U.S. patent application number 11/354326 was filed with the patent office on 2006-06-29 for use of ap-1 activators to treat glaucoma and ocular hypertension.
Invention is credited to Abbot F. Clark, Iok-Hou Pang, Debra L. Shade.
Application Number | 20060142379 11/354326 |
Document ID | / |
Family ID | 35922729 |
Filed Date | 2006-06-29 |
United States Patent
Application |
20060142379 |
Kind Code |
A1 |
Shade; Debra L. ; et
al. |
June 29, 2006 |
Use of AP-1 activators to treat glaucoma and ocular
hypertension
Abstract
Compositions comprising AP-1 activators and methods of use for
treating glaucoma and ocular hypertension are disclosed.
Inventors: |
Shade; Debra L.; (Benbrook,
TX) ; Pang; Iok-Hou; (Grand Prairie, TX) ;
Clark; Abbot F.; (Arlington, TX) |
Correspondence
Address: |
ALCON RESEARCH, LTD.
R&D COUNSEL, Q-148
6201 SOUTH FREEWAY
FORT WORTH
TX
76134-2099
US
|
Family ID: |
35922729 |
Appl. No.: |
11/354326 |
Filed: |
February 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09913098 |
Aug 9, 2001 |
7005446 |
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PCT/US00/09503 |
Apr 7, 2000 |
|
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11354326 |
Feb 14, 2006 |
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60130133 |
Apr 20, 1999 |
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Current U.S.
Class: |
514/456 ;
514/734 |
Current CPC
Class: |
A61K 31/40 20130101;
Y10S 514/913 20130101 |
Class at
Publication: |
514/456 ;
514/734 |
International
Class: |
A61K 31/353 20060101
A61K031/353; A61K 31/05 20060101 A61K031/05 |
Claims
1. A topical composition for treating glaucoma or ocular
hypertension comprising an AP-1 Activator and a pharmaceutically
acceptable vehicle.
2. A composition according to claim 1, wherein the AP-1 Activator
is selected from the group consisting of: .beta.-naphthoflavone,
tert-butylhydroquinone, and sulpiride.
3. A composition according to claim 2, wherein the AP-1 Activator
is tert-butylhydroquinone.
4. A composition according to claim 1, wherein the composition
comprises: about 0.01 to 2.0% w/v t-HBQ; about 0.28% w/v sodium
phosphate; about 0.8% w/v sodium chloride; about 0.01% w/v
benzalkonium chloride about 0.5% w/v HPMC; about 0.1% w/v edetate
disodium; and water
5. A method for treating glaucoma or ocular hypertension which
comprises administering to a mammal a composition comprising an
AP-1 Activator and a pharmaceutically acceptable vehicle.
6. A method according to claim 5, wherein the AP-1 Activator is
selected from the group consisting of: .beta.-naphthoflavone,
tert-butylhydroquinone, and sulpiride.
7. A method according to claim 6, wherein the AP-1 Activator is
tert-butylhydroquinone.
8. A method according to claim 5, wherein the composition
comprises: about 0.01 to 2.0% w/v t-HBQ; about 0.28% w/v sodium
phosphate; about 0.8% w/v sodium chloride; about 0.01% w/v
benzalkonium chloride about 0.5% w/v HPMC; about 0.1% w/v edetate
disodium; and water.
Description
[0001] This application claims continuation from U.S. Ser. No.
09/913,098 filed Aug. 9, 2001; which is a 371 application of
PCT/US00/09503 filed Apr. 7, 2000; which claims priority from U.S.
Ser. No. 60/130,133 filed Apr. 20, 1999.
[0002] The present invention relates to the treatment of glaucoma
and ocular hypertension. In particular, the present invention
relates to the use of compounds that increase the activity of
Activator Protein-1 (AP-1) to treat glaucoma and ocular
hypertension.
