CA2575204A1 - Methods of treating ophthalmic conditions - Google Patents

Abstract

Methods of treating ophthalmic conditions include administering one or more therapeutic agents to an individual. In one aspect, a method includes administering one or more therapeutic agents to an individual at a time when the individual is not aware of a visual field loss associated with the ophthalmic condition. In another aspect, a method includes administering one or more therapeutic agents to an individual with an ophthalmic condition associated with retinal neurodegeneration, wherein the administering of the therapeutic agent is effective in reducing a decrease in a central nervous system response associated with the retinal neurodegeneration.

Description

METHODS OF TREATING PFiTHALMIC CONDITIONS
by William A. Hare, Elizabeth WoldeMussie, and Larry A. Wheeler Cross-Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 60/591,423, filed July 26, 2004, the entire contents of which are hereby incorporated by reference.
Background of the Invention The present invention relates to methods of providing therapeutic effects using therapeutic agents. More particularly, this invention relates to methods of treating ophthalmic conditions of individuals, that is humans or animals, at early stages of the ophthalmic conditions and of modifying responses of the central nervous system (CNS) to ophthalmic injury or disease by administering therapeutic agents to the individuals.
Glaucoma refers to a group of ocular disorders characterized by disease of the retinal ganglion cell (RGC) bodies and degeneration of the optic nerve. It is one of the leading causes of blindness worldwide. In a patient having glaucoma, the retinal ganglion cells slowly lose their ability to transmit nerve impulses. As a result, vision diminishes, often so slowly that a patient afflicted with this disease does not notice the degradation in vision until significant damage has occurred. Because glaucoma has few overt symptoms, it is difficult to detect early.
One approach to testing for glaucoma is to use a tonometer to measure intra-ocular pressure (IOP). This test is based on the notion that high intra-ocular pressure can damage the retinal ganglion cell layer. However, in practice, intra-ocular pressure has not proven to be a reliable indicator for glaucoma. In addition, some patients with glaucoma have an IOP in the normal range. But, these patients have visual field loss typical of glaucoma.
Another test for glaucoma is a visual field test in which light is directed to various portions of the retina.
By asking the patient whether he sees the light, one can map the sensitivity of the retina. Because the field vision test measures optic nerve function more directly, it is a more accurate indicator of glaucoma than the tonometric test.
Treatment in individuals with hypertensive or normotensive IOP is directed at lowering the IOP, even though the pressure is "normal". However, existing treatments of glaucoma do not distinguish between asymptomatic and symptomatic types of glaucoma. This may be due to the difficulty of diagnosing glaucoma at an early stage.
The use of neuroprotective agents to treat retinal cells has been disclosed. For example, U.S. Patent Nos.
5,922,773 and 6,482,854 (Lipton et al.) disclose administration of a compound capable of reducing glutamate induced excitotoxicity in a concentration effective to cause reduction of such excitotoxicity. U.S. Patent No. 6,573,280 (Dreyer) discloses anti-excitotoxic agents, such as glutamate receptor antagonists, and calcium blockers to prevent proliferative vitreoretinopathy. U.S. Patent No.

6,573,280 discloses administration of a compound to a patient to reduce glutamate-induced retinal cell migration to help treat proliferative vitreoretinopathy.

Neuroprotective effects of memantine are also described in a number of articles, see Woldemussie, "Neuroprotection of retinal ganglion cells in experimental models of glaucoma", Minerva Oftalmol, 42(2):71-8 (2000); Wheeler, "Experimental studies of agents with potential neuroprotective properties", Acta Ophthalmol Scand, 77(229):27-28 (1999); Schuettauf et al., "Effects of anti-glaucoma medications on ganglion cell survival: the DBA/2J
mouse model", Vision Res, 42(20):2333-7 (2002); WoldeMussie et al., "Neuroprotective effects of memantine in different retinal injury models in rats", J Glaucoma 11(6):474-480 (2002); and Hare et al., "Efficacy and safety of memantine, an NMDA-Type Open-Channel Blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey", Surv Ophthalmol 45(Suppl 3): S284-S289 (2001).
In many cases, a patient is administered a therapeutic agent to treat glaucoma after the patient experiences a substantial loss in vision. In these cases, it may be difficult to prevent further vision loss or successfully treat the glaucoma.
Thus, there remains a need for improved methods of treating ophthalmic conditions, such as conditions associated with ocular hypertension, including glaucoma.

Summary of the Invention New therapeutic methods employing therapeutic agents have been invented. The present methods involve systemic, such as oral, administration to a human or animal of one or more therapeutic agents to provide a desired therapeutic effect in treating an ophthalmic condition or conditions.
The present methods can successfully prevent further vision loss associated with the ophthalmic condition if administered at an early stage of disease, and/or can mitigate against a reduction in a visual response of the central nervous system that is typically associated with the ophthalmic condition.
In one embodiment, a method for treating an ophthalmic condition or mitigating against an ophthalmic condition comprises administering a therapeutic agent or therapeutic component to an individual at a time when the individual is not aware of visual field loss associated with the ophthalmic condition. The therapeutic agent is effective in treating the ophthalmic condition or mitigating against the ophthalmic condition.
In another embodiment, a method for treating an ophthalmic condition comprises administering a therapeutic agent or therapeutic component to an individual with an ophthalmic condition associated with retinal neurodegeneration. The administering of the therapeutic agent is effective in reducing a decrease in a central nervous system response associated with the retinal neurodegeneration.
The therapeutic agent of the present methods may be an anti-excitotoxic agent, such as a glutamate receptor antagonist. When administered systemically, the present therapeutic agents are able to cross the blood-brain barrier and/or blood-retinal barrier and provide a therapeutic effect or effects with little adverse side effects or toxicity. In certain methods, the therapeutic agent is selected from the group consisting of memantine (1-amino-3,5-dimethyladamantane), salts thereof, and mixtures thereof.
Each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present invention provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention.
These and other aspects and advantages of the present invention are set forth in the following detailed description, examples and claims.

Brief Description of the Drawings FIG. 1 is a graph of mean intraocular pressure (IOP) of hypertensive (OD) eye of one animal as a function of time.
FIG. 2 is a graph of average OD IOP of eyes for memantine-treated and vehicle-treated animals.
FIG. 3 provides graphs of ERG responses for a normotensive (OS) eye. Panel A is a flash response. Panel B is an oscillatory potential (OP) response. Panel C is a flicker response.
FIG. 4 provides graphs of conventional ERG response amplitude as a function of mean IOP for flash a-wave (panel A), b-wave (panel B), OP (panel C), and flicker (panel D).
FIG. 5 provides graphs of multifocal ERG responses obtained from one OS eye. Panel A is a trace array of first order responses. Panel B is the average response of the seven central traces in Panel A. Panel C is a trace array of the second order responses. Panel D is the average response of the second order responses in Panel C.
Calibrations are 800nV, 200 msec (panels A and C); 10 nV/deg2, 20 msec (panel B), and 5 nV/deg2, 20 msec (panel D).

FIG. 6 provides graphs of normalized macular multifocal ERG response amplitudes as a function of RGC count in the RGC layer.
FIG. 7 provides graphs of multifocal ERG macular response normalized peak amplitude as a function of mean IOP
for responses obtained at time T1.
FIG. 8 provides graphs of averaged response amplitudes (nV/degree2) for hypertensive (OD) eyes from vehicle-(filled squares) or memantine- (open circles) treated animals at times Ti, T2, and T3.
FIG. 9 provides graphs of the VECP response amplitude.
Panel A is a response from stimulation of a normotensive (OS) eye (calibration bars equal to 10 microvolts and 50 msec). Panel B is a plot of normalized (OD/OS) peak amplitude as a function of mean IOP for both treatment groups.
FIG. 10 is a graph of VECP response amplitude as a function of perifoveal counts of cells in the RGC layer.
FIG. 11 provides graphs summarizing electrophysiology measures obtained from stimulation of OS eyes of both treatment groups at time T3.
FIG. 12 is a graph of average glutamate levels obtained from vitreous samples from both eyes of animals in both treatment groups at time T3.
FIG. 13 is a graph of a hypothetical model showing the percentage of surviving RGCs as a function of time.
FIG. 14 is a graph of average IOP history for laser-treated hypertensive (OD) eyes of memantine treated and vehicle treated animals.
FIG. 15 is a diagram of the locations of retinal samples used for histological analysis.

