U.S. patent application number 10/925193 was filed with the patent office on 2005-01-27 for ultrasound contrast using halogenated xanthenes.
This patent application is currently assigned to Xantech Pharmaceuticals, Inc.. Invention is credited to Dees, H. Craig, Scott, Timothy C., Wachter, Eric A..
Application Number | 20050019264 10/925193 |
Document ID | / |
Family ID | 32505865 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050019264 |
Kind Code |
A1 |
Dees, H. Craig ; et
al. |
January 27, 2005 |
Ultrasound contrast using halogenated xanthenes
Abstract
New contrast agents for ultrasound imaging and methods for use
of such agents for imaging of human or animal tissue are described,
wherein a primary active component of such medicaments is a
halogenated xanthene or halogenated xanthene derivative.
Preferably, the halogenated xanthene is Rose Bengal or a functional
derivative of Rose Bengal.
Inventors: |
Dees, H. Craig; (Knoxville,
TN) ; Scott, Timothy C.; (Knoxville, TN) ;
Wachter, Eric A.; (Oak Ridge, TN) |
Correspondence
Address: |
Edward D. Manzo
Cook, Alex, McFarron, Manzo,
Cummings & Mehler, Ltd.
200 West Adams St., Ste. 2850
Chicago
IL
60606
US
|
Assignee: |
Xantech Pharmaceuticals,
Inc.
|
Family ID: |
32505865 |
Appl. No.: |
10/925193 |
Filed: |
August 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10925193 |
Aug 24, 2004 |
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10314840 |
Dec 9, 2002 |
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10314840 |
Dec 9, 2002 |
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09184388 |
Nov 2, 1998 |
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6493570 |
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Current U.S.
Class: |
424/9.52 |
Current CPC
Class: |
A61K 41/008 20130101;
A61K 49/0041 20130101; A61N 5/0601 20130101; A61K 49/222 20130101;
A61K 41/0057 20130101; A61P 35/00 20180101; A61N 5/062
20130101 |
Class at
Publication: |
424/009.52 |
International
Class: |
A61K 049/00 |
Claims
1. A method for imaging human or animal tissue comprising the steps
of: administering an ultrasound contrast agent to a patient, a
portion of said ultrasound contrast agent being retained in tissue
of interest; and imaging said tissue with ultrasound to identify
said tissue, wherein said ultrasound contrast agent is a
halogenated xanthene.
2. The method of claim 1 wherein said halogenated xanthene is
present in a concentration of greater than about 0.001% to less
than about 20%.
3. The method of claim 1 wherein said halogenated xanthene is Rose
Bengal.
4. A medicament comprising at least one halogenated xanthene as a
primary active component, wherein said medicament is useful for
ultrasound imaging of human and animal tissue.
5. The medicament of claim 4 wherein said halogenated xanthene is
present in a concentration of greater than about 0.001% to less
than about 20%.
6. The medicament of claim 4 wherein said halogenated xanthene
comprises Rose Bengal.
Description
[0001] This is a continuation-in-part of U.S. patent application
Ser. No. 09/184,388, filed on Nov. 2, 1998, entitled "Method for
Improved Imaging and Photodynamic Therapy".
BACKGROUND OF THE INVENTION
[0002] The present invention is directed to new contrast agents for
ultrasound imaging. Ultrasound imaging (and diagnostic ultrasound,
hereinafter referred to collectively as ultrasound imaging) is
commonly used to obtain non-invasive information about internal
body structures and the function and motion of such structures.
When acoustic energy is coupled into an object to be imaged (such
as part of a human body), it propagates through the body with a
small portion being reflected, scattered, absorbed or otherwise
redirected. The properties of this propagation are affected by
various acoustic variables, including pressure, density,
temperature and particle motion.
[0003] A key variable affecting acoustic propagation is impedance,
which comprises the product of material density and the propagation
speed of acoustic energy in the material. An acoustic reflection
occurs when there exists a boundary between materials of differing
impedance. Thus, ultrasound imaging allows detection of impedance
boundaries, such as those that occur due to the differences in
density between bone and muscle or blood and vascular walls.
[0004] Considerable effort has been invested in development of
ultrasound contrast agents in an effort to improve contrast between
various anatomical features, such as between the vascular lumen and
surrounding vessel walls. This is particularly important in
assessing many myocardial, renal, respiratory, and oncologic
diseases, where the ability to visualize small blood vessels
enables physicians to accurately identify and assess disease
severity. Moreover, when certain agents are injected directly into
tissues, such as ablative agents used for destruction of diseased
tissue, or instilled into internal body cavities, such as the
bladder, it is desirable to be able to observe such agents using
ultrasound imaging. Thus, new agents capable of exhibiting
ultrasound contrast are needed for these and other medical
applications of ultrasound imaging.
[0005] Therefore, it is an object of the present invention to meet
these characteristics and to overcome the drawbacks in prior
methods and agents.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to certain ultrasound
contrast agents and methods for using agents exhibiting ultrasound
contrast.