BACKGROUND OF THE INVENTION
[0003] Glaucoma is a progressive disease which leads to optic nerve
damage and, ultimately, total loss of vision. The causes of this
disease have been the subject of extensive studies for many years,
but are still not fully understood. The principal symptom of,
and/or risk factor for, the disease is elevated intraocular
pressure (IOP) or ocular hypertension.
[0004] The reasons why IOP is increased in glaucoma patients are
not fully understood. It is known that elevated IOP can be at least
partially controlled by administering drugs which either reduce the
production of aqueous humor within the eye, such as beta-blockers
and carbonic anhydrase inhibitors, or increase the flow of aqueous
humor out of the eye, such as cholinergic agonists and
sympathomimetics.
[0005] All types of drugs currently being used to treat glaucoma
have potentially serious side effects. Cholinergic agonists such as
pilocarpine can cause blurring of vision and other ocular side
effects, which may lead either to decreased patient compliance or
to termination of therapy. Systemically administered carbonic
anhydrase inhibitors can also cause serious side effects, such as
nausea, dyspepsia, fatigue, and metabolic acidosis which can affect
patient compliance and/or necessitate the withdrawal of treatment.
Moreover, some beta-blockers have been known to be associated with
pulmonary side effects attributable to their effects on beta-2
receptors in the pulmonary tissue. Sympathomimetics cause
tachycardia, arrhythmia and hypertension. There is therefore a
continuing need for new therapies which control elevated IOP
associated with glaucoma.
[0006] Activator protein-1 (AP-1) is a dimeric gene transcription
promoter comprised of subunit proteins which are the products of at
least three different proto-oncogene families: the Jun (c-Jun,
v-Jun, JunB, JunD), Fos (c-Fos, v-Fos, FosB, FosB2, Fra-1, Fra-2)
or activating transcription factor (B-ATF, ATF2, ATF3/LRF1)
families. Uncomplexed monomers and homo- and hetero-dimers of these
protein subunits have been observed in a variety of mammalian and
non-mammalian tissues (Foletta et al., Transcriptional regulation
in the immune systems: all roads lead to AP-1, J. Leukoc Biol.
volume 63, pages 139-152 (1998); and Karin et al., AP-1 function
and regulation, Curr. Opin. Cell Biol., volume 9, pages 240-246
(1997)).
[0007] AP-1 binds to specific DNA sequences within enhancer regions
of many genes (e.g., TPA (12-O-tetradecanoylphorbol-13-acetate)
response elements (TREs) or cyclic AMP response elements (CREs))
and promotes the activation of the particular gene. Examples of
genes which contain AP-1 consensus seqences in their enhancer
regions include the genes for SV40 and human metallothionein IIA
(Lee et al., Activation of transcription by two factors that bind
promoter and enhancer sequences of the human metallothionein gene
and SV40, Nature, volume 325, pages 368-372). The binding affinity
of AP-1 for the various response elements appears to depend on the
specific protein subunit dimer complex. Dimers composed of Jun/Jun
or Jun/Fos generally bind TREs, whereas ATF/ATF or Jun/ATF dimers
preferentially bind CREs (Whitmarsh et al., Transcription factor
AP-1 regulation by mitogen-activated protein kinase signal
transduction pathways, J. Mol. Med., volume 74, pages 589-607
(1996); and Karin et al., Current Opin. Cell Biol., volume 9, pages
240-246 (1997)). The biological consequences of AP-1 mediated gene
transcription may also vary, depending upon the dimer composition.
For example, induction of murine glutathione-S-transferase genes is
apparently mediated by a Fos/Jun heterodimer which binds at least
one TRE sequence within the gene's antioxidant response element
(Ainbinder et al., Regulatory mechanisms involved in
activator-protein-1 (AP-1)-mediated activation of
glutathione-S-transferase gene expression by chemical agents, Eur.
J. Biochem., volume 243, pages 49-57 (1997); Xie et al., ARE- and
TRE-mediated regulation of gene expression, J. Biol. Chem., volume
270, pages 6894-6900 (1995)), and a c-Jun/ATF-2 complex has been
shown to bind to a CRE involved in activation of the T-cell gene
for tumor necrosis factor-alpha (Foletta et al., J. Leukoc. Biol.,
volume 63, pages 139-152 (1998)).
