U.S. patent application number 10/331735 was filed with the patent office on 2003-07-17 for medicaments for chemotherapeutic treatment of disease.
This patent application is currently assigned to Photogen, Inc.. Invention is credited to Dees, H. Craig, Scott, Timothy C..
Application Number | 20030133940 10/331735 |
Document ID | / |
Family ID | 26912931 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030133940 |
Kind Code |
A1 |
Dees, H. Craig ; et
al. |
July 17, 2003 |
Medicaments for chemotherapeutic treatment of disease
Abstract
New chemotherapeutic medicaments and certain medical uses and
methods for use of such chemotherapeutic medicaments for treatment
of disease in 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. The halogenated xanthenes constitute a family of
useful chemotherapeutic agents that afford selective, persistent
accumulation in certain tissues. In preferred embodiments, such
medicaments are used for treatment of a variety of conditions
affecting the skin and related organs, the mouth and digestive
tract and related organs, the urinary and reproductive tracts and
related organs, the respiratory tract and related organs, the
circulatory system and related organs, the head and neck, the
endocrine and lymphoreticular systems and related organs, various
other tissues, such as connective tissues and various tissue
surfaces exposed during surgery, as well as various tissues
exhibiting microbial or parasitic infection. In another preferred
embodiment, such medicaments are produced in various formulations
useful for intracorporeal or topical administration, including in
liquid, semisolid, solid or aerosol delivery vehicles.
Inventors: |
Dees, H. Craig; (Knoxville,
TN) ; Scott, Timothy C.; (Knoxville, TN) |
Correspondence
Address: |
Edward D. Manzo
Cook, Alex, McFarron, Manzo,
Cummings & Mehler, Ltd.
200 West Adams St., Ste. 2850
Chicago
IL
60606
US
|
Assignee: |
Photogen, Inc.
|
Family ID: |
26912931 |
Appl. No.: |
10/331735 |
Filed: |
December 30, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10331735 |
Dec 30, 2002 |
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09900355 |
Jul 6, 2001 |
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10331735 |
Dec 30, 2002 |
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09130041 |
Aug 6, 1998 |
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10331735 |
Dec 30, 2002 |
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09635276 |
Aug 9, 2000 |
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10331735 |
Dec 30, 2002 |
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09799785 |
Mar 6, 2001 |
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60218464 |
Jul 14, 2000 |
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Current U.S.
Class: |
424/178.1 ;
514/44R; 514/455 |
Current CPC
Class: |
A61P 43/00 20180101;
A61F 7/00 20130101; A61K 47/10 20130101; A61N 5/0601 20130101; A61K
41/0071 20130101; A61B 2017/22062 20130101; A61B 2017/22087
20130101; A61P 17/06 20180101; A61K 9/0019 20130101; C07D 311/82
20130101; A61P 35/00 20180101; A61K 9/0014 20130101; A61K 47/12
20130101; Y02A 50/473 20180101; Y10T 436/193333 20150115; A61K
31/352 20130101; A61K 41/0057 20130101; Y02A 50/30 20180101; A61N
5/062 20130101; A61P 31/00 20180101; A61K 47/20 20130101 |
Class at
Publication: |
424/178.1 ;
514/455; 514/44 |
International
Class: |
A61K 039/395; A61K
031/353; A61K 048/00 |
Claims
We claim:
1. A medicament comprising at least one halogenated xanthene as a
primary active component, wherein said medicament is useful for
chemotherapeutic treatment of human and animal tissue.
2. The medicament 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 medicament of claim 1 wherein said halogenated xanthene
comprises Rose Bengal.
4. The medicament of claim 1 wherein said halogenated xanthene
includes at least one compound selected from the group consisting
of 4',5'-Dichlorofluorescein; 2',7'-Dichlorofluorescein;
4,5,6,7-Tetrachlorofluorescein; 2',4',5',7'-Tetrachlorofluorescein;
Dibromofluorescein; Solvent Red 72; Diiodofluorescein; 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-Tetrafluoroflu-
orescein; 2',4,5,6,7,7'-Hexafluorofluorescein; and
4,5,6,7-Tetrafluorofluo- rescein.
5. The medicament of claim 1 further comprising at least one
targeting moiety coupled to said halogenated xanthene.
6. The medicament of claim 5 wherein said targeting moiety is
selected from the group consisting of deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), amino acids, proteins, antibodies, ligands,
haptens, carbohydrate receptors, carbohydrate complexing agents,
lipid receptors, lipid complexing agents, protein receptors,
protein complexing agents, chelators, encapsulating vehicles,
short-chain aliphatic hydrocarbons, long-chain aliphatic
hydrocarbons, aromatic hydrocarbons, aldehydes, ketones, alcohols,
esters, amides, amines, nitrites, azides, hydrophilic moieties and
hydrophobic moieties.
7. The medicament of claim 1 wherein said medicament is formulated
in a delivery vehicle selected from the group consisting of
liquids, semisolids, solids and aerosols.
8. The medicament of claim 7 wherein said vehicle is selected from
the group consisting of aqueous suspensions, non-aqueous
suspensions, solutions, creams, ointments, gels, syrups,
suppositories, tablets, capsules and micro-droplet sprays.
9. The medicament of claim 1 wherein said halogenated xanthene is
in a delivery vehicle that includes an adjuvant selected from the
group consisting of builders, stabilizers, emulsifiers,
dispersants, preservatives, buffers, electrolytes, tissue
penetrating agents and tissue softening agents.
10. The medicament of claim 1 wherein said medicament is useful for
the treatment of indications selected from the group consisting of
conditions affecting the skin and related organs, conditions
affecting the mouth and digestive tract and related organs,
conditions affecting the urinary and reproductive tracts and
related organs, conditions affecting the respiratory tract and
related organs, conditions affecting the circulatory system and
related organs, conditions affecting the head and neck, conditions
affecting the endocrine and lymphoreticular systems and related
organs, conditions affecting connective tissues, conditions
affecting tissue surfaces exposed during surgery, and conditions
related to microbial, viral, fungal, and parasitic infection.
11. The medicament of claim 1 wherein said medicament is
administered using a route of administration selected from the
group consisting of intravenous injection, intraperitoneal
injection, intramuscular injection, intracranial injection,
intratumoral injection, intraepithelial injection, transcutaneous
delivery, per oesophageal administration, intraabdominal
administration, intraapendicular administration, intraarterial
administration, intraarticular administration, intrabronchial
administration, intrabuccal administration, intracapsular
administration, intracardial administration, intracartilaginous
administration, intracavitary administration, intracephalic
administration, intracolic administration, intracutaneous
administration, intracystic administration, intradermal
administration, intraductal administration, intraduodenal
administration, intrafascicular administration, intrafat
administration, intrafilar administration, intrafissural
administration, intragastric administration, intraglandular
administration, intrahepatic administration, intraintestinal
administration, intralamellar administration, intralesional
administration, intraligamentous administration, intralingual
administration, intramammary administration, intramedullary
administration, intrameningeal administration, intramyocardial
administration, intranasal administration, intraocular
administration, intraoperative administration, intraoral
administration, intraosseous administration, intraovarian
administration, intrapancreatic administration, intraparietal
administration, intrapelvic administration, intrapericardial
administration, intraperineal administration, intraperitoneal
administration, intraplacental administration, intrapleural
administration, intrapontine administration, intraprostatic
administration, intrapulmonary administration, intrarachidian
administration, intrarectal administration, intrarenal
administration, intrascleral administration, intrascrotal
administration, intrasegmental administration, intrasellar
administration, intraspinal administration, intrasplenic
administration, intrasternal administration, intrastromal
administration, intrasynovial administration, intratarsal
administration, intratesticular administration, intrathoracic
administration, intratonsillar administration, intratracheal
administration, intratubal administration, intratympanic
administration, intraureteral administration, intraurethral
administration, intrauterine administration, intravaginal
administration, intravascular administration, intraventricular
administration, intravertebral administration, intravesical
administration, and intravitreous administration.