FIG. 16 provides fundus images (top panels) of normotensive (OS) and hypertensive (OD) eyes, and micrographs (bottom panels) of sections from the perifoveal retinal sample region obtained from the same eye shown in the fundus images.
FIG. 17 is a graph of RGC number as a function of IOP.
FIG. 18 is a graph of inferior RGC numbers for vehicle treated animals and memantine treated animals.
FIG. 19 is a graph of RGC counts obtained from OS eyes of both treatment groups.
FIG. 20 provides graphs of normalized cup measurements from confocal laser scans at T2 for the five animals having the highest mean IOPs in each treatment group.
FIG. 21 provides graphs of normalized neuroretinal rim measurements at T2 from the animals in FIG. 20.
FIG. 22 provides graphs of three of the five cup measurements shown in FIG. 20 from the hypertensive eye of all five animals in each treatment group as a function of time.
FIG. 23 provides graphs of three of the five neuroretinal rim measurements shown in FIG. 21 from the hypertensive eye of all five animals in each treatment group as a function of time.

Detailed Description The present methods provide desired therapeutic effects employing certain therapeutic agents or therapeutic components, such as anti-excitotoxic or neuroprotective agents. The therapeutic agents are administered to an individual, such as a human or an animal, to treat one or more ophthalmic conditions, including disorders and diseases of one or both eyes of the individual. The present methods may reduce one or more symptoms associated with the ophthalmic condition or conditions, and may prevent further vision loss associated with the condition or conditions.

As used herein, an "anti-excitotoxic agent" is an agent that reduces or prevents glutamate-induced cellular toxicity.
As used herein, a "neuroprotective agent" is an agent that reduces or prevents neuronal degeneration or neuronal death.
As used herein, "treating" refers to the management, prevention, reduction, and/or elimination of one or more symptoms of one or more ophthalmic conditions. Treating thus includes prophylactic treatment of an individual.
As used herein, an "ophthalmic condition" includes diseases and disorders of one or more eyes of an individual.
Ophthalmic conditions typically negatively affect the health of the individual, such as by negatively affecting the vision of the individual, or by causing pain to the individual. For example, an ophthalmic condition, such as glaucoma, can be associated with vision loss, increased intraocular pressure, retinal damage, and the like.
The present methods comprise administering one or more therapeutic agents to an individual to treat one or more ophthalmic conditions. The administration of the therapeutic agent can include administering the agent orally, topically, intraocularly, or by other systemic routes, such as by intravenous injection, intramuscular injection, and the like. The therapeutic agent or agents are typically administered in compositions suitable for pharmaceutical use, such as injectable compositions or tablets, capsules, drops, and the like suitable for oral and/or topical administration.

At least one of the therapeutic agents employed in the present methods is an anti-excitotoxic agent. The anti-excitotoxic agent may be administered with one or more therapeutic agents that may be effective in treating ophthalmic conditions. For example, the anti-excitotoxic agent may be administered at approximately the same time as an agent that is effective in reducing intraocular pressure of an individual. The anti-excitotoxic agent may be understood to be a neuroprotective agent since the anti-excitotoxic agent reduces toxic effects induced by excessive glutamate concentrations or amounts. Anti-excitotoxic agents useful in the present methods may be agents which prevent or reduce excessive intracellular calcium concentrations. Thus, in accordance with the disclosure herein, anti-excitotoxic agents include calcium channel inhibitors, such as calcium channel blockers and antagonists, and glutamate receptor inhibitors, such as glutamate receptor antagonists or blockers. As used herein, an "inhibitor" refers to an agent that reduces the activity, such as ion flux, through a channel, or receptor-channel complex. The inhibitor may provide its effect either by directly binding to a channel or receptor, or may do so indirectly by affecting one or more parameters that affect the channel or receptor activity.

In certain of the present methods, the anti-excitotoxic agent is an inhibitor of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. Or, stated differently, the anti-excitotoxic agent is an NMDA receptor antagonist.

An NNIDA receptor antagonist is typically an agent that reduces neuronal damage mediated by the N.NDA receptor complex. Examples of NMDA receptor antagonists useful in the present methods are described in U.S. Patent Nos.

5,922,773, 6,482,854; and 6,573,280. In short, an NNIDA
receptor antagonist includes NMDA receptor channel blockers (e.g., antagonists that operate uncompetitively to block the NMDA receptor channel); receptor antagonists (e.g., antagonists that compete with NMDA or glutamate to act at the NMDA or glutamate binding site); agents acting at either the glycine co-agonist site or any of several modulation sites, such as the zinc site, the magnesium site, the redox modulatory site, or the polyamine site; or agents that inhibit the downstream effects of NMDA receptor stimulation, such as agents that inhibit activation of protein kinase C
activation by NMDA or glutamate stimulation, antioxidants, and agents that decrease phosphatidyl metabolism. Some specific examples of anti-excitotoxic agents include amantadine derivates, salts thereof, and combinations thereof. For example, the amantadine derivates may be memantine, amantadine, and rimantadine. Other anti-excitotoxic agents may include nitroglycerin, dextorphan, dextromethorphan, and CGS-19755. Some compounds include those in the following table NMDA Antagonists NMDA Antagonists NMDA Antagonists 1. Competitive NMDA 2. Channel Blockers 3. Antagonists at Antagonists (act at (Un-Competitve NMDA Glydne Site of the agonist binding site) Antagonists) NMDA Receptor CGS-19755 (CIBA- MK-801 (Dizocilpine) Kynurenate, 7-GEIGY) and other and other chloro-kynurenate, piperdine derivatives of 5,7- chloro-derivatives, D-2- dibenzyocycloheptene kynurenate, thio-amino-5- (Merck) derivatives, and phosphovalerate, D-2- other derivatives.
amino-7- Sigma receptor (Merck) phosphosoheptanoate ligands, e.g.
(AP7) CPP {[3-2- Dextrorphan, Indole-2-carboxylic carboxypiperazin-4-y- dextromethorphan and acid propyl-l-phosphonic morphiasn acid]} derivatives (Hoffman DNQX
La Roche) such as caramiphen and Quinoxaline or rimcazole (which oxidiazole also block calcium derivatives LY 274614, CGP39551, channels) including CNQX, CGP37849, LY233053, Ketamine, Tiletamine NBQX
LY233536 and other Glycine partial 0-phosphohomoserine cyclohexanes agonist (e.g.
Phencyclidine (PCP) Hoecht- Roussel P-MDL100,453 and derivatives, and 9939 pyrazine compounds 4. Polyamine Site-of Memantine, 6. Other Non-NMDA Receptor amantadine, Competitve NMDA
rimantadine and Antagonists Arcaine and relate derivatives Hoechst 831917189 biguanidines and CNS 1102 (and biogenic polyamines related bi- and tri- SKB Carvedilol Ifenprodil and substituted related drugs guanidines) Diethylenetriamine SL Diamines 82,0715 Conantokan peptide from Conus 1,10-diaminodecane geographus (and related inverse Agatoxis-489 agonists) 5. Redox Site of NMDA Receptor Oxidized and reduced glutathione PQQ
(pyrroloquinoline quinone) Compounds that generate Nitric Oxide (NO) or other oxidation states of nitrogen monoxide (NO+, NO-) including those listed in the box below Nitroglycerin and derivatives, Sodium Nitroprusside, and other NO generating listed on p.5 of this table Nitric oxide synthase (NOS) Inhibitors:
Arginise analogs including N-mono-methyl-L-arginine (NMA); N-amino-L-arginine (NAA); N-nitro-L arginine (NNA); N-nitro-L-arginine methyl ester; N-iminoethyl-L-omithine Flavin inhibitors;
diphenyliodinium;
Calmoduli inhibitors, trifluoperizine Calcineurin Inhibitors, e.g., FK-506 (inhibits calcineurin and thus NOS diphosphorylase) Inhibitors of Inhibitors of Non-NMDA Receptor Downstream Effects of Downstream Effects Antagonists NMDA of NMDA