[0008] Several AP-1 Activators have been reported previously,
including .beta.-naphthoflavone and tert-butylhydroquinone (tBHQ)
(Ainbinder et al., Eur. J. Biochem., volume 243, pages 49-57
(1997); Ainbinder et al., Signaling pathways in the induction of
c-fos and c-jun proto-oncogenes by 3-methylcholanthrene, Receptors
and Signal Transduction, volume 7, pages 279-289 (1998); and Oazki
et al., The comparative effects of haloperidol, (-)-sulpiride, and
SCH23390 on c-fos and c-jun mRNA expressions, and AP-1 DNA binding
activity, Eur. Neuropsychopharmacol., volume 7, pages 181-187
(1997)). Nowhere in the art, however, has it been taught or
suggested that AP-1 activators may be useful in treating glaucoma
or ocular hypertension.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to compositions and
methods of use for the treatment of glaucoma and ocular
hypertension. More specifically, the invention is directed to
compositions comprising AP-1 activators and methods of use.
[0010] Preferred methods involve the topical administration of
compositions comprising tBHQ.
DESCRIPTION OF THE DRAWING
[0011] FIG. 1 is a graph showing the effects of tBHQ on IOP in a
human ocular perfusion organ culture model.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention is directed to compositions and
methods of use for the treatment of glaucoma and ocular
hypertension.
[0013] The compounds useful in the present invention compositions
and methods are AP-1 Activators. While not intending to be bound by
any theory, it is believed that the stimulation of AP-1 activity
leads to the transcription of mRNAs and corresponding translation
of proteins useful in effecting the maintenance or lowering of IOP.
As used herein, "AP-1 Activator" refers to those molecules which
lower IOP via AP-1 mediated transcription. Such activators may
include agents which (1) increase the formation and expression of
proteins comprising AP-1 complex(es), (2) enhance the formation of
such complexes, or (3) promote binding of an AP-1 complex to
regulatory/promoter sites on cellular genes. Examples of AP-1
Activators include .beta.-naphthoflavone, tert-butylhydroquinone
(tBHQ), sulpiride, haloperidol, and 3-methylcholanthrene. The most
preferred AP-1 Activator is tBHQ.
[0014] Other AP-1 Activators may be elucidated by methods known in
the art. For example, an increase in the level of DNA-bound AP-1
complex, as assessed by electrophoretic mobility shift assay, is an
accepted means for detection of activated AP-1 activity. Such
DNA-binding can be determined by the following protocol:
DNA-Binding Assay:
[0015] Target cellular tissue (e.g., human trabecular meshwork
tissue and/or cultured cells) is treated with or without an AP-1
Activator candidate(s). Nuclear extracts of the cells are then
prepared according to the method of Schreiber et al., Rapid
detection of octamer binding proteins with `mini-extracts `
preparedfrom a small number of cells, Nucleic Acids Res., volume
17, page 6419 (1989). Electrophoretic mobility shift assays are
then carried out with the nuclear extracts as described by
Ainbinder et al., Regulatory mechanisms involved in
activator-protein-1 (AP-1)-mediated activation of
glutathione-S-transferase gene expression by chemical agents, Eur.
J. Biochem., volume 243, pages 49-57 (1997). Briefly, extracts are
incubated with a .sup.32P-labelled AP-1 oligonucleotide probe and
the resulting complexes are then separated by non-denaturing
acrylamide gel electrophoresis. Levels of DNA binding activity can
then be determined from analysis of autoradiograms of the dried
gels. By using this method, compounds such as tBHQ have been
demonstrated to be AP-1 Activators.