12. Use of a halogenated xanthene in the preparation of a
medicament for chemotherapeutic treatment of human and animal
tissue.
13. The use of claim 12 for preparation of a medicament for the
treatment of indications selected from the group consisting of
conditions affecting the skin and related organs, conditions
affecting the mouth and digestive tract and related organs,
conditions affecting the urinary and reproductive tracts and
related organs, conditions affecting the respiratory tract and
related organs, conditions affecting the circulatory system and
related organs, conditions affecting the head and neck, conditions
affecting the endocrine and lymphoreticular systems and related
organs, conditions affecting connective tissues, conditions
affecting tissue surfaces exposed during surgery, and conditions
related to microbial, viral, fungal, and parasitic infection.
14. The use of claim 12 wherein said halogenated xanthene comprises
Rose Bengal.
15. Use of a halogenated xanthene comprising: administering a
therapeutically effective amount of a halogenated xanthene into or
proximate to human or animal tissue for chemotherapeutic
treatment.
16. The use of claim 15 wherein said halogenated xanthene comprises
Rose Bengal.
17. The use of claim 15 wherein said halogenated xanthene is at a
concentration of greater than approximately 0.001% to less than
approximately 20%.
18. The use of claim 15 wherein said administering comprises use of
a route of administration selected from the group consisting of
intravenous injection, intraperitoneal injection, intramuscular
injection, intracranial injection, intratumoral injection,
intraepithelial injection, transcutaneous delivery, per oesophageal
administration, intraabdominal administration, intraapendicular
administration, intraarterial administration, intraarticular
administration, intrabronchial administration, intrabuccal
administration, intracapsular administration, intracardial
administration, intracartilaginous administration, intracavitary
administration, intracephalic administration, intracolic
administration, intracutaneous administration, intracystic
administration, intradermal administration, intraductal
administration, intraduodenal administration, intrafascicular
administration, intrafat administration, intrafilar administration,
intrafissural administration, intragastric administration,
intraglandular administration, intrahepatic administration,
intraintestinal administration, intralamellar administration,
intralesional administration, intraligamentous administration,
intralingual administration, intramammary administration,
intramedullary administration, intrameningeal administration,
intramyocardial administration, intranasal administration,
intraocular administration, intraoperative administration,
intraoral administration, intraosseous administration, intraovarian
administration, intrapancreatic administration, intraparietal
administration, intrapelvic administration, intrapericardial
administration, intraperineal administration, intraperitoneal
administration, intraplacental administration, intrapleural
administration, intrapontine administration, intraprostatic
administration, intrapulmonary administration, intrarachidian
administration, intrarectal administration, intrarenal
administration, intrascleral administration, intrascrotal
administration, intrasegmental administration, intrasellar
administration, intraspinal administration, intrasplenic
administration, intrasternal administration, intrastromal
administration, intrasynovial administration, intratarsal
administration, intratesticular administration, intrathoracic
administration, intratonsillar administration, intratracheal
administration, intratubal administration, intratympanic
administration, intraureteral administration, intraurethral
administration, intrauterine administration, intravaginal
administration, intravascular administration, intraventricular
administration, intravertebral administration, intravesical
administration, and intravitreous administration.
19. A pharmaceutical composition for intracorporeal administration
comprising a halogenated xanthene for chemotherapeutic
treatment.
20. The pharmaceutical composition of claim 19 wherein said
halogenated xanthene is present in a concentration of greater than
about 0.001% to less than about 20%.
21. The pharmaceutical composition of claim 19 wherein said
halogenated xanthene comprises Rose Bengal.
22. The pharmaceutical composition of claim 19 wherein said
halogenated xanthene includes at least one compound selected from
the group consisting of 4',5'-Dichlorofluorescein;
2',7'-Dichlorofluorescein; 4,5,6,7-Tetrachlorofluorescein;
2',4',5',7'-Tetrachlorofluorescein; Dibromofluorescein; Solvent Red
72; Diuodofluorescein; 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-Tetrafluoroflu-
orescein; 2',4,5,6,7,7'-Hexafluorofluorescein; and
4,5,6,7-Tetrafluorofluo- rescein.
23. The pharmaceutical composition of claim 19 further comprising
at least one targeting moiety coupled to said halogenated
xanthene.
24. The pharmaceutical composition of claim 23 wherein said
targeting moiety is selected from the group consisting of
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), amino acids,
proteins, antibodies, ligands, haptens, carbohydrate receptors,
carbohydrate complexing agents, lipid receptors, lipid complexing
agents, protein receptors, protein complexing agents, chelators,
encapsulating vehicles, short-chain aliphatic hydrocarbons,
long-chain aliphatic hydrocarbons, aromatic hydrocarbons,
aldehydes, ketones, alcohols, esters, amides, amines, nitriles,
azides, hydrophilic moieties and hydrophobic moieties.
25. The pharmaceutical composition of claim 19 wherein said
pharmaceutical composition is formulated in a delivery vehicle
selected from the group consisting of liquids, semisolids, solids
and aerosols.
26. The pharmaceutical composition of claim 25 wherein said vehicle
is selected from the group consisting of aqueous suspensions,
non-aqueous suspensions, solutions, creams, ointments, gels,
syrups, suppositories, tablets, capsules and micro-droplet
sprays.
27. The pharmaceutical composition of claim 19 wherein said
halogenated xanthene is in a delivery vehicle that includes an
adjuvant selected from the group consisting of builders,
stabilizers, emulsifiers, dispersants, preservatives, buffers,
electrolytes, tissue penetrating agents and tissue softening
agents.
28. A method of treating comprising: applying a medicament
including at least one halogenated xanthene into or proximate to
human or animal tissue for chemotherapeutic treatment.
29. The method of claim 28 wherein said human or animal tissue
comprises the skin and related organs, the mouth and digestive
tract and related organs, the urinary and reproductive tracts and
related organs, the respiratory tract and related organs, the
circulatory system and related organs, the head and neck, the
endocrine and lymphoreticular systems and related organs,
connective tissue, tissue surfaces exposed during surgery, and
tissue with microbial, viral, fungal, or parasitic infection.
30. The method of claim 28 wherein said halogenated xanthene is
Rose Bengal.
31. A medicament comprising at least one halogenated xanthene as a
primary active component, wherein such medicament is useful for
chemotherapeutic treatment, of human and animal tissue.
32. A pharmaceutical composition adapted for chemotherapeutic
effect, comprising a dosage unit of a halogenated xanthene.
33. The pharmaceutical composition of claim 36 wherein said
halogenated xanthene is Rose Bengal.
