WO1999025350A1 - Treatment of diabetic retinopathy - Google Patents
Treatment of diabetic retinopathy Download PDFInfo
- Publication number
- WO1999025350A1 WO1999025350A1 PCT/US1998/021423 US9821423W WO9925350A1 WO 1999025350 A1 WO1999025350 A1 WO 1999025350A1 US 9821423 W US9821423 W US 9821423W WO 9925350 A1 WO9925350 A1 WO 9925350A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antagonist
- glutamate
- diabetic retinopathy
- antagonists
- nmda receptor
- Prior art date
Links
- 206010012689 Diabetic retinopathy Diseases 0.000 title claims abstract description 14
- 239000005557 antagonist Substances 0.000 claims abstract description 28
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 16
- 229930195712 glutamate Natural products 0.000 claims abstract description 16
- 230000003492 excitotoxic effect Effects 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 231100000063 excitotoxicity Toxicity 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 9
- 229920000768 polyamine Polymers 0.000 claims description 9
- 108091006146 Channels Proteins 0.000 claims description 5
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 5
- GGUSQTSTQSHJAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanol Chemical group C=1C=C(Cl)C=CC=1C(O)CN(CC1)CCC1CC1=CC=C(F)C=C1 GGUSQTSTQSHJAH-UHFFFAOYSA-N 0.000 claims description 4
- 229950005455 eliprodil Drugs 0.000 claims description 3
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 claims 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 7
- 102000018899 Glutamate Receptors Human genes 0.000 description 4
- 108010027915 Glutamate Receptors Proteins 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000649 photocoagulation Effects 0.000 description 4
- 210000001525 retina Anatomy 0.000 description 4
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 description 3
- 210000003994 retinal ganglion cell Anatomy 0.000 description 3
- UYNVMODNBIQBMV-UHFFFAOYSA-N 4-[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]propyl]phenol Chemical compound C1CC(CC=2C=CC=CC=2)CCN1C(C)C(O)C1=CC=C(O)C=C1 UYNVMODNBIQBMV-UHFFFAOYSA-N 0.000 description 2
- 229940122459 Glutamate antagonist Drugs 0.000 description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000002518 glial effect Effects 0.000 description 2
- 239000003825 glutamate receptor antagonist Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- YSGASDXSLKIKOD-UHFFFAOYSA-N 2-amino-N-(1,2-diphenylpropan-2-yl)acetamide Chemical compound C=1C=CC=CC=1C(C)(NC(=O)CN)CC1=CC=CC=C1 YSGASDXSLKIKOD-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229960003998 ifenprodil Drugs 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229950000659 remacemide Drugs 0.000 description 1
- 230000004243 retinal function Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Definitions
- This invention relates to the use of suitable antagonists of glutamate-induced excitotoxicity for the treatment of diabetic retinopathy, particularly that of the proliferative type.
- Panretinal photocoagulation and the dietary and/or pharmacological control of hyperglycemia are the only methods currently in use to treat diabetic retinopathy. Nision loss is associated with the use of panretinal photocoagulation. Consequently, there is a need for new ways for treating diabetic retinopathy.
- the present compositions and methods fill that need. Summary of the Invention
- the present invention is directed to compositions and methods for treating diabetic retinopathy using an antagonist of the excitatory amino acid receptors involved in glutamate- induced excitotoxicity.
- an antagonist of the excitatory amino acid receptors involved in glutamate- induced excitotoxicity hi particular, N-methyl-D-aspartate (NMD A) receptor antagonists and more particularly antagonists of the polyamine receptor are useful for treating diabetic retinopathy.
- NMD A N-methyl-D-aspartate
- Tliis invention provides a pharmacological method for preventing further damage to retinal ganglion cells resulting from diabetes and associated with glutamate-induced excitotoxicity. It is expected to be used instead of panretinal photocoagulation and thus avoid the near-term loss of vision that accompanies such photocoagulation.
- the invention is a treatment for diabetic retinopathy, particularly of the proliferative type, comprising the local or systemic administration of a suitable antagonist of the excitatory amino acid receptors involved in glutamate-induced excitotoxicity.
- the purpose is to prevent damage to retinal ganglion cells resulting from the excitotoxic effects produced by excessive glutamate found in the retinas of patients who have proliferative diabetic retinopathy.
- a suitable glutamate antagonist is one which has the appropriate physicochemical properties to allow it to gain access to the site of action, i.e., the retina, following administration, either locally to the eye or systemically, of a pharmaceutically effective amount of such antagonist.