7. Agents to inhibit 8. Downstream 9A. Non-NMDA
protein kinase C effects from antagonists activation by NMDA Receptor Activation (Competitive) stimulation (Involved in NMDA toxicity) 8a. To decrease CNQX, NBQX, YM900, MDL 27,266 (Merrill phosphatidylinositol DNQX.
Dow) and triazoleone metabolism PD140532 derivatives kappa opioid AMOA (2-amino-3[3-Mososialoganglioxides receptor agonist: 9carboxymethoxyl-5-(eg GMI of Fidin U50488 (Upjohn) and methoxylisoxazol-4-Corp.) and other dynorphan yl]propionate]
ganglioside derivatives LIGA20, kapp opioid receptor 2-phosphophonoethyl LIGA4 (may also agonist: PD117302, phenylalanine affect calcium CI-977 derivatives, i.e., extrusion via calcium 5-ethyl, 5-methyl, ATPase) 8b. To decrease 5-trifluoromethyl hydrogen peroxide and free radical 9B. Non-NMDA Non injury, eg competitive antioxidants 21- antagonists aminosteroid GYK152466 (lazaroids) such as U74500A, U75412E and Evans Blue U74006F U74389F, FLE26749, Trolox (water soluble alpha tocophenol), 3,5-dialkoxy-4-hydroxy-benzylamines Compounds that generate Nitric Oxide (NO) or other oxidation states of nitrogen monoxide (NO+, NO-) including those listed in the box below Nitroglycerin and derivatives, Sodium Nitroprusside, and other NO generating listied on p.5 of this table Nitric oxide Synthase (NOS) In.hibition :
Arginine analogs including N-mono-methyl-L-arginine (NMA); N-amino-L-arginine (NAA); N-nitro-L arginine (NNA); N-nitro-L-arginine methyl ester; N-iminoethyl-L-omithine Agents Active at Decrease Glutamate Drugs to decrease Metabotropic Release intracellular Glutamate Receptors calcium following glutamate receptor stimulation 10a. Blockers of 11. Agents to 12a. Agents to Metabotropic decrease glutamate decrease Glutamate Receptors release Intracellular AP3 (2-amino-3- calcium release phosphonoprionic Adenosine, and Dantrolen (sodium acid) derivatives, e.g., dantrium: Ryanodine cyclohexyladenosine (or 10b. Agonists of CN51145 ryanodine+caffeine) Metabotropic Glutamate Receptors Conopeptides: SNX- 12b. Agents (1S, 3R)-l-Amino- 111, SNX-183, SNX- Inhibiting cyclopentane-l,3- 230 intracellular dicarboxylic acid Calcium-ATPase [(1S,3R)-ACPD], Omega-Aga-IVA, toxin Thaprigargin, commonly referred to from venom of funnel cyclopiazosic acid, as 'trans'-ACPD spider BHQ ([2,5-di-(tert Compounds that butyl)-1,4-generate Nitric benzohydroquinose]) Oxide (NO) or other oxidation states of nitrogen monoxide (NO+, NO-) including those listed in the box below Nitroglycerin and derivatives, Sodium Nitroprusside, and other NO generating listied on p.5 of this table Nitric oxide Synthase (NOS) Inhibitors:
Arginine analogs including N-mono-methyl-L-argini.ne (NMA); N-amino-L-arginine (NAA) ; N-nitro-L arginine (NNA); N-nitro-L-arginine methyl ester; N-iminoethyl-L-omithine Additional NO-generating compounds Isosorbide dinitrate (isordil) S-nitrosocaptopril (SnoCap) Serum albumin coupled to nitric oxide (SA-NO) Cathepsin coupled to nitric oxide (cathepsin-NO) Tissue plasminogen activator coupled to NO (TPA-NO) SIN-i (also known as SIN1 or molsidonmine) Ion-nitrosyl complexes (e.g., nitrosyl-iron complexes, with iron in the Fe2+ state) Nicorandil Other agents which may be understood to be anti-excitotoxic and useful in the present methods include voltage-dependent calcium channel antagonists and antagonists of non-NMDA receptors (glutamate receptor types other than the NMDA receptor complex discussed above).
These non-NMDA receptor antagonists include agents which block ionotropic glutamate receptors or interact with metabotropic glutamate receptors, as understood by persons of ordinary skill in the art. Other anti-excitotoxic agents may act to limit or reduce release of glutamate from cells, thereby acting upstream from the glutamate receptors in the excitatory neurotoxicity process. Still other agents may act by blocking downstream effects of glutamate receptor stimulation, e.g., the intracellular consequences of glutamate interaction with a cell membrane glutamate receptor, such as agents (like dantrolene) that block the rise in intracellular calcium following stimulation of membrane glutamate receptors.
The therapeutic agents used in the present methods preferably are those capable of crossing the blood-brain barrier or the blood-retinal barrier; these agents may be administered orally, intravenously, or topically and cross intervening barriers including the blood brain barrier to reach the retinal ganglion cells. Therapeutic agents that do not freely cross the blood-brain barrier may be administered intraocularly, such as by intravitreal injection and the like so that the agent is delivered to the retina. In the case of agents that have an intermediate ability to cross the blood-brain barrier, the mode of administration will depend on the dosage required and other factors.
In certain methods of the present invention, the therapeutic agent comprises an adamantane having the following formula:

ZD Formula I
Adamantane An adamantane-based amine is a compound having an amine which is directly or indirectly bonded to or coupled with an adamantane. In other words, the adamantane may be directly bonded to the nitrogen of the amine, or a linking group consisting of one or more atoms may connect the adamantane to the amine. Additionally, the adamantane may have additional substituents, such as a methyl group or a small alkyl group, attached. A group comprising the basic cage structure of adamantane and one or more substituents is referred to as an "adamantyl" moiety. The term "amine"
should be understood as being broadly applied to both a molecule, or a moiety or functional group, as generally understood in the art, and may be primary, secondary, or tertiary. While not intending to limit the scope of the invention in any way, three compounds which are adamantane based neuroprotective-amines, and are also neuroprotective compounds comprising an adamantyl moiety and an amine moiety, are amantadine, rimantadine, and memantine, as illustrated below:

b --Memantine Amantadine Rimantadine The terms memantine, amantadine, and rimantadine as used herein refer to the free base forms of the amine, or any of the various salts, such as memantine hydrochloride, which can be prepared by the addition of an acid to the free base. The determination of the amount of memantine used in the pharmaceutical or ophthalmic compositions is well within the ability of one having ordinary skill in the art. An "effective" amount of memantine is an amount which has a detectable effect over a similar composition or method which comprises no memantine or any other active ingredient which would be expected to have an effect similar to that of memantine.
In referring to concentrations of memantine herein, the numeric value for the concentration is understood to be the concentration of the free base, regardless of the form in which the memantine is used. Since there is a large range of concentrations or amounts at which memantine is effective, the concentration or amount of memantine as used herein may vary. In certain methods, a composition may comprise from 0.05 to 5% memantine. Other compositions may comprise from 0.05% to 2% memantine. Some compositions may comprise from 0.05% to 2.5% memantine. Another composition may comprise from 0.2% to 3% memantine. Some compositions comprise from 0.1% to 2% memantine. Other compositions comprise from 0.5% to 2% memantine. Other compositions comprise from 0.5% to 3.5% memantine. Other compositions comprise from 0.3 % to 1.5%. Another composition comprises from 0.5% to 1.3% memantine. Other compositions comprise from 0.1% to 1% memantine. Another compositions comprises from about 0.5% to about 1% memantine. Other compositions comprise about 0.5% memantine. Other compositions comprise about 1% memantine.
With respect to the present methods, the therapeutic agent may be an adamantane-based neuroprotective amine. For example, the therapeutic agent may be an agent selected from the group consisting of memantine, amantadine, rimantadine, salts thereof, and mixtures thereof. In certain methods, the therapeutic agent comprises memantine, salts thereof, and mixtures thereof.
The therapeutic agents useful in the present methods may be purchased from companies, such as Sigma Chemicals (St. Louis, MO), or the therapeutic agents may be synthesized using conventional chemical synthesis methods readily known by persons of ordinary skill in the art.
Potential anti-excitotoxic agents, such as glutamate receptor inhibitors, and the like, can be identified using routine screening assays. For example, such agents can be tested for binding to glutamate receptors in vitro, for inhibition of glutamate-mediated electrical signals using electrophysiological methods, or using the methods disclosed in the examples herein. Anti-excitotoxic agents may be further identified based on structural or functional similarities with other anti-excitotoxic agents/
As discussed herein, the therapeutic agents may be administered to an individual using any technique, including conventional techniques, known to persons of ordinary skill in the art, which are effective in delivering the therapeutic agent to an eye of an individual, such as to the retina of an eye, or to the brain or a region of the brain of the individual. The therapeutic agent may be administered in a liquid composition, such as a solution, suspension, or emulsion, which may be administered by injection or orally. For example, the therapeutic agent may be provided in an aqueous liquid composition, a non-aqueous liquid composition, or an oil-containing emulsion, such as an oil-in-water emulsion or a water-in-oil emulsion. Or, the composition may be in the form of tablets or capsules which may be ingested to provide systemic delivery of the therapeutic agent to the individual. Thus, the therapeutic agent or agents used in the present methods may be provided in formulations or compositions that may be administered by topical, oral, rectal or parenteral (e.g. intravenous, subcutaneous or intramuscular) routes, among others.
The compositions may be prepared using conventional pharmaceutical techniques. Such techniques may include a step of bringing into association the therapeutic agent, and pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly combining the therapeutic agent or agents with the carriers or excipients.
The therapeutic agents may be provided in single unit or single dosage compositions, if desired.
Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing, in a suitable machine, the therapeutic agent is presented as a powder or granules, and optionally a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally coated or scored and may be formulated so as to provide a slow or controlled release of the therapeutic agent therein.

Compositions suitable for topical administration in the mouth, include lozenges comprising the therapeutic agent in a flavored basis, usually sucrose and acacia or tragacanth;

pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
Compositions suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the therapeutic agent to be administered in a pharmaceutical acceptable carrier. A preferred topical delivery system is a transdermal patch containing the therapeutic agent to be administered.
Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
It should be understood that in addition to the ingredients, particularly mentioned above, the compositions useful in the present methods may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
The exact formulation and dosage of the therapeutic agent depends upon a number of factors known by persons of ordinary skill in the art, including without limitation, the route of administration, the size of the individual, and the health of the individual. Generally, an effective daily dose of the therapeutic agent will range from 0.01 mg/kg to 1000 mg/kg. For example, in an oral administration method, the dose of the therapeutic agent may be from about 0.01 mg/kg/day to about 100 mg/kg/day. In certain methods, the therapeutic agent may be administered in an amount of 0.1 mg/kg/day to about 10 mg/kg/day. In the examples described herein, the therapeutic agent was memantine, which was administered orally at a dose of about 4 mg/kg.
In certain embodiments, such as methods using a liquid composition, it may be useful to include a buffer in ophthalmic compositions to maintain the pH from about 6 to about 8 for optimal comfort. Buffers used are those known to those skilled in the art, and, while not intending to be limiting, some examples are acetate, borate, carbonate, citrate, and phosphate buffers. Tonicity agents such as glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes may also be used in ophthalmic compositions to adjust the concentration of dissolved material to the desired isotonic range. Surfactants such as polysorbates, poloxamers, alcohol ethoxylates, ethylene glycol-propylene glycol block copolymers, fatty acid amides, alkylphenol ethoxylates, or phospholipids may also be used in ophthalmic compositions. Chelating agents may also be used in ophthalmic compositions to enhance preservative effectiveness. While not intending to be limiting, some useful chelating agents are edetate salts, like edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium, and edetate dipotassium.
The administration of the therapeutic agent in accordance with the present methods is effective in treating, that is preventing, reducing, or eliminating one or more symptoms, of one or more ophthalmic conditions.
Non-limiting examples of ophthalmic conditions which may be treated with present methods include the following:
MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age Related Macular Degeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD), Choroidal Neovascularization, Diabetic Retinopathy, Acute Macular Neuroretinopathy, Central Serous Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema.

UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid Pigment Epitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome.

VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease, Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle Cell Retinopathy and other Hemoglobinopathies, Angioid Streaks, Familial Exudative Vitreoretinopathy.

TRAUMA.TIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow Transplant Retinopathy.
PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy and Epiretinal Membranes, Proliferative Diabetic Retinopathy, Retinopathy of Prematurity (retrolental fibroplastic).
INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular Toxocariasis, Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis, Toxoplasmosis, Retinal Diseases Associated with HIV Infection, Choroidal Disease Associated with HIV Infection, Uveitic Disease Associated with HIV
Infection, Viral Retinitis, Acute Retinal Necrosis, Progressive Outer Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis.

GENETIC DISORDERS: Systemic Disorders with Accosiated Retinal Dystrophies, Congenital Stationary Night Blindness, Cone Dystrophies, Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy, pseudoxanthoma elasticum, Osler Weber syndrome.

RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant Retinal Tear.

TUMORS: Retinal Disease Associated with Tumors, Solid Tumors, Tumor Metastasis, Benign Tumors, for example, hemangiomas, neurofibromas, trachomas, and pyogenic granulomas, Congenital Hypertrophy of the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma, Choroidal Metastasis, Combined Hamartoma of the Retina and Retinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal Degeneration, Acute Retinal Pigment Epithelitis, cular inflammatory and immune disorders, ocular vascular malfunctions, Corneal Graft Rejection, Neovascular Glaucoma, closed-angle glaucoma, primary open-angle glaucoma, pseudoexfoliation glaucoma, and the like.
In certain of the present methods, the ophthalmic condition is associated with a loss of a visual field. For example, the loss of the visual field, including a partial loss or a complete loss, may be a symptom of the ophthalmic condition, or may be a cause of the ophthalmic condition.

For example, ophthalmic conditions associated with elevated intraocular pressure may result in a loss or a reduction in the size of an individual's visual field. One example of such a condition is glaucoma. Some ophthalmic conditions treated by the present methods include retinal neurodegenerative conditions, such as disorders or diseases.
In one embodiment of the present invention, a method for treating an ophthalmic condition comprises administering one or more therapeutic agents to an individual at a time when the individual is not aware of a visual field loss.

The visual field loss is associated with the ophthalmic condition. Thus, the administration of the therapeutic agent may be understood to mitigate against the ophthalmic condition.
As an example, a patient may not be aware of any visual field loss, e.g., the patient believes he has normal vision, but a physician may be able to diagnose the ophthalmic condition at an early stage, before the visual field loss is too substantial or noticeable by the patient. Thus, when the ophthalmic condition is glaucoma, the individual or patient may be understood to be a glaucoma suspect, that is an individual who is suspected of being at an early stage of glaucoma or is predisposed to developing glaucoma. High risk glaucoma suspects, such as individuals who are ocular hypertensive and/or exhibit suspicious optic cupping, may have normal white on white Sita-Standard visual fields. The therapeutic agent may be any therapeutic agents, including the anti-excitotoxic agent, such as memantine, salts thereof, and mixtures thereof, as described above.

In accordance with the present methods, the therapeutic agent may be administered at a time when the individual has less than about 80% of visual field loss. In certain methods, the therapeutic agent is administered at a time when the individual has less than about 40% of visual field loss. For example, the therapeutic agent may be administered at a time when the individual has less than about 20%, such as less than about 10%, of visual field loss. In certain embodiments, a method in accordance with the disclosure herein is effective in preventing a detectable decrease in visual field. The prevention of a detectable decrease in visual field may be related to a preservation of one or more visual responses within the central nervous system, such as in the brain stem, thalamus, and/or cortex.
As discussed herein, the ophthalmic condition may comprise or be associated with an increased intraocular pressure. For example, the method may be practiced to treat glaucoma. As discussed herein, since the therapeutic agent is administered before the patient is aware of a visual field loss, the method may be effective in treating either asymptomatic glaucoma or symptomatic glaucoma. The present method may be effective in treating a retinal neurodegenerative condition, which may or may not be associated with glaucoma, but which typically results in a loss or reduction of visual field.