Description
[0001] This application is based on provisional application U.S.
Ser. No. 60/218,464 filed Jul. 14, 2000 and is a
continuation-in-part of U.S. Ser. No. 09/130,041, filed on Aug. 6,
1998; U.S. Ser. No. 60/149,015, filed on Aug. 13, 1999 and U.S.
Ser. No. 09/635,276 filed on Aug. 9, 2000; and U.S. Ser. No.
60/191,803, filed on Mar. 24, 2000 and U.S. Ser. No. 09/799,785
filed on Mar. 6, 2001, which are herein incorporated by reference
in their entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention is related to certain chemotherapeutic
medicaments and methods for treatment of human or animal tissue
using chemotherapy.
[0003] Chemotherapy was developed to treat cancer and other disease
with the promise of limiting the invasiveness of the therapeutic
intervention. Ideally in the practice of chemotherapy, chemical
agents that afford selective toxicity to diseased or otherwise
undesirable tissue are administered to a patient. Frequently, these
agents are administered systemically, with the expectation that the
viability of certain tissues, such as the rapidly proliferating
tissues of a cancerous tumor, will be selectively inhibited or
destroyed. Unfortunately, most chemotherapeutic agents presently
available offer limited specificity for such tissue, resulting in a
high incidence of disagreeable side-effects, such as immune system
suppression, nausea, and hair loss. While tremendous strides have
been made in an effort to reduce or mitigate such side-effects,
there still continues to be great difficulty in enhancement of
specificity of the drug for tissues to be treated.
[0004] Therefore, it is an object of the present invention to
provide new chemotherapeutic medicaments, new medical uses for such
medicaments based on improved specificity of such medicaments for
the desired target tissue to be treated, and methods for treatment
using such medicaments, thereby resulting in improved treatment
outcomes, increased efficacy and safety and reduced cost of
treatment.
SUMMARY OF THE PRESENT INVENTION
[0005] The present invention is directed to new chemotherapeutic
medicaments and certain medical uses of such medicaments, and
methods for treatment using such medicaments, for treatment of
human or animal tissue, wherein a primary active component of such
medicaments is a halogenated xanthene or a halogenated xanthene
derivative. In a preferred embodiment, the halogenated xanthene is
Rose Bengal or a functional derivative of Rose Bengal. The
halogenated xanthenes constitute a family of extremely useful
agents that can be selectively delivered at high concentrations to
certain tissues. Selective retention of such agents at high
concentrations in the desired tissues results in decreased
viability or death of such tissues (and hence provides a
chemotherapeutic use of medicaments containing agents). Such
medicaments are suitable for intracorporeal administration, and are
thus intracorporeal chemotherapeutic medicaments. Such medicaments
are also suitable for topical administration, and are thus topical
chemotherapeutic medicaments. Such medicaments can also be called
pharmaceutical compositions or agents.
[0006] Such chemotherapeutic medicaments are useful for the
treatment of a variety of conditions affecting the skin and related
organs, the mouth and digestive tract and related organs, the
urinary and reproductive tracts and related organs, the respiratory
tract and related organs, the circulatory system and related
organs, the head and neck, the endocrine and lymphoreticular
systems and related organs, various other tissues, such as
connective tissues and various tissue surfaces exposed during
surgery, as well as various tissues exhibiting microbial, viral,
fungal or parasitic infection. These medicaments are available in
various formulations that may include liquid, semisolid, solid or
aerosol delivery vehicles, and are suitable for intracorporeal
administration via various conventional modes and routes, including
intravenous injection (i.v.), intraperitoneal injection (i.p.),
intramuscular injection (i.m.), intracranial injection (i.c.),
intratumoral injection (i.t.), intraepithelial injection (i.e.),
transcutaneous delivery (t.c.), and per oesophageal (p.o.)
administration. Additionally, such medicaments are suitable for
topical administration via various conventional modes and routes,
including topical application directly to or proximal to certain
tissues. The active ingredients in such chemotherapeutic
medicaments produce a desirable therapeutic response, such as
destruction of microbial infection, reduction or elimination of
tissue irritation, reduction or elimination of hyperproliferative
tissue, reduction or elimination of cancerous or precancerous
tissue, reduction or elimination of surface or subsurface lipocytes
or lipid deposits, and many other similar indications.
[0007] In a preferred embodiment, such chemotherapeutic medicaments
are used for treatment of a variety of conditions affecting the
skin and related organs.
[0008] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting the mouth and digestive tract and related organs.
[0009] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting the urinary and reproductive tracts and related
organs.
[0010] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting the respiratory system and related organs.
[0011] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting the circulatory system and related organs.
[0012] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting the head and neck.
[0013] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting the endocrine and lymphoreticular systems and related
organs.
[0014] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
affecting various other tissues, such as connective tissues and
various tissue surfaces exposed during surgery.
[0015] In another preferred embodiment, such chemotherapeutic
medicaments are used for treatment of a variety of conditions
related to microbial or parasitic infection.
[0016] In another preferred embodiment, such chemotherapeutic
medicaments are produced in various formulations including liquid,
semisolid, solid or aerosol delivery vehicles, as well as in
tablet, capsule, suppository, and other similar forms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] In describing the preferred embodiments, reference is made
to the accompanying drawings wherein:
[0018] FIG. 1(a) shows the generalized chemical structure of the
halogenated xanthenes.
[0019] FIG. 1(b) shows the chemical structure of Rose Bengal.
[0020] FIG. 2 shows example pharmacokinetic behavior of Rose Bengal
upon intraperitoneal injection into nude mice with an implanted
MCF-7 human breast cancer tumor.
[0021] FIG. 3 illustrates cytotoxic effects in bacteria upon
exposure to either Rose Bengal or Erythrosin B as a function of
agent concentration.
[0022] FIG. 4 illustrates the cytotoxic effects of exposure to
either Rose Bengal or Erythrosin B as a function of exposure
duration.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0023] The present invention is directed to new chemotherapeutic
medicaments and certain medical uses of such chemotherapeutic
medicaments, and methods for chemotherapeutic treatment using such
medicaments, for treatment of human or animal tissue, wherein a
primary active component of such medicaments is a halogenated
xanthene or halogenated xanthene derivative. The inventors of the
present invention have discovered that such halogenated xanthenes,
as discussed in more detail infra, exhibit desirable
chemotherapeutic effects when applied to or otherwise delivered to
certain human or animal tissues. The desirable effects include
reduction or elimination of disease or diseased tissue or other
undesirable conditions, including eradication of cancerous or
pre-cancerous tumors and infectious agents. The treatment is
applicable to a variety of conditions affecting the skin and
related organs, the mouth and digestive tract and related organs,
the urinary and reproductive tracts and related organs, the
respiratory tract and related organs, the circulatory system and
related organs, the head and neck, the endocrine and
lymphoreticular systems and related organs, various other tissues,
such as tissues exposed during surgery, as well as various tissues
exhibiting microbial, viral, fungal or parasitic infection.