[0007] In a preferred embodiment, a primary component of such
ultrasound contrast agent is a halogenated xanthene or a functional
derivative of a halogenated xanthene. In a further preferred
embodiment, the halogenated xanthene is Rose Bengal or a functional
derivative of Rose Bengal.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1a is an illustration of the chemical structure of a
halogenated xanthene;
[0009] FIG. 1b is an illustration of the chemical structure of Rose
Bengal;
[0010] FIG. 2 illustrates an ultrasound image of a region of animal
tissue following injection of a small volume of saline;
[0011] FIG. 3 illustrates an ultrasound image of a region of animal
tissue following injection of a small volume of 10% Rose Bengal in
saline;
[0012] FIG. 4 illustrates an ultrasound image of a region of animal
tissue following injection of a small volume of 20% Rose Bengal in
saline.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENT
[0013] The present invention is directed to certain ultrasound
contrast agents and methods for using agents exhibiting ultrasound
contrast. In a preferred embodiment, a primary component of such
ultrasound contrast agent is a halogenated xanthene or a functional
derivative of a halogenated xanthene. In a further preferred
embodiment, the halogenated xanthene is Rose Bengal or a
functional. derivative of Rose Bengal (i.e.,
4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein).
[0014] The halogenated xanthenes constitute a family of extremely
useful agents that can be selectively delivered at high
concentrations to certain tissues. Certain properties of the
halogenated xanthenes are described in U.S. Ser. No. 09/635,276,
filed on Aug. 9, 2000, and in U.S. Ser. No. 09/900,355, filed on
Jul. 6, 2001, which are herein incorporated by reference in their
entirety. The generalized chemical structure of the halogenated
xanthenes is illustrated in FIG. 1a, where the symbols X, Y, and Z
represent various elements present at the designated positions, and
the symbols R.sup.1 and R.sup.2 represent various functionalities
present at the designated positions. The chemical structure of a
specific example of a halogenated xanthene, Rose Bengal, is
illustrated in FIG. 1b. Physical properties of representative
halogenated xanthenes are summarized in attached Table 1.
[0015] When used as a chemoablative agent, selective retention of a
halogenated xanthene at a high concentration in a treated tissue
can result in decreased viability or death of such tissue (and
hence provides a chemotherapeutic use for medicaments containing
such halogenated xanthene). When used as a photodynamic agent,
selective retention of a halogenated xanthene in a treated tissue,
followed by illumination of such tissue with light between 500 and
600 nm, can result in a photodynamic effect in such tissue (and
hence provides a photodynamic use for medicaments containing such
halogenated xanthene). When instilled into internal body cavities,
such as the bladder, the distribution of the agent and the shape of
the cavity may be observed. In these and various other medical
applications, it may be desirable to image or otherwise monitor
distribution of such medicarnents during or subsequent to
administration, for example to assure uniform delivery of agent to
a tissue to be treated by photodynamic therapy.
[0016] The applicants have discovered that the halogenated
xanthenes are capable of interacting with ultrasound to produce
strong ultrasound signatures that allow detection and observation
of their presence and distribution within tissue using conventional
ultrasound imaging. Such properties facilitate imaging or otherwise
monitoring distribution of medicaments containing such halogenated
xanthenes.
[0017] The applicants speculate that this ultrasound signature
arises from differences in acoustic impedance between regions of
unaltered tissue (i.e., tissue not containing significant
quantities of a halogenated xanthene) and regions containing
halogenated xanthenes, and that such differences arise due to
anomalous density of regions containing halogenated xanthenes. For
example, the data in Table 2 show that a solution of 10% Rose
Bengal is at least 6% more dense than saline (i.e., saline is
representative of the primary interstitial fluid in tissue); in
contrast, deionized water and saline have less than 1% difference
in density. Since acoustic impedance, z, is directly related to
density, , according to the equation z=c, where c is the
propagation speed of acoustic energy in a particular medium, it is
likely that the applicants' model is accurate to a first
approximation.
[0018] Nonetheless, regardless of the validity of the applicants'
physical model the following data vividly illustrate the
applicants' observations and validate their invention. FIGS. 2, 3
and 4 illustrate ultrasound images of animal tissue following
injection of a small volume of saline (i.e., FIG. 2, light region
demarcated with arrows), following injection of a small volume of
10% Rose Bengal in saline (i.e., FIG. 3, dark region demarcated
with arrows), and following injection of a small volume of 20% Rose
Bengal in saline (i.e., FIG. 4, dark region demarcated with
arrows). The tissue specimens in these examples comprise
spontaneous tumor tissue in a recently deceased rat, illustrating
that useful contrast can be obtained using agents containing a
halogenated xanthene. Thus, a medicament containing a halogenated
xanthene not only is detectable using ultrasound imaging, but is
readily distinguishable from isotonic liquid (i.e., saline) and
tissue. Thus, FIGS. 2-4 demonstrate that a medicament containing a
halogenated xanthene may be observed and its distribution noted
within tissue using conventional ultrasound imaging.