The therapeutic agent may be chronically administered to the individual. For example, the therapeutic agent may be administered on a repeating schedule from the time of original diagnosis by a physician until the individual no longer requires treatment, such as when the ophthalmic condition has been eliminated, or the patient is no longer living. In certain methods, the administration may occur on a daily basis, and may occur by administering one or more units of single dose compositions disclosed herein.

Thus, the administration of the therapeutic agent may be effective as a prophylactic to further deterioration of the individual's vision resulting from the ophthalmic condition. For example, the therapeutic agent may prevent any noticeable vision loss from occurring thereby maintaining the individual's vision and treating the ophthalmic condition. In certain methods, the administration of the therapeutic agent is effective in reducing further visual field loss of the individual. For example, an individual with a 20% loss of visual field may be administered a therapeutic agent in accordance with the present methods, and the individual may not experience any greater loss of visual field.

The administration of the therapeutic agent may be associated with reducing a decrease in a visually-evoked cortical potential (VECP) in response to stimulation of an eye. Additional information regarding the VECP may be found in the examples herein. In short, a visual stimulus activates retinal neurons which send an electrical signal into one or more visual regions within the central nervous system of an individual. A signal that can be recorded in the visual cortex of the individual that receives the visual signal is a VECP. When retinal ganglion cells are injured or are destroyed resulting from an ophthalmic condition, such as elevated intraocular pressure, the VECP, or one or more components of the VECP, is decreased relative to the VECP in an eye without the ophthalmic condition. This decrease can be reduced by practicing the present methods.
While not wishing to be bound by any specific mechanism of action, it is possible that the administration of the therapeutic agent, such as the anti-excitotoxic agents disclosed herein, prevents further retinal neuron degeneration. The surviving retinal neurons, such as the surviving retinal ganglion cells, may thus experience changes and show an increase in neuronal growth, such as axon terminal sprouting. This enhancement of interneuronal connections (connections between neurons) may be effective in maintaining the VECP of individuals having an ophthalmic condition that results in a decrease of the VECP.

Thus, in one embodiment of the present methods, the therapeutic agent is an NMDA receptor inhibitor, and chronic administration of the NMDA receptor inhibitor is effective in enhancing transfer of visual signals from surviving retinal ganglion cells of the individual to at least one central visual region of the central nervous system. The neuronal growth may occur at one or more regions of the visual system, such as the lateral geniculate of the thalamus, the visual cortex, or the superior colliculus.

The therapeutic agent may be administered at or before the onset of the ophthalmic condition, which is a time when symptoms of the ophthalmic condition are first exhibited.
While a precise moment of onset of the ophthalmic condition may not be determinable, with respect to glaucoma, a high intraocular pressure at initial diagnosis of glaucoma is indicative of a high IOP at onset of the ophthalmic condition.
In certain embodiments, the therapeutic agent is administered prior to an abnormal increase in glutamate concentration in the vitreous of an eye of the individual.

For example, the therapeutic agent may be administered when the vitreal concentration of glutamate is sub-toxic.

In certain embodiments, the therapeutic agent is administered to the individual prior to the individual undergoing any anti-glaucoma treatment. For example, prior to receiving an intraocular pressure lowering drug. Or, prior to a an individual undergoing a ophthalmic filtering operation currently used to reduce intraocular pressure.
For example, the therapeutic agent may be administered to an individual without operating on the individual to reduce intraocular pressure of the individual.

Individual's who are not aware of a visual field loss may be identified by one or more methods, which may be conventional to persons of ordinary skill in the art.

For example, such individual's may be identified by assessing retinal function. At least one method of assessing retinal function is disclosed in U.S. Patent Publication No. 2002/0133089 (Pasquale et al.).

In short, a patient having normal retinal function will perceive an entoptic signal, which most commonly appears to the patient as a blue arc. A patient's inability to perceive this entoptic signal is correlated with the likelihood that the patient's retina has experienced damage.
Thus, such an individual may be identified by selecting a test site on the individual's retina and stimulating that test site to cause the generation of an entoptic signal.
The patient may provide information whether he/she detects the entoptic signal, or the entoptic signal, or the lack thereof, may be detected using an ophthalmic instrument.
The entoptic signal is preferably detected after a period of time in which the electrical activity of the retina has decreased or become quiescent.

As another example, individuals who have an ophthalmic condition and are not aware of visual field loss may be identified using a method such as the method of diagnosing glaucoma, as disclosed in U.S. Patent Publication No.
2003/0068632 (Garchon).
In short, the method disclosed by Garchon comprises assessing an individual's alleles of the apolipoprotein E
(ApoE) gene, and/or assessing the individual's alleles of the promoter of an ApoE gene, in order to determine whether the individual has an ApoE4 allele (or two ApoE4 alleles), and/or whether the individual has a "T" allele (or two "T"
alleles) of an ApoE gene promoter at (-491) (e.g., by detection of the presence or absence of ApoE4 allele(s), and/or by detection of the presence or absence of "T"

allele(s) of an ApoE gene promoter); and/or whether the individual has an ApoE(-219G) gene promoter allele. Such methods may be useful in individual's who have a mutation in the gene for trabecular meshwork inducible glucocorticoid response (TIGR) protein (a "carrier of a TIGR gene mutation") or a mutation in the promoter of the TIGR gene (a "carrier of a TIGR gene promoter mutation"). If it is not known whether the individual is a carrier of a TIGR gene mutation or a TIGR gene promoter mutation, the presence or absence of a mutation in the TIGR gene or promoter can be determined concurrently with the assessment of the ApoE
alleles and/or the ApoE gene promoter alleles.

In a carrier of a TIGR gene mutation, the presence of an ApoE4 allele is indicative of an increased risk of developing early-onset glaucoma, compared with the risk of a carrier of a TIGR gene mutation with no ApoE4 alleles. The presence of an ApoE4 allele in a carrier of a TIGR gene promoter mutation is indicative of a decreased risk of developing glaucoma with a high intraocular pressure at onset of disease, compared with the risk of a carrier of a TIGR gene promoter mutation with no ApoE4 alleles. The absence of any ApoE4 alleles in a carrier of a TIGR gene mutation is indicative of a decreased risk of developing early-onset glaucoma, compared with the risk of a carrier of a TIGR gene mutation with an ApoE4 allele. The absence of any ApoE4 alleles in a carrier of a TIGR gene promoter mutation is also indicative of an increased risk of developing glaucoma with a high intraocular pressure at onset of disease, compared with the risk of a carrier of a TIGR gene promoter mutation with an ApoE4 allele.

The combination of an ApoE4 allele and a "T" allele of a ApoE gene promoter (at -491) in an individual carrying a mutation in the TIGR gene is also indicative of an increased risk of developing early-onset glaucoma, compared with the risk of a carrier of a TIGR mutation with an ApoE4 allele but no "T" alleles of a ApoE gene promoter. The absence of any "T" alleles of an ApoE gene promoter in a carrier of a TIGR mutation with an ApoE4 allele is indicative of a decreased risk of developing early-onset glaucoma, compared with the risk of a carrier of a TIGR mutation with an ApoE4 allele and a"T" allele of an ApoE gene promoter.

The presence of a "T" allele of an ApoE gene promoter in an individual, regardless of whether a mutation in the TIGR gene is present or absent, is indicative of an increased risk of developing glaucoma with a high intraocular pressure at onset of disease, compared with the risk of an individual who has no "T" alleles of an ApoE gene promoter. The absence of a"T" allele of an ApoE gene promoter in an individual, is indicative of a decreased risk of developing glaucoma with a high intraocular pressure at onset of disease, compared with the risk of an individual who has a "T" allele of an ApoE gene promoter. Furthermore, if the individual is a carrier of a TIGR gene promoter mutation (e.g., a (-1000G) mutation), the presence of an ApoE(-491T) gene promoter allele is indicative of an even greater increased risk of developing glaucoma with a high intraocular pressure at onset of disease, compared with the risk of such an individual who has no ApoE(-491T) gene promoter allele or TIGR gene promoter mutation.