[0024] In a preferred embodiment, such medicaments are produced in
various formulations suitable for intracorporeal or topical
administration, including in various liquid, semisolid, solid or
aerosol delivery vehicles, as well as in tablet, capsule,
suppository, and other similar forms. Such medicament formulations
are suitable for delivery via various conventional modes and routes
(hereafter defined as administration), including intravenous
injection (i.v.), intraperitoneal injection (i.p.), intramuscular
injection (i.m.), intracranial injection (i.c.), intratumoral
injection (i.t.), intraepithelial injection (i.e.), transcutaneous
delivery (t.c.), per oesophageal (p.o.) administration, and topical
application; additional administrative modes and routes include
intraabdominal, intraapendicular, intraarterial, intraarticular,
intrabronchial, intrabuccal, intracapsular (such as for example
capsule in knee, elbow and eye), intracardial, intracartilaginous,
intracavitary, intracephalic, intracolic, intracutaneous,
intracystic, intradermal, intraductal, intraduodenal,
intrafascicular, intrafat, intrafilar, intrafissural, intragastric,
intraglandular, intrahepatic, intraintestinal, intralamellar,
intralesional, intraligamentous, intralingual, intramammary,
intramedullary, intrameningeal, intramyocardial, intranasal,
intraocular, intraoperative, intraoral, intraosseous, intraovarian,
intrapancreatic, intraparietal, intrapelvic, intrapericardial,
intraperineal, intraperitoneal, intraplacental, intrapleural,
intrapontine, intraprostatic, intrapulmonary, intrarachidian,
intrarectal, intrarenal, intrascleral, intrascrotal,
intrasegmental, intrasellar, intraspinal, intrasplenic,
intrastemal, intrastromal, intrasynovial, intratarsal,
intratesticular, intrathoracic, intratonsillar, intratracheal,
intratubal, intratympanic, intraureteral, intraurethral,
intrauterine, intravaginal, intravascular, intraventricular,
intravertebral, intravesical, or intravitreous administration.
[0025] 1. Properties of the Preferred Active Components and
Medicament Formulations.
[0026] The inventors of the present invention have discovered a
class of agents that are broadly applicable for producing
chemotherapeutic medicaments for treatment of disease in certain
human and animal tissues. These agents are referred to as
halogenated xanthenes and are 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.
[0027] Selected properties (such as chemical constituents at
positions X, Y, and Z and functionalities R.sup.1 and R.sup.2) of
representative halogenated xanthenes are summarized in attached
Table 1. Certain general properties of this class of agent are
discussed in further detail in U.S. Ser. No. 09/130,041 filed on
Aug. 6, 1998, U.S. Ser. No. 09/184,388 filed on Nov. 2, 1998, U.S.
Ser. No. 09/216,787 filed on Dec. 21, 1998, U.S. Ser. No.
09/635,276 filed on Aug. 9, 2000, U.S. Ser. No. 09/799,785 filed on
Mar. 6, 2001, and U.S. Ser. No. 09/817,448 filed on Mar. 26, 2001,
which are herein incorporated by reference in their entirety. In
general, the halogenated xanthenes are characterized by a low
cytotoxicity (toxicity to cells) at low concentration, a propensity
for selective concentration or retention in certain tissues and
cells, a high cytotoxicity upon such concentration or retention,
and by chemical and physical properties that are substantially
unaffected by the local chemical environment or by the attachment
of functional derivatives at positions R.sup.1 and R.sup.2. Such
factors make these chemical agents, and in particular
chemotherapeutic medicaments formulated from such agents, excellent
for the treatment of disease in human and animal tissues.
[0028] It is thus one preferred embodiment of the present invention
that a chemotherapeutic medicament 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.
[0029] It is preferred that this medicament include the halogenated
xanthene Rose Bengal
(4,5,6,7-Tetrachloro-2',4',5',7'-tetraiodofluorescei- n,
illustrated in FIG. 1b).
[0030] Examples of other halogenated xanthenes which can be used in
the medicaments of the present invention include one or more of the
following Fluorescein derivatives: 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'-Hexafluorofluorescein;
4,5,6,7-Tetrafluorofluorescein,
2',4',5,5',6,7'-Hexaiodofluorescein;
2',4',5,5',7,7'-Hexaiodofluorescein;
2',4',5',6,7,7'-Hexaiodofluorescein;
2',4',5,5',6,7,7'-Heptaiodofluoresce- in;
4-Chloro-2',4',5,5',6,7'-hexaiodofluorescein;
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',5,5',6',7'-hexaiodofluorescein.
[0031] As an example of these desirable chemical, biochemical, and
physical properties, the inventors have found that the prototypical
halogenated xanthene, Rose Bengal, will accumulate preferentially
in (e.g., target) some tumors and other tissues and pathogenic
entities and exhibit high cytotoxicity within such tumors, tissues
and pathogenic entities, while exhibiting negligible systemic
cytotoxicity or local cytotoxicity in surrounding healthy tissues.
Such agents also possess the ability to clear rapidly from healthy
tissue in the body. Furthermore, such agents have a relatively low
cost.
[0032] For example, to a first approximation, an agent's potential
for tissue accumulation can be estimated based on the partition
coefficient, K.sub.p. This in vitro parameter is purported to have
predictive value relating to in vivo agent delivery at the cellular
level. In particular, a value greater than unity is considered to
indicate agents capable of localizing in tumor or other diseased
tissue, and thereby being capable of exhibiting enhanced
chemotherapeutic efficacy in such tissue. K.sub.p is determined by
measuring the ratio of equilibrium concentrations of an agent in a
lipophilic phase (n-octanol) contacted with an aqueous phase
(phosphate buffered saline, PBS, pH=7.4). Comparative values of
K.sub.p are shown in Table 2. The large K.sub.p values for the
halogenated xanthenes suggest that the halogenated xanthenes will
exhibit a preference for concentration or accumulation in tumor or
other diseased tissue, and should thereby be capable of exhibiting
superior chemotherapeutic efficacy in such tissue. However, as
explained below, the inventors have discovered that halogenated
xanthenes exhibit a much greater chemotherapeutic efficacy in such
tissue than could be predicted solely from the K.sub.p values shown
in Table 2.
[0033] The following examples illustrate this preference for
accumulation in tumor tissue by the halogenated xanthenes:
[0034] Tumor cell suspensions (e.g., melanoma, breast tumor, liver
tumor, renal carcinoma, gall bladder tumor or prostate tumor) were
injected subcutaneously into the flanks of nude mice and resulted
in the formation of primary tumors, within a few weeks, at the
injection site having a volume of approximately 0.25 cm.sup.3. A
solution of Rose Bengal (50-100 .mu.L of 0.5% Rose Bengal in
saline) was then administered by intraperitoneal injection (i.p.)
to the tumor-bearing mice, and the injected mice sacrificed at
timed intervals following injection. Tissue samples (liver,
abdominal wall, and tumor) were immediately obtained from the
sacrificed mice, homogenized, centrifuged for 10 minutes at
1520.times.g, and the resulting supernatant collected and analyzed
fluorimetrically. This allowed the pharmacokinetics of the
administered Rose Bengal to be easily observed, as illustrated in
FIG. 2. The data in FIG. 2 show that Rose Bengal rapidly diffuses
from normal tissue (e.g., abdominal wall) and is efficiently
entrapped and excreted through the liver, with concentrations in
these tissues diminishing to unmeasurable levels within 24 hours.
At the same time, persistent accumulation occurs in tumor tissue,
with greater than 50% of maximum measured agent concentration
maintained in such tissues for periods in excess of 24 hours.