- the glutamate antagonist can work directly or indirectly to prevent the sequence of cellular events that ensues from the action of glutamate upon excitatory amino acid receptors at which glutamate can act. Glutamate receptors are classified as NMDA and non-NMDA receptors.
- Tliis invention includes antagonists that act on NMDA and non-NMDA receptors for glutamate.
- Particularly preferred antagonists are those which act on the NMDA receptor- calcium channel complex.
- Such antagonists may act by competing with glutamate at the receptor site, may act at one or all of several regulatory or modulatory sites associated with the NMDA receptor-calcium channel complex, or can inhibit one or more of the downstream effects that result from activation of the NMDA receptor-calcium channel complex. Examples include, but are not limited to, polyamine site antagonists, receptor antagonists (compete with NMDA), and channel blockers that operate uncompetitively to block the NMDA receptor channel. Polyamine site antagonists are particularly useful according to this invention. Examples of specific examples are set out in U.S. Patent No.
- the antagonist be able to cross these barriers to reach the site of action.
- the antagonist could be given intraocularly or periocularly by an acceptable method to deliver the antagonist to its site of action. All modes of delivery that result in placing the antagonist at its site of action are contemplated.
- the antagonists useful in the present invention will be administered orally.
- Daily dosage of these compounds will range between about 0.1 and about 500 milligrams (mg), preferably between about 5 and about 100 mg.
- Local administration of these compounds will require a dosage range of between about 0.1 and about 50 mg, preferably between about 0.5 and about 5 mg.
- An aqueous composition will generally contain between about 0.1 and about 10 percent by weight (wt%) of the active, preferably between about 1 and about 5 wt%.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The use of compositions of antagonists of glutamate induced excitotoxicity for the treatment of diabetic retinopathy is disclosed.
Description
TREATMENT OF DIABETIC RETINOPATHY
This invention relates to the use of suitable antagonists of glutamate-induced excitotoxicity for the treatment of diabetic retinopathy, particularly that of the proliferative type.
Background of the Invention
.Ambati, et al., "Elevated GAB A, Glutamate, and VEGF in the Vitreous of Humans With Proliferative Diabetic Retinopathy," Invest. Ophthalmol. Vis. Sci., 38:S771, 1997, reported elevated levels of glutamate in vitreous samples obtained from patients with proliferative diabetic retinopathy who underwent pars plana vitrectomy. They suggested that these levels of glutamate are potentially toxic to retinal ganglion cells.
Lieth, et al., "Glial Glutamate to Glutamine Conversion is Impaired in Retinas of Diabetic Rats," Invest. Ophthalmol. Vis. Sci., 38:S695, 1997, reported that glial glutamate to glutamine conversion is impaired in the retinas of diabetic rats.
Hudson, et al., "Short- Wavelength and White-on- White Automated Static Perimetiy in Patients With Clinically Significant Diabetic Macular Oedema (DMO)," Invest. Ophthalmol. Vis. Sci., 38:S768, 1997, reported deficits in retinal function related to ganglion cell function in patients with diabetic macular edema.
Panretinal photocoagulation and the dietary and/or pharmacological control of hyperglycemia are the only methods currently in use to treat diabetic retinopathy. Nision loss is associated with the use of panretinal photocoagulation. Consequently, there is a need for new ways for treating diabetic retinopathy. The present compositions and methods fill that need.
Summary of the Invention
The present invention is directed to compositions and methods for treating diabetic retinopathy using an antagonist of the excitatory amino acid receptors involved in glutamate- induced excitotoxicity. hi particular, N-methyl-D-aspartate (NMD A) receptor antagonists and more particularly antagonists of the polyamine receptor are useful for treating diabetic retinopathy.
Description of Preferred Embodiments
Tliis invention provides a pharmacological method for preventing further damage to retinal ganglion cells resulting from diabetes and associated with glutamate-induced excitotoxicity. It is expected to be used instead of panretinal photocoagulation and thus avoid the near-term loss of vision that accompanies such photocoagulation.
The invention is a treatment for diabetic retinopathy, particularly of the proliferative type, comprising the local or systemic administration of a suitable antagonist of the excitatory amino acid receptors involved in glutamate-induced excitotoxicity. The purpose is to prevent damage to retinal ganglion cells resulting from the excitotoxic effects produced by excessive glutamate found in the retinas of patients who have proliferative diabetic retinopathy. A suitable glutamate antagonist is one which has the appropriate physicochemical properties to allow it to gain access to the site of action, i.e., the retina, following administration, either locally to the eye or systemically, of a pharmaceutically effective amount of such antagonist. The glutamate antagonist can work directly or indirectly to prevent the sequence of cellular events that ensues from the action of glutamate upon excitatory amino acid receptors at which glutamate can act. Glutamate receptors are classified as NMDA and non-NMDA receptors.