The presence of an ApoE(-219G) gene promoter allele is indicative of an increased risk of developing glaucoma with a high visual field score, a high cup/disk ratio, or both, compared with the risk of an individual who has no ApoE(-219G) gene promoter allele. The absence of an ApoE(-291G) gene promoter allele in an individual is indicative of a decreased risk of developing glaucoma with a high visual field score or a high cup/disk ratio, compared with the risk of an individual who has an ApoE(-219G) gene promoter allele.
The ApoE alleles and/or the ApoE gene promoter alleles in an individual can be assessed by a variety of methods, including hybridization methods (e.g., Southern or Northern analysis), sequencing of the gene and/or the gene promoter, allele-specific oligonucleotide analysis, analysis by restriction enzyme digestion, or (in the case of the ApoE
alleles) by analysis of the ApoE protein(s) (e.g., spectroscopy, enzyme-linked immunosorbent assay, colorimetry, electrophoresis, isoelectric focusing, radioimmunoassay, immunoblotting (such as Western blotting)). Several methods of assessing the ApoE alleles are described in detail in U.S. Pat. No. 5,508,167 (Roses et al.). Similar methods can be used to assess the alleles of the ApoE promoter.
For example, in one method of assessing the ApoE
alleles in the individual, hybridization methods, such as Southern analysis, can be used (see Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley &
Sons, including all supplements through 1998). For example, a test sample containing genomic DNA, RNA, or cDNA that includes the ApoE gene or encodes ApoE protein can be used.

Such genomic DNA, RNA and cDNA are referred to herein collectively as "nucleic acids comprising the ApoE gene".
The test sample is obtained from an individual (the "test individual"). The individual can be an adult, child, or fetus. The test sample can be from any source which contains DNA, RNA or cDNA, such as a blood sample, cerebrospinal fluid sample, or tissue sample (e.g., from skin or other organs). In a preferred embodiment, a test sample containing nucleic acids comprising ApoE gene is obtained from a blood sample, a fibroblast skin sample, from hair roots, or from cells obtained from the oral cavity (e.g., via mouthwash).
In another preferred embodiment, a test sample containing nucleic acids comprising the ApoE gene is obtained from fetal cells or tissue by appropriate methods, such as by amniocentesis or chorionic villus sampling.

To assess the ApoE alleles, a hybridization sample is formed by contacting the test sample containing the nucleic acid comprising the ApoE gene, with at least one nucleic acid probe. The hybridization sample is maintained under conditions which are sufficient to allow specific hybridization of the nucleic acid probe to the nucleic acid comprising the ApoE gene. "Specific hybridization", as used herein, indicates exact hybridization (e.g., with no mismatches). Specific hybridization can be performed under high stringency conditions or moderate stringency conditions, for example. "Stringency conditions" for hybridization is a term of art which refers to the conditions of temperature and buffer concentration which permit hybridization of a particular nucleic acid to another nucleic acid in which the first nucleic acid may be perfectly complementary to the second, or the first and second nucleic acids may share only some degree of complementarity. For example, certain high stringency conditions can be used which distinguish perfectly complementary nucleic acids from those of less complementarity. "High stringency conditions" and "moderate stringency conditions" for nucleic acid hybridizations are explained in chapter 2.10 and 6.3, particularly on pages 2.10.1-2.10.16 and pages 6.3.1-6 in Current Protocols in Molecular Biology, supra, the teachings of which are hereby incorporated by reference. The exact conditions which determine the stringency of hybridization depend on factors such as length of nucleic acids, base composition, percent and distribution of mismatch between the hybridizing sequences, temperature, ionic strength, concentration of destabilizing agents, and other factors. Thus, high or moderate stringency conditions can be determined empirically. In one embodiment, the hybridization conditions for specific hybridization are moderate stringency. In a particularly preferred embodiment, the hybridization conditions for specific hybridization are high stringency.
= Specific hybridization, if present, is then detected using standard methods. If specific hybridization occurs between the allele-specific nucleic acid probe and an ApoE

gene in the test sample, then the individual has the allele of ApoE to which that nucleic acid probe hybridizes. More than one nucleic acid probe can also be used concurrently in this method (e.g., a probe that hybridizes to an ApoE2 allele and a probe that hybridizes to an ApoE3 allele).

Similar methods can also be used to assess the ApoE
gene promoter alleles, using a sample which contains nucleic acids of the gene promoter (and amplified copies of the gene promoter or portion of the gene promoter, if amplification is performed) and allele-spepific nucleic acid probes that hybridize to only one of the two ApoE gene promoter alleles.
In addition, these methods can be used to assess both the ApoE alleles and the ApoE gene promoter alleles concurrently, using a sample which contains nucleic acids comprising the ApoE gene and also comprising the ApoE gene promoters (and amplified copies of the gene and gene promoter, or portions of the gene or gene promoter, if amplification is performed), at least one allele-specific nucleic acid probe that hybridizes to one of the ApoE

alleles, and an allele-specific nucleic acid probe that hybridizes to an allele of the ApoE promoter. For example, genomic DNA comprising the ApoE promoter and the ApoE gene can be amplified concurrently and then assessed for the alleles of the gene and the promoter.

Additional methods which may be used in conjunction with or instead of the methods described above, are well known and routine to persons of ordinary skill in the art.

In addition or alternatively, individual's having an ophthalmic condition without a noticeable loss of visual field may be identified using scanning laser polarimetry.
For example, the scanning laser polarimetry may be used to evaluate the optic nerve of one of the eyes of the individual. This method may be particularly useful in individual's with normal-tension glaucoma. This method examines the retinal nerve fiber layer (RNFL) using imaging techniques. Thus, it is possible to check neural rim integrity for thinning and notching, and assess any loss in the RNFL. The contour, cupping, curvature of the optic nerve, and hemorrhage on the disc margin, may suggest damage to the individual's eye.

In another embodiment, a method of treating an ophthalmic condition comprises administering a therapeutic agent to an individual with an ophthalmic condition associated with retinal neurodegeneration. The administering of the therapeutic agent is effective in reducing a decrease in a central nervous system response associated with the retinal neurodegeneration.

Similar to that described above, the ophthalmic condition of the foregoing method may comprise an increased or elevated intraocular pressure. For example, the ophthalmic condition may be glaucoma, including asymptomatic or symptomatic glaucoma. Or the ophthalmic condition may be a condition other than glaucoma. The ophthalmic condition may be an early stage retinal neurodegenerative disorder.
The administration of the therapeutic agent may be systemic or intraocular, such as by injection or ingestion or topical application.

As discussed hereinabove, the administration of the therapeutic agent may be effective in reducing a decrease in the VECP in response to stimulation of the eye, the decrease being associated with or a result of the ophthalmic conditions.
In a further embodiment of the present invention, a method for treating an ophthalmic condition comprises administering a therapeutic agent to an individual with a reduced visual field caused by the ophthalmic condition.
The administration of the therapeutic agent may be effective in enhancing the reduced visual field. For example, after a prolonged administration of the therapeutic agent, such as memantine, it is believed that retinal neurons may also exhibit neuronal growth. This neuronal growth may be effective in increasing the size of the visual field, or in enhancing the efficacy of transmission of visual signals within a visual field.
The methods of the present invention may be effective in preserving a visually-evoked cortical response without substantially reducing retinal ganglion cell loss resulting from the ophthalmic condition. However, as discussed above, it may be possible to enhance the visual field with the remaining retinal neurons. In addition, chronic administration of the therapeutic agent may be effective in enhancing transfer of electrical signals from surviving retinal ganglion cells to at least one central visual region of the central nervous system. The present methods may be effective in enhancing adaptive response to injury within the central nervous system.
The following non-limiting examples illustrate certain aspects of the present invention.