[0035] If such implanted tumors are directly injected with Rose
Bengal, similar selective, persistent accumulation occurs.
[0036] For example, BNL/SV40 liver cell tumor cells injected into
the flanks of nude mice, as described supra, resulted in the
formation of primary tumors, within a few weeks, at the injection
site and have a volume of approximately 0.25 cm.sup.3. Intratumoral
(i.t.) and peritumoral (p.t.) injection of a 10% solution of Rose
Bengal (50 .mu.L of 10% Rose Bengal in saline) resulted in marked
red staining of the tumor and the surrounding flank. Within 7 days
this Rose Bengal cleared from normal tissue, but the tumor tissue
remained stained. Over a period of several weeks the previously
rapidly growing tumor exhibited stasis, with no significant change
in tumor volume and a marked absence of mitotic figures (e.g.,
exhibiting only non-hyperproliferative cells).
[0037] Further, peritumoral injection alone (e.g., injection into
normal tissue around the outside margins of the tumor) of the above
Rose Bengal exhibited no detectable retention in normal tissue
after 24 hours. Notably, no significant effect on normal tissue,
nor on the adjacent tumor tissue, was noted upon peritumoral
injection alone.
[0038] Hence, the administered Rose Bengal in these examples not
only exhibited selective, persistent accumulation in tumor tissue,
but this accumulated agent also exhibits chemotherapeutic efficacy
with minimal or no measurable side effects in healthy tissue.
[0039] This chemotherapeutic effect for Rose Bengal is further
illustrated by the following example. An adult, female dog with a
naturally-occurring, recurrent aggressive sarcoma tumor
(approximately 20 cc in volume) was treated by injection of
approximately 5 cc of a 10% solution of Rose Bengal at several
locations throughout the tumor volume. After a period of five days,
a follow-up examination of the animal indicated a measurable
decrease in tumor density along with significant edema and apparent
necrosis of large sections of the tumor. Another follow-up
examination after 19 days indicated a further measurable decrease
in tumor size. Such a response is indicative of chemotherapeutic
activity of the injected Rose Bengal within the tumor mass. It is
also notable that no significant side-effects were noted in the
healthy tissue surrounding the tumor.
[0040] In contrast, i.t. administration of a different class of
agent, indocyanine green (K.sub.p=99), into various murine tumors
showed that within 24 hours this agent substantively migrates out
of tumors, with residual agent tending to accumulate in peritumoral
tissues. Moreover, no chemotherapeutic effect was evidenced upon
such administration of such agent. Hence, while the K.sub.p value
for indocyanine green is nearly ten-fold larger than that of Rose
Bengal (and as such, indocyanine green is, by the conventional
model based solely on K.sub.p, expected to accumulate strongly in
tumor tissue), the tissue localization properties of the two agents
are clearly completely different. Furthermore, even at the
relatively high concentrations in the immediate vicinity of the
injection site, indocyanine green was found to exhibit no
chemotherapeutic activity.
[0041] Thus, the halogenated xanthenes, and in particular Rose
Bengal, exhibit an unexpectedly marked preference for selective
accumulation and retention in tumor and other diseased tissue upon
administration, and that once present in such tissue, said
halogenated xanthenes can be utilized as potent, highly tissue- or
disease-specific chemotherapeutic agents.
[0042] The toxicology data shown in Table 2 indicate that the
halogenated xanthenes are relatively non-toxic, and yet, in
contrast to agents such as indocyanine green, they exhibit
unanticipated chemotherapeutic properties. One possible explanation
for this may be that such chemotherapeutic properties of the
halogenated xanthenes, and in particular of Rose Bengal, are the
result of their special combination of modest intrinsic
cytotoxicity and marked propensity for persistent, selective
accumulation in certain cells, such as cancerous cells: based, for
example, on simple first-order kinetics, such modestly cytotoxic
agents, upon becoming present in cells at high local concentrations
for extended periods of time, should exhibit chemotherapeutic
properties.
[0043] The inventors tested this hypothesis by evaluating the
chemotherapeutic properties of Rose Bengal and Erythrosin B on
cultures of the bacterium Staphylococcus aureus. These data are
illustrated in FIGS. 3 and 4. In both illustrations, test cultures
were exposed to the indicated agents at the indicated
concentrations for the indicated times; cytotoxicity was
subsequently estimated by serial dilution (10.times. dilution per
step) of the treated cell cultures into 96-well plates containing
fresh culture media; these samples were then incubated under
standard conditions. Viability (e.g., Logs of Growth) for each test
culture was then estimated by counting the number of dilution steps
resulting in positive cell growth. Cytotoxicity upon exposure to a
particular agent is thereby estimated by the reduction in viability
relative to unexposed (e.g., control) cultures. FIG. 3 illustrates
the cytotoxic effects of a 90 minute exposure of S. aureus to
either Rose Bengal or Erythrosin B. In this figure, Rose Bengal
exhibits a marked chemotherapeutic response that is concentration
dependent, while Erythrosin B exhibits no significant
chemotherapeutic response for this brief exposure duration over the
range of concentrations tested. FIG. 4 illustrates the cytotoxic
effects on S. aureus for various durations of exposure to Rose
Bengal or Erythrosin B (each administered at a concentration of 0.5
mg/mL). These data show that the chemotherapeutic properties of the
halogenated xanthenes are dependent on exposure time. Notably, the
negative slopes for the trend lines of both agents are indicative
of cumulative cytotoxicity that is time dependent. The shallower
slope for Erythrosin B indicates lower cytotoxicity in this model
(e.g. S. aureus), consistent with the results illustrated in FIG.
3. Hence, certain agents that exhibit a modest, but nonetheless
finite, cytotoxicity (such as for example, but not limited to, the
halogenated xanthenes) should afford chemotherapeutic modality when
administered to certain tissues, wherein such administration
results in sufficient local concentration of such agents for a
sufficient period so as to cause local cytotoxic effects (e.g.,
chemotherapy) in such tissues.
[0044] In addition to superior suitability for direct
administration into desired targeted tissue to be treated, such as
a focal tumor, the preference of the halogenated xanthenes for
accumulation in certain types of tissues provides a basis for
highly-selective, systemic delivery of the halogenated xanthenes to
such tissues. For example, Rose Bengal's relatively large partition
coefficient is indicative of a preference for accumulation in
lipophilic tissue, such as cutaneous lipocytes. Systemic
administration of Rose Bengal, for example as an aqueous solution
administered via intraperitoneal injection (i.p.) or per oesophagus
(p.o.) administration, resulted in highly selective accumulation of
said agent in certain tissues, such as in the cutaneous fat
deposits of obese laboratory mice. Histologic examination of skin
samples from such animals showed that the accumulated agent was
substantively limited to cutaneous lipocytes.
[0045] Moreover, the facility with which the halogenated xanthenes
target specific tissues or other sites can be further optimized by
attachment of specific functional derivatives at positions R.sup.1
and R.sup.2, so as to change the chemical partitioning and/or
biological activity of the agent. For example, attachment of one
targeting moiety or more at positions R.sup.1 or R.sup.2 can be
used to improve targeting to specific tissues, such as cancerous
tumor tissues or sites of localized infection. An example of this
is esterification at position R.sup.1 with a short aliphatic
alcohol, such as n-hexanol, to produce a derivatized agent
exhibiting enhanced partitioning into lipid-rich tumor tissues.