[0016] Other AP-1 Activators may be identified by routine methods
known in the art. For example, methods disclosed in the following
publications may be useful in elucidating other AP-1 Activators of
the present invention: [0017] (1) Ainbinder et al., Regulatory
mechanisms involved in activator-protein-1 (AP-1)-mediated
activation of glutathione-S-transferase gene expression by chemical
agents, Eur. J. Biochem., volume 243, pages 49-57 (1997); [0018]
(2) Ainbinder et al., Signaling pathways in the induction of c-fos
and c-jun proto-oncogenes by 3-methylcholanthrene, Receptors and
Signal Transduction, volume 7, pages 279-289 (1998); [0019] (3)
Ozaki et al., The comparative effects of haloperidol,
(-)-sulpiride, and SCH23390 on c-fos and c-jun mRNA expressions,
and AP-1 DNA binding activity, Eur. Neuropsychopharmacol., volume
7, pages 181-187 (1997); and [0020] (4) Xie et al., ARE- and
TRE-mediated regulation of gene expression, J. Biol. Chem., volume
270, pages 6894-6900 (1995); the foregoing publications are
incorporated herein by reference.
EXAMPLE 1
[0021] The following example illustrates the effect of an AP-1
Activator, tBHQ, on aqueous outflow facility as demonstrated using
a human ocular perfusion organ culture model. Pharmaceutical
candidates which maintain or increase outflow facility are believed
to be useful in treating or controlling IOP and, hence, glaucoma.
The study was performed as follows:
[0022] Human donor eyes less than 24 hours post mortem were used.
The globe was sectioned equatorially followed by the removal of
vitreous, lens, zonules, iris, and most of the ciliary body. The
anterior segment was then mounted on a perfusion dish, perfused
with cell culture medium at a constant hydrostatic pressure of 10
mm Hg (Johnson et al., Human trabecular meshwork organ culture: A
new method, Invest Ophthalmol Vis Sci., volume 28, pages 945-953
(1987); Erickson-Lamy et al., Outflow facility studies in the
perfused human ocular anterior segment, Exp. Eye Res., volume 52,
pages 723-731 (1991); and Clark et al., Dexamethasone-induced
ocular hypertension in perfusion cultured human eyes, Invest.
Ophthalmol. Vis. Sci., volume 36, pages 478-489 (1995)). The flow
rate of the perfusate was measured by weighing the reservoir at
predetermined periods. After 2 to 4 days of equilibrium period, one
eye of each of the donor pair was perfused with the test compound,
t-BHQ (10 .mu.M), while the other was perfused with vehicle
(control). The results are shown in FIG. 1 and Table 1, below:
TABLE-US-00001 TABLE 1 Effect of t-BHQ (10 .mu.M) on Aqueous
Outflow Rate in Human Ocular Perfusion Organ Culture Flow Rate (%
of Time 0) Time after Treatment (Mean .+-. SEM, n = 6) (Hours)
Vehicle t-BHQ -4 100.0 .+-. 0.8 97.0 .+-. 4.0 0 100.0 100.0 4 92.0
.+-. 3.6 105.8 .+-. 5.4* 24 92.0 .+-. 4.8 102.9 .+-. 3.9* 48 86.6
.+-. 9.2 105.2 .+-. 10.1 72 76.6 .+-. 12.5 111.8 .+-. 11.8* 96 61.8
.+-. 12.1 120.9 .+-. 16.4* Note: (1) The basal flow rate at time 0
for vehicle-treated eyes was 3.55 .+-. 1.00 .mu.L/min, and that for
drug-treated eyes was 4.09 .+-. 0.63 .mu.L/min. (2) *represents p
< 0.05, paired t-test compared to the vehicle-treated eye of the
same time point.
[0023] While not intending to be bound by any theory, it is
believed that the AP-1 Activators of the present invention are
useful in increasing the outflow facility of a mammal's eye, which
leads to maintained or lowered IOP, and thus useful in the
treatment of glaucoma or ocular hypertension.