[0019] Thus, a medicament containing a halogenated xanthene can be
used as an ultrasound contrast agent. Moreover, when used as a
therapeutic medicament (i.e., as a chemoablative or photodynamic
medicament containing a halogenated xanthene), the presence and
distribution of such medicament can be monitored during, and
subsequent to, administration. Such facility is useful for assuring
proper delivery of such medicament.
[0020] It is thus one preferred embodiment of the present invention
that an ultrasound contrast agent be produced that contains, as an
active ingredient at a concentration of from greater than
approximately 0.001% to less than approximately 20%, at least one
halogenated xanthene.
[0021] It is further preferred that this medicament include the
halogenated xanthene Rose Bengal.
[0022] Examples of other halogenated xanthenes which can be used in
the medicaments of the present invention include one or more of the
following: 4',5'-Dichlorofluorescein; 2',7'-Dichlorofluorescein;
4,5,6,7-Tetrachlorofluorescein; 2',4',5',7'-Tetrachlorofluorescein;
Dibromofluorescein; Solvent Red 72; Diiodofluorescein; Eosin B;
Eosin Y; Ethyl Eosin; Erythrosin B; Phloxine B; Rose Bengal;
4,5,6,7-Tetrabromoerythrosin; Mono-, Di-, or Tribromoerythrosin;
Mono-, Di-, or Trichloroerythrosin; Mono-, Di-, or
Trifluoroerythrosin; 2',7'-Dichloro-4,5,6,7-Tetrafluorofluorescein;
2',4,5,6,7,7'-Hexafluorofl- uorescein;
4,5,6,7-Tetrafluorofluorescein, 2',4',5,5',6,7'-Hexaiodofluores-
cein; 2',4',5,5',7,7'-Hexaiodofluorescein;
2',4',5',6,7,7'-Hexaiodofluores- cein;
2',4',5,5',6,7,7'-Heptaiodofluorescein;
4-Chloro-2',4',5,5',6,7'-hex- aiodofluorescein;
4-Chloro-2',4',5,5',7,7'-hexaiodofluorescein;
4-Chloro-2',4',5',6,7,7'-hexaiodofluorescein;
4-Chloro-2',4',5,5',6,7,7'-- heptaiodofluorescein;
4,5-Dichloro-2',4', 5', 6,7,7'-hexaiodofluorescein;
4,6-Dichloro-2',4',5,5',7,7'-hexaiodofluorescein; and
4,7-Dichloro-2',4',5',6,7,7'-hexaiodofluorescein.
[0023] In an alternate preferred embodiment ultrasound imaging is
used to image, detect or otherwise observe the presence of a
medicament that contains, at a concentration of from greater than
approximately 0.001% to less than approximately 20%, at least one
halogenated xanthene. It is further preferred that this medicament
include the halogenated xanthene Rose Bengal.
[0024] As a salient example of these preferred embodiments, certain
chemoablative agents are injected into diseased tissue, such as
that of liver tumors, using ultrasound imaging for guidance. A
common therapeutic regimen comprises injection of a volume of
concentrated ethanol into liver tumors to ablate such tumors.
Unfortunately, it is difficult to visualize the delivered volume of
ethanol with ultrasound imaging, making it commensurately difficult
to assure that the tumor tissue has been uniformly and adequately
treated. The ability to image an injected agent containing a
halogenated xanthene, as illustrated in FIGS. 3 and 4 using Rose
Bengal, overcomes this problem since the chemoablative agent is
readily imagabie using conventional ultrasound imaging.
[0025] This description has been offered for illustrative purposes
only and is not intended to limit the invention of this
application.
1TABLE 1 Physical Properties of Some Example Halogenated Xanthenes.
Substitution Compound X Y Z R.sup.1 R.sup.2 MW (g)
4',5'-Dichlorofluorescein Cl H H Na Na 445
2',7'-Dichlorofluorescein H Cl H Na Na 445
4,5,6,7-Tetrachlorofluorescein H H Cl H H 470
2',4',5',7'-Tetrachlorofluorescein Cl Cl H Na Na 514
Dibromofluorescein Br H H Na Na 534 Solvent Red 72 H Br H H H 490
Diiodofluorescein I H H Na Na 628 Eosin B NO.sub.2 Br H Na Na 624
Eosin Y Br Br H Na Na 692 Ethyl Eosin Br Br H C.sub.2H.sub.5 K 714
Erythrosin B I I H Na Na 880 Phloxine B Br Br Cl Na Na 830 Rose
Bengal I I Cl Na Na 1018 4,5,6,7-Tetrabromoerythrosin I I Br Na Na
1195
[0026]
2TABLE 2 Comparison of physical properties for liquid materials
Mass at 10 mL Density Relative Composition at 23.degree. C. to
Saline Deionized Water 10.002 g -0.6% Saline (0.9% Sodium Chloride)
10.058 g 0.0% 10% Rose Bengal (w/v) in 10.710 g +6.5% Saline (0.9%
Sodium Chloride)
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