Methods of Determining Efficacy and Safety of Memantine Treatment in Experimental Glaucoma Eighteen young adult cynomolgous monkeys, Macaca fascicularis, were randomly divided into two groups and base line measures of intraocular pressure (IOP) were made. One group of monkeys received oral doses of memantine (4 mg/kg), and the other group received oral doses of a vehicle control. This dose of memantine had no significant effect on IOP in normotensive or ocular hypertensive monkey eyes.
Chronic ocular hypertension (COHT) in the right eye of the monkeys was induced by exposure of the right eye to argon laser, as described in Gaasterland et al., "Experimental glaucoma in the rhesus monkey", Invest.

Ophthalmol., 13:455-457, 1974. Using an argon laser (model Novus 2000, Coherent, Inc., Palo Alto, CA), 30 to 40 spots of 50 m diameter, 1 watt power, and 0.5 second duration were applied over the superior 180 of the internal anterior chamber angle. Two weeks later, the inferior 180 of anterior chamber angle tissue was similarly treated.

IOP was measured under light ketamine sedation (5 mg/kg i.p.) at regular intervals for about 16 months following the laser treatment. IOP measurements were made between 8:00 AM
and 12:00 PM since this time of day is associated with little diurnal variation in IOP. For IOP less than or equal to 45 mm Hg, a Model RT pneumatonometer (Digilab, Norwell, MA) was used, and for IOP greater than 45 mm Hg, an Alcon pneumatonometer (Alcon, Fort Worth, TX) was used. Stable pressure traces of approximately 4.5 seconds duration were obtained. IOP was determined as the mean value of the maxima and minima associated with cardiac pulsation, which was less than 2 mm Hg peak-to-peak amplitude.

Memantine concentrations were determined by obtaining blood samples two hours after oral dosing from each animal at two months after the onset of dosing and at two-month intervals thereafter. Before sacrificing the treated animals (about 16 months after laser treatment), a sample of the vitreous humor was also obtained from each eye of each animal. An 18-guage needle was used to obtain the sample from the central vitreous. Vitreous samples were stored at -700 C and were kept for less than 3 months before the glutamate assay, described herein.
The amount of memantine in the plasma and vitreal samples was determined. Forty microliter memantine hydrochloride standards (0.2 M, 0.4 M, and 0.8 M) were added to 40 microliter plasma or vitreous samples. Protein was precipitated by adding 190 microliter acetonitrile, vortexing for 2 minutes, followed by centrifugation at 5000g for 4 minutes. 150 microliters of the supernatant was then derivatized with 9-flourenylmethyl chloroform chloride (FMOC-Cl) by mixing with 10 microliters of 15 mM FMOC-Cl in acetonitrile and 10 microliters of 0.5 M pH 8.5 borate buffer. Five minutes after derivitazation, 90 microliters of the derivatized mixture was injected into a Gold HPLC
system (Beckman Instruments, Brea, CA) coupled to a Shimadzu RF-551 fluorescence detector (Shimadzu, Sumo Sushi, Japan).

A Beckman ODS ultrasphere C-18 column (4.6 x 150 mm), a mobile phase consisting of 60% acetonitrile, and 40% 50 mM
borate buffer, and a flow rate of 2 mL/min were used to elute the memantine-FMOC at approximately 40 minutes. The quantity of memantine in each plasma or vitreous sample was determined, in triplicate, from a standard curve generated for each individual sample.

The amount of glutamate present in the vitreous samples was determined. Ten microliters of either a 10-, 20-, or 40-micromolar glutamate standard were added to a 90 microliter vitreous sample. Protein was precipitated by the addition of 190 microliters of acetonitrile, followed by vortexing for 2 minutes and centrifugation at 500g for 4 minutes. Twenty microliters of supernatant was mixed with 40 microliters of Fluoraldehyde OPA reagent (Pierce, Rockford, IL) followed, after 2 minutes, by the addition of 100 microliters pH 7 phosphate buffer (PB). Sixty microliters of this mixture was then injected into a Beckman Gold HPLC system (Beckman Instruments), which was coupled to a fluorescence detector (Shimadzu RF-551). A Beckman ODS
Ultrasphere C-18 column was used in combination with a mobile phase gradient of 10% methanol/90% 50 mM phosphate buffer to 75% methanol/25% phosphate buffer, a flow rate of 1.5 mL/min, and a duration of 8 minutes. Elution of 1-alkylthio-2-alkylisoindole glutamate was observed at approximately 6.5 minutes.
Data were collected and analyzed using software. Each concentration was determined in triplicate, and the quantity of glutamate in each vitreal sample was determined from a standard curve, which was generated for each sample.

Electroretinogram (ERG) recordings were made from both eyes of all animals at approximately 3 months (Tl), 5 months (T2), and immediately before sacrifice at 16 months after laser treatment (T3). Each normotensive (OS) eye was used as an internal control for the effects of ocular hypertension. The electrophysiological response amplitude measures from the hypertensive eyes were normalized with respect to the response amplitude measures obtained from the contralateral eye of the same animal at the same recording session.
ERG recordings were made under anesthesia and paralysis was maintained with periodic injections of ketamine (15 mg/kg) and constant infusion of norcuronium (0.04 mg/kg/h).
A single drop of 1% tropicamide yielded pupillary apertures of 5-6 mm diameter during recordings. Corneal voltage was recorded using a bipolar contact lens electrode of the Burian-Allen type (Hansen Ophthalmic Laboratories, Iowa City, IA) while a subcutaneous (s.c.) needle placed at the glabella was used as the indifferent electrode.
Conventional ERG responses were elicited with diffuse flash stimuli of approximately 10 microseconds duration, which were generated by a Grass Model P33 photostimulator (Astro Med, West Warwick, RI). The stimulus, positioned at 10 cm anterior to the cornea on the visual axis, subtended approximately 50 of visual angle centered on the fovea.
Flash responses and oscillatory potentials (OPs) were elicited with flashes of 124 photopic cd s/m2 intensity delivered at 10-second intervals after 5 minutes of dark adaptation at an ambient room illumination of approximately 0.05 footcandles. This initial 5-minute period of dark adaptation was chosen to ensure that the adaptational state during the recording was stable and consistent from one recording session to the next. Under these conditions, the adaptational state was determined by stimulus intensity in combination with stimulus frequency. Response amplitude and kinetics stabilized rapidly after onset of a stimulus series. For flicker responses, 30 Hz stimulus trains of 512 msec duration and 78 photopic cd s/m2 intensity were delivered every 1 second bandpass filtering from either 3-1000 Hz (flash and flicker responses) or 100-1000 Hz (OPs) used in conjunction with 60 Hz notch filtering. Flash and OP responses obtained under these conditions likely reflect activity of both rod and cone photoreceptors with a relatively greater contribution from cone activity. Thirty Hz flicker responses reflect predominantly cone-driven activity.
For multifocal recordings, stimuli were generated on a 21 inch monitor (Radius Intercolor, Radius, Inc., San Jose, CA) using VERIS 1 software and video driver board (Electro Diagnostic Imaging, San Mateo, CA) and consisted of an array of 61 hexagonal elements of equal size. The stimulus field was positioned such that the fovea projected to the center of the central stimulus element. At the test distance of 30 cm, the stimulus field subtended approximately 50 of visual angle and thus illuminated the same retinal area, which was stimulated for conventional recordings. The luminous intensity of each stimulus element was temporally modulated in a stepwise fashion at a frame rate of 67 Hz between a maximum intensity of 95 cd/m2 (white) and a minimum intensity of 5 cd/m2 (black) according to a binary m-sequence. An m-sequence of 15 (215 stimulus frames) was used in resulting records of approximately 8 minutes duration. Signals were bandpass filtered from 3-300 Hz in conjunction with 60 Hz notch filtering.
Recordings of the VECP were made using an active electrode located on the scalp immediately anterosuperior to the inion on the midline. The s.c. needle at the glabella was used as the reference and an a.c. needle placed at the base of the neck on the back was used as the indifferent electrode. Responses were elicited using the same stimuli, delivered at 2-second intervals, as that used for the ERG

flash and OP responses. VECP signals were bandpass filtered from 3-1000 Hz in conjunction with 60 Hz notch filtering.