[0046] It is thus a further preferred embodiment that at least one
of the at least one halogenated xanthene active ingredients
includes at least one targeting moiety selected from a group that
includes deoxyribonucleic acid (DNA), ribonucleic acid (RNA), amino
acids, proteins, antibodies, ligands, haptens, carbohydrate
receptors or complexing agents, lipid receptors or complexing
agents, protein receptors or complexing agents, chelators,
encapsulating vehicles, short- or long-chain aliphatic or aromatic
hydrocarbons, including those containing aldehydes, ketones,
alcohols, esters, amides, amines, nitrites, azides, or other
hydrophilic or hydrophobic moieties. A further example of this
embodiment is derivatization of Rose Bengal with a lipid (at
position R.sup.1, via esterification), so as to increase the
lipophilicity of Rose Bengal, and thereby modify its targeting
properties in a patient. An additional further example of this
embodiment is derivatization of Rose Bengal with folate (at
position R.sup.1, via esterification or other modes of attachment),
so as to increase selective targeting of cancer and other cells
exhibiting enhanced folate receptor activity or folate
metabolism.
[0047] As a further example of the desirable chemical, biochemical,
and physical properties of the halogenated xanthenes and
halogenated xanthene derivatives, the inventors of the present
invention have shown that these agents are readily cleared from
healthy tissues in a matter of several hours, and are rapidly
excreted in bile, urine and feces, without doing damage to healthy
tissue while in the body. Further examples of the desirable
properties of the halogenated xanthenes and halogenated xanthene
derivatives are that the halogenated xanthenes and halogenated
xanthene derivatives are easily synthesized using simple, low-cost
synthetic methods, can be readily purified, and exhibit excellent
stability (such as a long shelf life without need for refrigeration
or storage under an inert atmosphere).
[0048] Because the halogenated xanthenes and their derivatives are,
in general, fine solid powders in their pure form, it is preferred
that, for proper delivery to desired tissues, such agents be
formulated in appropriate delivery vehicles. Specifically, such
formulations are preferred so as to facilitate agent delivery into
the body and subsequent contact with, and delivery to, desired
tissues to be treated. Approaches to such formulation will be
generally known to those of ordinary skill in the art.
[0049] It is thus a further preferred embodiment of the present
invention that at least one halogenated xanthene or halogenated
xanthene derivative be formulated as a medicament in a form
suitable for intracorporeal or topical administration via various
conventional modes and routes. Such suitable forms include, for
example, medicaments formulated in a liquid, semisolid, solid or
aerosol delivery vehicle, including in vehicles of the following
natures: aqueous, non-aqueous or particulate suspensions,
solutions, creams, ointments, gels, syrups, micro-droplet sprays,
suppositories, tablets and capsules. The at least one halogenated
xanthene or halogenated xanthene derivative may be dissolved or
suspended in such delivery vehicle, wherein this vehicle may, in
addition to the at least one halogenated xanthene or halogenated
xanthene derivative, include various builders, stabilizers,
emulsifiers or dispersants, preservatives, buffers, electrolytes,
and tissue penetrating or softening agents. Such components of the
delivery vehicle may be present as the primary component (by weight
or volume) of the medicament, or as a minor component that serves
in an adjuvant role in agent delivery with no adverse affect on
tissue or treatment outcome.
[0050] Examples of appropriate builders include cellulose and
cellulose derivatives, such as starch, and alginates.
[0051] Examples of appropriate stabilizers, emulsifiers or
dispersants include liposomes, nanoparticulates and
nanodispersions, microparticulates and microdispersions, as well as
various lipids, detergents and other surfactants.
[0052] Examples of appropriate preservatives include benzalkonium
chloride, thimerosal, quaternary amines and urea.
[0053] Examples of appropriate buffers include monobasic or dibasic
phosphate salts, citrate salts, bicarbonate salts, and
ethanolamine.
[0054] Examples of appropriate electrolytes include sodium,
potassium, calcium and magnesium chlorides, phosphates, and
nitrates.
[0055] Examples of appropriate tissue penetrating, softening or
solvating agents and adjuvants include:
[0056] various sulfoxides, such as DMSO and
decylmethylsulfoxide;
[0057] various aliphatic and fatty alcohols, such as ethanol,
propanol, hexanol, octanol, benzyl alcohol, decyl alcohol, lauryl
alcohol, and stearyl alcohol;
[0058] various linear and branched, saturated and unsaturated fatty
acids, such as lauric acid, caproic acid, capric acid, myristic
acid, stearic acid, oleic acid, isovaleric acid, neopentanoic acid,
trimethyl hexanoic acid, neodecanoic acid and isostearic acid;
[0059] various aliphatic and alkyl fatty acid esters, such as
isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate,
isopropyl myristate, isopropyl palmitate, octyldodecyl myristate,
ethyl acetate, butyl acetate, methyl acetate, methylvalerate,
methylpropionate, diethyl sebacate and ethyl oleate;
[0060] various polyols, such as propylene glycol, polyethylene
glycol, ethylene glycol, diethylene glycol, triethylene glycol,
diproplyene glycol, glycerol, propanediol, butanediol, pentanediol
and hexanetriol;
[0061] various amides, such as urea, dimethylacetamide,
diethyltoluamide, dimethylformamide, dimethyloctamide,
dimethyldecamide; biodegradable cyclic urea, such as
1-alkyl-4-imidazolin-2-one; pyrrolidone derivatives, such as
1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone,
1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone,
1-lauryl-4-carboxy-2-pyrrolidone,
1-methyl-4-methyoxycarbonyl-2-pyrrolido- ne,
1-methyl-4-methyoxycarbonyl-2-pyrrolidone,
1-lauryl-4-methyoxycarbonyl-
-2-pyrrolidone,N-cyclohexylpyrrolidone,
N-dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone,
N-tallowalkylpyrrolidone; biodegradable pyrrolidone derivatives,
such as fatty acid esters of N-(2-hyroxyethyl)-2-pyrrolidone;
cyclic amides, such as 1-dodecylazacycloheptane-2-one (Azone.RTM.),
1-geranylazacycloheptan-2-on- e, 1-farnesylazacycloheptan-2-one,
1-geranylgeranylazacycloheptan-2-one,
1-(3,7-dimethyloctyl)azacycloheptan-2-one,
1-(3,7,11-trimethydodecyl)azac- ycloheptan-2-one,
1-geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2- ,5-dione,
1-farnesylazacyclopentan-2-one; hexamethylenelauramide and its
derivatives; and diethanolamine and triethanolamine;
[0062] various surfactants, such as anionic surfactants, including
sodium laurate and sodium lauryl sulfate; cationic surfactants,
including cetyltrimethyl ammonium bromide,
tetradecyltrimethylammonium bromide, benzalkonium chloride,
octadecyltrimethylammonium chloride, cetylpyridinium chloride,
dodecyltrimethylammonium chloride, hexadecyltrimethylammonium
chloride; nonionic surfactants, such as Polaxamer (231, 182, 184),
Brij (30, 93, 96, 99), Span (20, 40, 60, 80, 85), Tween (20, 40,
60, 80), Myrj (45, 51, 52), Miglyol 840; various bile salts, such
as sodium cholate, sodium salts of taurocholic, glycholic,
desoxycholic acids; lecithin;
[0063] various terpenes, including hydrocarbons, such as
D-limonene, .alpha.-pinene, .beta.-carene; various terpene
alcohols, including .alpha.-Terpineol, terpinen-4-ol, carvol;
various terpene ketones, including carvone, pulegone, piperitone,
menthone; various terpene oxides, including cyclohexane oxide,
limonene oxide, .alpha.-pinene oxide, cyclopentene oxide,
1,8-cineole; various terpene oils, including ylang ylang, anise,
chenopodium, eucalyptus;
[0064] various alkanones, such as N-heptane, N-octane, N-nonane,
N-decane, N-undecane, N-dodecane, N-tridecane, N-tetradecane,
N-hexadecane;
[0065] various organic acids, such as salicylic acid and
salicylites (including their methyl, ethyl, and propyl glycol
derivatives), citric and succinic acid.