Tliis invention includes antagonists that act on NMDA and non-NMDA receptors for glutamate. Particularly preferred antagonists are those which act on the NMDA receptor- calcium channel complex. Such antagonists may act by competing with glutamate at the receptor site, may act at one or all of several regulatory or modulatory sites associated with the NMDA receptor-calcium channel complex, or can inhibit one or more of the downstream effects that result from activation of the NMDA receptor-calcium channel complex. Examples include, but are not limited to, polyamine site antagonists, receptor antagonists (compete with NMDA), and channel blockers that operate uncompetitively to block the NMDA receptor channel.
Polyamine site antagonists are particularly useful according to this invention. Examples of specific examples are set out in U.S. Patent No. 4,690,931, which is incorporated herein by reference. The most preferred compounds in the patent are 2-[4-(4- fluorobenzyl)-piperidino]-l-(4-chlorophenyl)ethanol, also k . nown as eliprodil and 2-(4- benzylpiperidino)-l-(4-hydroxyphenyl)-propanol, also k . nown as ifenprodil.
Other compounds which are particularly useful include remacemide and memantine.
Because the site of action is located within the eye, which is normally protected by the blood-ocular barriers (i.e., blood-aqueous humor and blood-retinal barriers), it is preferred that the antagonist be able to cross these barriers to reach the site of action. Alternatively, the antagonist could be given intraocularly or periocularly by an acceptable method to deliver the antagonist to its site of action. All modes of delivery that result in placing the antagonist at its site of action are contemplated.
In general, the antagonists useful in the present invention will be administered orally. Daily dosage of these compounds will range between about 0.1 and about 500 milligrams (mg), preferably between about 5 and about 100 mg. Local administration of these compounds will require a dosage range of between about 0.1 and about 50 mg, preferably between about 0.5 and about 5 mg. An aqueous composition will generally contain between about 0.1 and about 10 percent by weight (wt%) of the active, preferably between about 1 and about 5 wt%.
Claims
1. A composition for treating diabetic retinopathy comprising a pharmaceutically effective amount of an antagonist of glutamate-induced excitotoxicity.
2. The composition of Claim 1 wherein the antagonist is selected from the group consisting of polyamine site antagonists, NMDA receptor antagonists, and channel blockers which operate uncompetitively to block the NMDA receptor channel.
3. The composition of Claim 2 wherein the antagonist is a polyamine site antagonist.
4. The composition of Claim 3 wherein the polyamine site antagonist is eliprodil.
5. A method for treating diabetic retinopathy which comprises, administering a pharmaceutically effective amount of an antagonist of glutamate-induced excitotoxicity.
6. The method of Claim 5 wherein the antagonist is selected from the group consisting of polyamine site antagonists, NMDA receptor antagonists, and channel blockers which operate uncompetitively to block the NMDA receptor channel.