[0024] The preferred route of administration for the methods of the
present invention is topical. The preparation of topical ophthalmic
compositions is well known in the art. Generally, topical
ophthalmic compositions useful in the present invention will be in
the form of a solution, suspension, gel, or formulated as part of a
device, such as a collagen shield or other bioerodible or
non-bioerodible device. Various excipients may be contained in the
topical ophthalmic solutions, suspensions or gels of the present
invention. For example, buffers (e.g., borate, carbonate,
phosphate), tonicity agents (e.g., sodium chloride, potassium
chloride, polyols), preservatives (e.g., polyquatemiums,
polybiguanides, benzalkonium chloride), chelating agents (e.g.,
EDTA), viscosity enhancing agents (e.g., polyethoxylated glycols)
and solubilizing agents (e.g., polyethoxylated castor oils,
including polyoxl-35 castor oil (Cremophor EL.RTM., BASF Corp.,
Parsippany, N.J.); Polysorbate 20, 60 and 80; Pluronic.RTM. F-68,
F-84 and P-103 (BASF Corp.); or cyclodextrin) may be included in
the topical ophthalmic compositions. However, preferable
compositions of the present invention will not include
preservatives or tonicity agents which are known to adversely
affect or irritate the eye.
[0025] A variety of gels may be useful in topical ophthalmic gel
compositions of the present invention, including, but not limited
to, carbomers, polyvinyl alcohol-borates complexes, or xanthan,
gellan, or guar gums. Topical ophthalmic bioerodible and
non-bioerodible devices are known in the art and may be useful in
the topical administration of the AP-1 Activators. See, for
example, Weiner, A. L., Polymeric Drug Delivery Systems For the
Eye, in Polymeric Site-specific Pharmacotherapy, Ed., A. J. Domb,
John Wiley & Sons, pages 316-327 (1994). While the particular
ingredients and amounts to be contained in topical ophthalmic
compositions useful in the methods of the present invention will
vary, particular topical ophthalmic compositions will be formulated
to effect the administration of one or more AP-1 Activators
topically to the eye.
[0026] In general, the doses of AP-1 Activators used for the above
described purposes will vary, but will be in an amount effective to
maintain or lower IOP, or otherwise treat glaucoma or ocular
hypertension. As used herein, the term "pharmaceutically effective
amount" refers to that amount of an AP-1 Activator administered to
a mammal which maintains or lowers IOP, or otherwise ameliorates
the glaucomatous condition of the patient. The AP-1 Activators will
normally be contained in the compositions described herein in an
amount from about 0.00001 to about 2.0 percent weight/volume ("%
w/v"), preferably 0.01 to 2% w/v. The compositions of the present
invention may be delivered topically to the eye, about one to six
times a day.
[0027] As used herein, the term "pharmaceutically acceptable
vehicle" refers to any formulation which is safe, and provides the
appropriate delivery for the desired route of administration of an
effective amount of at least one AP-1 Activator of the present
invention.
[0028] Preferred formulations of AP-1 Activators combinations of
the present invention include the following Examples 2-3:
EXAMPLE 2
[0029] Topical Ophthalmic Formulation: TABLE-US-00002 Ingredient
Amount (% wt) AP-1 Activator 0.01 to 2 Phosphate Buffered Saline
1.0 Benzalkonium Chloride 0.01 Polysorbate 80 0.5 Purified water
q.s. to 100%
EXAMPLE 3
[0030] Topical Ophthalmic Formulation: TABLE-US-00003 Ingredient
Amount (% wt) t-HBQ 0.01 to 2 Phosphate Buffered Saline 1.0
Hydroxypropyl-.beta.-cyclodextrin 4.0 Purified water q.s.to
100%
EXAMPLE 4
[0031] Preferred Formulation for a Topical Ophthalmic Solution:
TABLE-US-00004 Component Amount (% wt) t-HBQ 0.01 to 2 Benzalkonium
chloride 0.01 HPMC 0.5 Sodium chloride 0.8 Sodium phosphate 0.28
Edetate disodium 0.01 NaOH/HCl q.s. to pH 7.2 Purified Water q.s.
to 100%
* * * * *