[0066] The present invention is not limited to the above recited
examples, as other formulations familiar to those of ordinary skill
in the art, including various simple or complex combinations of
vehicles and adjuvants, are also useful for improving delivery of
the photoactive component of the medicament to target tissues.
[0067] 2. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Skin and
Related Organs.
[0068] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the skin and related organs of humans and animals. The medicament
can be applied, using conventional intracorporeal or topical
administration modes, directly or indirectly to, or substantially
proximal to, tissues to be treated, including those of the skin,
nails and scalp. Such administration modes provide direct delivery
of medicament to, into or substantially proximal to, tissues to be
treated, or systemic delivery of medicament to, into or
substantially proximal to, tissues to be treated.
[0069] Example indications include treatment for: Psoriasis and
Pustular Psoriasis; Reiter's Syndrome; Skin Ulcers, including
Stasis Dermatitis, Stasis Ulcers, Ischemic Ulcers, Sickle Cell Leg
Ulcers, Diabetic Ulcers, Inflammatory Ulcers; Eczematous Disease
and Eczematous Reaction; various Ichthyoses; Atopic Dermatitis;
Superficial Wrinkles; Near Surface Fat Reduction; Benign and
Malignant Proliferative Disorders, such as Benign Epithelial Tumors
and Hamartomas; Premalignant and Malignant Epithelial Tumors,
including Actinic Keratoses, Basal Cell Carcinoma, Squamous Cell
Carcinoma, and Keratoacanthoma; Benign and Malignant Adnexal
Tumors; Tumors of Pigment-Producing Cells, including Malignant
Melanoma, Solar Lentigines, Nevi, and Caf-au-lait; Sarcomas;
Lymphomas; Vascular Disorders, such as Hemangiomas and Port Wine
Stain; Microbial Infection, such as Bacterial, Fungal, Yeast,
Parasitic or Other Infections; Warts; and Acne. These examples are
provided for illustrative purposes, as the present invention is not
limited to the recited examples and includes other indications
known to those skilled in the art.
[0070] 3. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Mouth and
Digestive Tract and Related Organs.
[0071] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the mouth and digestive tract and related organs of humans and
animals. The medicament can be applied, using conventional
intracorporeal or topical administration modes, directly or
indirectly to, or substantially proximal to, tissues to be treated,
including those of the mouth, gums, tongue, larynx, pharynx,
esophagus, stomach, intestines and colon. Such administration modes
provide direct delivery of medicament to, into or substantially
proximal to, tissues to be treated, or systemic delivery of
medicament to, into or substantially proximal to, tissues to be
treated.
[0072] Example indications include treatment for: Benign Esophageal
Lesions, Barretts Esophagus and other Esophageal Hyperplasia and
Dysplasia, and Esophageal Cancer, including Squamous Cell
Carcinoma, Adenocarcinoma, Carsinosarcoma, Pseudosarcoma, and
Sarcoma; Gastric Ulcers, Leiomyomas, Polyps, Neoplasms, Lymphoma
and Pseudolymphoma, Adenocarcinoma, Primary Lymphoma,
Leiomyosarcoma; Oral and Oropharynx Cancer and Premalignancies,
Ulcers and Inflammatory Lesions, including Squamous Cell Carcinoma,
Lymphoma, Actinic Cheilitis, Nicotine Stomatitis, Leukoplakia,
Erythroplakia; Gum and Other Peridontal Disease, including
Gingivitis; Laryngeal Hyperplasia, Dysplasia and Neoplasms;
Colorectal Cancer and Polyps. These examples are provided for
illustrative purposes, as the present invention is not limited to
the recited examples and includes other indications known to those
skilled in the art.
[0073] 4. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Urinary and
Reproductive Tracts and Related Organs.
[0074] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the urinary and reproductive tract and related organs of humans and
animals. The medicament can be applied, using conventional
intracorporeal or topical administration modes, directly or
indirectly to, or substantially proximal to, tissues to be treated,
including those of the urethra, bladder, ureter, kidneys, vulva,
vagina, cervix, uterus, fallopian tubes, ovaries, penis, testes,
vas deferens, prostate, and epididymis. Such administration modes
provide direct delivery of medicament to, into or substantially
proximal to, tissues to be treated, or systemic delivery of
medicament to, into or substantially proximal to, tissues to be
treated.
[0075] Example indications include treatment for: Urinary Tract
Disease, including Cancerous and Pre-Cancerous Hyperplasia,
Dysplasia and Neoplasms, Tumors and other Growths, Inflammation,
and Infection of the Bladder, Ureter, Urethra, and Kidney;
Cancerous and Pre-Cancerous Hyperlasia, Dysplasia and Neoplasms,
Tumors and other Growths, Inflammation, and Infection of the
Cervix, Endometrium, Myometrium, Ovaries, Fallopian Tubes, Uterus,
Vulva, and Vagina, including Vaginal Warts; Cancerous and
Pre-Cancerous Hyperlasia, Dysplasia and Neoplasms, Tumors and other
Growths, Inflammation, and Infection of the Prostate and Testes;
Cancerous and Pre-Cancerous Hyperlasia, Dysplasia and Neoplasms,
Tumors and other Growths, Inflammation, and Infection of the
Breast; Reproductive Tract Infections, including Tinea Cruris,
Candidiasis, Condylomata Acuminata, Molluscum Contagiosum, Genital
Herpes Simplex Infection, Lymphogranuloma Venereum, Chancroid,
Granuloma Inguinale, Erythrasma; Psoriais; and Lichen Planus and
Lichen Sclerosus. These examples are provided for illustrative
purposes, as the present invention is not limited to the recited
examples and includes other indications known to those skilled in
the art.
[0076] 5. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Respiratory
Tract and Related Organs.
[0077] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the respiratory tract and related organs of humans and animals. The
medicament can be applied, using conventional intracorporeal or
topical administration modes, directly or indirectly to, or
substantially proximal to, tissues to be treated, including those
of the lung and alveoli, bronchi, trachea, hypopharynx, larynx,
nasopharynx, tear ducts, sinuses and nasal cavities. Such
administration modes provide direct delivery of medicament to, into
or substantially proximal to, tissues to be treated, or systemic
delivery of medicament to, into or substantially proximal to,
tissues to be treated.