7. The method of Claim 6 wherein the antagonist is a polyamine site antagonist.
8. The method of Claim 7 wherein the polyamine site antagonist is eliprodil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU97975/98A AU9797598A (en) | 1997-11-14 | 1998-10-09 | Treatment of diabetic retinopathy |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6569497P | 1997-11-14 | 1997-11-14 | |
| US60/065,694 | 1997-11-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999025350A1 true WO1999025350A1 (en) | 1999-05-27 |
Family
ID=22064483
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/021423 WO1999025350A1 (en) | 1997-11-14 | 1998-10-09 | Treatment of diabetic retinopathy |
Country Status (4)
| Country | Link |
|---|---|
| AR (1) | AR013749A1 (en) |
| AU (1) | AU9797598A (en) |
| WO (1) | WO1999025350A1 (en) |
| ZA (1) | ZA989514B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005058293A1 (en) * | 2003-12-12 | 2005-06-30 | Allergan, Inc. | Use of memantine for the treatment of proliferative retinal diseases |
| WO2006015075A1 (en) * | 2004-07-26 | 2006-02-09 | Allergan, Inc. | Methods of treating ophthalmic conditions |
| WO2007084473A3 (en) * | 2006-01-17 | 2007-11-29 | Allergan Inc | The use of memantine and brimonidine to attenuate vitreoretinal vascular endothelial growth factor (vegf) protein levels in animals |
| US20120329879A1 (en) * | 2010-03-08 | 2012-12-27 | The University Of Tennessee Research Foundation | Beta-adrenergic receptor agonists and uses thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990006118A1 (en) * | 1988-12-05 | 1990-06-14 | Houston Biotechnology Incorporated | Therapeutic use of dihydropyrimidones and benzazepine and benzothiazepine derivatives in retinal or optic nerve dysfunction |
| US5521215A (en) * | 1989-11-07 | 1996-05-28 | Ramot University Authority For Applied Research And Industrial Development Ltd. | NMDA-blocking pharmaceuticals |
| WO1997001339A1 (en) * | 1995-06-28 | 1997-01-16 | Allergan | Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular neural injury |
| FR2738568A1 (en) * | 1995-09-08 | 1997-03-14 | Synthelabo | New 4-cycloalkyl and 4-cycloalkylalkyl piperidine derivs. with neuroprotective and neurotrophic activity |
| WO1997038691A1 (en) * | 1996-04-17 | 1997-10-23 | Sumitomo Pharmaceuticals Co., Ltd. | Remedy for retinal neuropathy |
-
1998
- 1998-10-09 WO PCT/US1998/021423 patent/WO1999025350A1/en active Application Filing
- 1998-10-09 AU AU97975/98A patent/AU9797598A/en not_active Abandoned
- 1998-10-19 ZA ZA989514A patent/ZA989514B/en unknown
- 1998-11-09 AR ARP980105654A patent/AR013749A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990006118A1 (en) * | 1988-12-05 | 1990-06-14 | Houston Biotechnology Incorporated | Therapeutic use of dihydropyrimidones and benzazepine and benzothiazepine derivatives in retinal or optic nerve dysfunction |
| US5521215A (en) * | 1989-11-07 | 1996-05-28 | Ramot University Authority For Applied Research And Industrial Development Ltd. | NMDA-blocking pharmaceuticals |
| WO1997001339A1 (en) * | 1995-06-28 | 1997-01-16 | Allergan | Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular neural injury |
| FR2738568A1 (en) * | 1995-09-08 | 1997-03-14 | Synthelabo | New 4-cycloalkyl and 4-cycloalkylalkyl piperidine derivs. with neuroprotective and neurotrophic activity |
| WO1997038691A1 (en) * | 1996-04-17 | 1997-10-23 | Sumitomo Pharmaceuticals Co., Ltd. | Remedy for retinal neuropathy |
Non-Patent Citations (3)
| Title |
|---|
| DATABASE WPI Section Ch Week 9802, Derwent World Patents Index; Class B02, AN 98-018014, XP002088198 * |
| KAPIN M A ET AL: "PROTECTIVE EFFECTS OF THE POLYAMINE ANTAGONIST, ELIPRODIL HYDROCHLORIDE IN RETINA SUBJECTED TO AN EXITOTOXIC-OR ISCHEMIC- INSULT", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 22, no. 1 - 03, 16 November 1996 (1996-11-16), pages 1279, XP000677227 * |
| LANGEVIN J. ET AL.: "Etude du tartrate d' ifenprodil dans le traitement des accidents vasculaires cérébraux aigus", OUEST MÉDICAL, vol. 29, 1976, pages 853 - 854, XP002088157 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005058293A1 (en) * | 2003-12-12 | 2005-06-30 | Allergan, Inc. | Use of memantine for the treatment of proliferative retinal diseases |
| WO2006015075A1 (en) * | 2004-07-26 | 2006-02-09 | Allergan, Inc. | Methods of treating ophthalmic conditions |
| WO2007084473A3 (en) * | 2006-01-17 | 2007-11-29 | Allergan Inc | The use of memantine and brimonidine to attenuate vitreoretinal vascular endothelial growth factor (vegf) protein levels in animals |
| EP2380632A1 (en) * | 2006-01-17 | 2011-10-26 | Allergan, Inc. | The use of NMDA antagonists to attenuate vitreoretinal vascular endothelial growth factor (VEGF) protein levels in animals |
| US20120329879A1 (en) * | 2010-03-08 | 2012-12-27 | The University Of Tennessee Research Foundation | Beta-adrenergic receptor agonists and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU9797598A (en) | 1999-06-07 |
| AR013749A1 (en) | 2001-01-10 |
| ZA989514B (en) | 1999-06-15 |
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