[0078] Example indications include treatment for: Hyperplasia,
Dysplasia and Neoplasia, Cancer, Inflammation and Infection of the
Nasal Cavity, Paranasal Sinuses, Tear Ducts, Eustachian Tubes,
Nasopharynx, Hypopharynx, Larynx, Trachea, Bronchi, Lung and
Alveoli. These examples are provided for illustrative purposes, as
the present invention is not limited to the recited examples and
includes other indications known to those skilled in the art.
[0079] 6. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Circulatory
System and Related Organs.
[0080] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the circulatory system and related organs of humans and animals.
The medicament can be applied, using conventional intracorporeal or
topical administration modes, directly or indirectly to, or
substantially proximal to, tissues to be treated, including those
of the heart, kidneys, liver and blood vessels. Such administration
modes provide direct delivery of medicament to, into or
substantially proximal to, tissues to be treated, or systemic
delivery of medicament to, into or substantially proximal to,
tissues to be treated.
[0081] Example indications include treatment for: Disease of
Cardiac and Pericardial Tissues and Circulatory Tissues, including
Arteries and Veins, including Plaques and Infections of such
tissues, such as Bacterial Endocarditis; and destruction of
unwanted blood vessels, such as spider veins. These examples are
provided for illustrative purposes, as the present invention is not
limited to the recited examples and includes other indications
known to those skilled in the art.
[0082] 7. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Head and
Neck.
[0083] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the head and neck of humans and animals. The medicament can be
applied, using conventional intracorporeal or topical
administration modes, directly or indirectly to, or substantially
proximal to, tissues to be treated, including those of the head,
neck, brain, eyes and ears. Such administration modes provide
direct delivery of medicament to, into or substantially proximal
to, tissues to be treated, or systemic delivery of medicament to,
into or substantially proximal to, tissues to be treated.
[0084] Example indications include treatment for: Tumors or
Resected Tumor Beds of Intra-cranial and other Head and Neck
Tumors; Ophthalmic Tumors and other diseases, including Macular
Degeneration and Diabetic Retinopathy; Metastatic Tumors, such as
Metastases of Melanoma, Breast or Other Tumors to the Skin of the
Head or Neck. These examples are provided for Illustrative
purposes, as the present invention is not limited to the recited
examples and includes other indications known to those skilled in
the art.
[0085] 8. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting the Endocrine
and Lymphoreticular Systems and Related Organs.
[0086] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
the endocrine and lymphoreticular systems and related organs of
humans and animals. The medicament can be applied, using
conventional intracorporeal or topical administration modes,
directly or indirectly to, or substantially proximal to, tissues to
be treated, including those of the thyroid gland, the thalamus and
hypothalamus, the pituitary gland, lymph nodes and lymphoreticular
system. Such administration modes provide direct delivery of
medicament to, into or substantially proximal to, tissues to be
treated, or systemic delivery of medicament to, into or
substantially proximal to, tissues to be treated.
[0087] Example indications include treatment for: Hyperplasia,
Dysplasia and Neoplasia, Cancer, Inflammation and Infection of the
thyroid, Thalamus and Hypothalamus, Pituitary Gland, Lymph Nodes
and Lymphoreticular system, including Graves' Disease. These
examples are provided for Illustrative purposes, as the present
invention is not limited to the recited examples and includes other
indications known to those skilled in the art.
[0088] 9. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Affecting Various other
Tissues such as Connective Tissues and Various Tissue Surfaces
Exposed During Surgery.
[0089] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions affecting
various other internal or external tissues of humans and animals,
such as connective tissues and various tissue surfaces that become
exposed during surgery. The medicament can be applied, using
conventional intracorporeal or topical administration modes,
directly or indirectly to, or substantially proximal to, tissues to
be treated, including those of tissue surfaces exposed during
surgery, including endoscopic surgery or other endoscopic
procedures. Such application modes provide direct delivery of
medicament to, into or substantially proximal to, tissues to be
treated, or systemic delivery of medicament to, into or
substantially proximal to, tissues to be treated.
[0090] Example indications include treatment for: Joint
Inflammation, such as that of Arthritis; Resected Tumor Beds of
Thoracic, Abdominal, or other Tumors; Metastatic Tumors, such as
Metastases of Breast Tumors to the Skin; Tumors or Infections of
the Pleura, Peritoneum or Pericardium; and various other
substantially similar indications. These examples are provided for
illustrative purposes, as the present invention is not limited to
the recited examples and includes other indications known to those
skilled in the art.
[0091] 10. Methods and Medical use of the Subject Medicament for
Chemotherapeutic Treatment of Conditions Related to Microbial,
Viral Fungal or Parasitic Infection.
[0092] The medicaments disclosed herein are broadly applicable to
improved chemotherapeutic treatment of various conditions related
to microbial, viral, fungal or parasitic infection of humans and
animals. The medicament can be applied, using conventional
intracorporeal or topical administration modes, directly or
indirectly to, or substantially proximal to, tissues to be treated,
including those of tissue surfaces exposed during surgery,
including endoscopic surgery or other endoscopic procedures. Such
administration modes provide direct delivery of medicament to, into
or substantially proximal to, tissues to be treated, or systemic
delivery of medicament to, into or substantially proximal to,
tissues to be treated.
[0093] Example indications include treatment for: Bacterial and
Antibiotic Resistant Bacterial Infection, including those caused by
Gram Positives and Gram Negatives, Streptomycetes, Actinomycetes,
Staphylococci, Streptococci, Pseudomonas, Escherichia coli,
Mycobacteria and others; Infection caused by Filamentous Fungi and
Non-filamentous Fungi like Cryptosporidium, Histoplasma,
Aspergillus, Blastomyces, Candida and others; Parasitic Infection
caused by Amoeba (including for use in lysing and killing amoeba in
amoebic cysts), Trichinella, Dirodfilaria (Heart worm in dogs) and
various other substantially similar indications. These examples are
provided for illustrative purposes, as the present invention is not
limited to the recited examples and includes other indications
known to those skilled in the art.
1TABLE 1 Physical Properties of Fluorescein and Some Example
Halogenated Xanthenes. Substitution Compound X Y Z R.sup.1 R.sup.2
MW(g) Fluorescein H H H Na Na 376 4',5'-Dichlorofluorescein Cl H H
Na Na 445 2',7'-Dichlorofluorescein H Cl H Na Na 445
4,5,6,7-Tetrachlorofluo- rescein 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
EosinY 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
[0094] Table 2. Partition coefficients and toxicology data for
several halogenated xanthenes (i.e. Rose Bengal, Erythrosin B and
Phloxine B) and selected other therapeutic agents. Partition
coefficient, K.sub.p, is the ratio of equilibrium concentrations of
agent in a lipophilic phase (n-octanol) contacted with an aqueous
phase (phosphate buffered saline, PBS, pH=7.4). Toxicology data
(LD.sub.50) for murine intravenous (i.v.) or oral (p.o.)
administration.
2 LD.sub.50 (mg/kg) Agent K.sub.p i.v. p.o. Phloxine B 1.1 310 310
Erythrosin B 1.9 370 >1,000 Rose Bengal 11.5 >>1,000
Indocyanine Green 99 60 Porphyrin HpIX 1.5 >1,000
[0095] This description has been offered for illustrative purposes
only and is not intended to limit the invention of this
application. What is claimed as new and desired to be protected by
Letters Patent is set forth in the appended claims.
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