The same recording sequence was used for all animals at all time points: 1) multifocal ERG, OD; 2) conventional ERG
(VECP), OD; 3) multifocal ERG, OS; and 4) conventional ERG

(VECP), OS. During recording, the contralateral eye was occluded. After placement of the contact lens electrode over the eye, retinoscopy determined the best spherical equivalent lens power to make the retina optically conjugate to the multifocal ERG stimulus monitor. This lens (typically +3 to +5 diopters) was then positioned at 1 cm anterior to the cornea. The stimulus monitor was then positioned at 30 cm anterior to the cornea such that the estimated visual axis projected to the center of the stimulus field. A series of multifocal recordings of approximately 2 minutes duration (m sequence = 13) was then used to adjust the monitor position such that the fovea projected to the center of the stimulus field and a clear amplitude maximum was obtained for the first-order response associated with the central stimulus element. Since a prominent central macular peak was always observed, even in eyes with severe retinal ganglion cell loss, this method provided reliable stimulus alignment in all eyes of both treatment groups. The precision of this method for stimulus alignment was verified in several eyes by optically projecting the fundus onto the stimulus monitor and noting the location of the optic nerve head and macular image.
Stimulus alignment was also verified for each recording by observing the location of the optic nerve head projection (response minimum) in the first-order response trace array.
After stimulus alignment, a multifocal recording of approximately 8 minutes duration (m sequence = 15) was made.

Maintenance of neuromuscular block ensured that proper stimulus alignment was maintained during the entire recording session. The stimulus monitor was then covered with a light-tight shield, the corrective lens was removed, and the xenon flash stimulator was positioned. After a 5-minute period of dark adaptation, conventional recordings of the flash, OP, and flicker ERG responses were made in that order. At the final time point (T3), the VECP response was recorded after the flicker ERG response.

Simultaneous stereo pair fundus images were obtained using a stereo fundus camera (Nidek Inc., Fremond, CA) through pupils dilated approximately 6 mm diameter with 1%
tropicamide, as discussed herein. Rigid contact lenses were used to provide an optical surface for retinal imaging.

Images were captured using Kodak Lumiere 100 ASA color slide film in combination with a flash level (intensity) of 3.
Optic disc morphology measurements were made using a confocal scanning laser ophthalmoscope (HRT; Heidelberg Engineering GMBh, Heidelberg, Germany). Each image series contained 32 transverse optic sections obtained at consecutive height planes over a scan depth of 1.5 to 2.5 mm. For each eye, three separate 15 images were taken and mean topography was determined using HRT software version 2.01. For each image, disc margins were manually outlined with the aid of stereo optic disc photographs obtained at approximately the same time. Image magnification errors were corrected using keratometric measurements of corneal anterior surface curvature. The standard reference plane was positioned at 50 micrometers posterior to the mean height of the optic disc margin contour over the temporal segment from 350 to 356 . Scans were made under general anesthesia induced with i.m. ketamine (10 mg/kg) in combination with paralysis maintained with continuous IV
infusion of norcuronium bromide (0.04 mg/kg/h). Scans were obtained at approximately 3, 5, and 10 months after laser treatment, as shown in FIG. 14. Measurements were made on both eyes of ten animals including the five animals with the highest IOPs (OD) in each of the two treatment groups.

To count retinal ganglion cells (RGCs), fixed retinas were flat mounted and 3 mm x 3 mm samples were obtained from eight regions including one centered on the fovea. After paraffin embedding, ten radial sections were obtained from each sample region. For the sample centered on the fovea, sections were obtained from the region of highest RGC
density at 500 to 700 micrometers from the center of the foveal pit. Locations from which retinal histological sections were obtained are illustrated in FIG. 15. After staining with hematoxylin/eosin, the nuclei in the RGC layer were counted along the entire 3 mm length of all ten sections from each sample region. Glia and vascular cell nuclei were identified using size and morphology (greater than 4 micrometer diameter and round, respectively) and were not counted. For sections from the perifoveal region, cell counts were made using a Bioquant imaging system and stereology software (R&M Biometrics, Nashville, TN).
Sections from all other sample regions were counted manually. Examples of parifoveal (PF) sections obtained from hypertensive (OD) and normotensive (OS) eyes of a vehicle treated animal are shown in FIG. 16.

For each animal, OD IOP was plotted as a function of time over the duration of the study. Heidelberg Retina Tomograph (HRT) measurements were obtained at three time points (T1 = 3 months; T2 = 5 months; and T3 = 10 months) .
Mean IOP elevation was estimated over each time interval (TO

to T1, TO to T2, or TO to T3) by first integrating the area of this plot over the limits defined by the time at which the first elevated IOP measure was obtained (soon after laser treatment; TO) and the time at which the electrophysiological measures were obtained (either T1, T2, or T3). The integral was then divided by the number of days in that interval to provide the mean IOP for that interval.
This method is illustrated in FIG. 1 for the OD IOP plot from one animal. Values obtained from all animals for the average of the three baseline (before laser treatment) measures, the peak IOP measure, and the mean of the IOP
integral for all three time intervals are summarized in Table 1, where values for normotensive (OS) eyes are shown in parenthesis. The range and mean ( SEM) values are also shown for each treatment group. Since IOP in the normotensive eyes was similar to baseline at all time points, values for the three intervals were determined for these eyes as the average of measures over each interval.

Table 1 I(?p (mM ag) I3ase3line TOP peal.c 1CO7P
1Vf.cankey # (,n.m Hg) (sum .EW T!. T2 T3 Vehicle-Trea'ted Animals 79 18.5 (I8.3) 34.5 24.0 (2C1.1) 23.4 (1.9.5) 105 19.3 td9.'1) 46.5 28.6 (20A) 26.4 M.41) 27.3 (21.8) 106 18.8 (18.7) 55.0 32.9 (26,1) 31.5 (i9,7? 28,9 (20.6) 98 21.5 (21.7) 45.0 30.8 (19.2) 30.0(19.3) 31.2 (20.3) 104 19.1(19.5) 61.0 54.5 (19.3) 49.2 C20.0) 36.3 C19.4) gd 22.1 (21.8) 50.0 38.7 (19.4) 40.t1 C18.5) 37A (20.9) 91 18,5 (18.5) 55.0 511.0 ('19.'i) 49.6 (13.it) 49.0(19.9) 93 1.9.0 {19.03 55.9 53.4 (19.7) 52.6 ('18.5) 52.5(19.2) 92 18.7(19.1) 61,5 51.1 (20.~i 53.1 Q1,t1=) 57.7 (Z0.2) Range 38.5-22.1 34.5-61.5 24.3-54.5 24.0-53.1 23.4-57.7 (1I3.3-21.8) (18.9-2,D.6) (18.5w22.(3) (19 2-21.8) x t sFnl 19,5 - 0.45 51.6 2.8 4o.6 t 4.o 3916 3.9 38.1 4.0 (19.5 UA3) (19.7 (1.20) (20.t7 Q.4) (20.2 -!' 0.3) Memantine "['r.eated A'ci.tnuls 108 19.3 (38.7) 46.5 25.4 (18.4) 24.3 (18.8) 23,9 (19.5) 102 17.5 ('17.0) 55.0 317 (18.9) 28.47 (16.8) 25.6 (17,8) 99 21.1(211.7) 31.5 25.2 t17.3..) 24.7 (x13.1i) 26.2 (20.1) 107 19.1 09.0) 48. + 35.6 (20.5) 31.4(16.0) 29.2 (18.6) 97 21. ],01.C1) 47.0 43.3 (2ll.t) 38,8 (2'J.Et) 29.3 (4.0) 100 193 (19.3) 59.0 51.5 (21.4) 42.6(20.6) 34.1. (20.0) 94 18.5 (18.5) 53.0 43.6 (j.9.6) 30.9 Cx6.5) -35.3 (18.7) 95 21.1(14.7a 60.0 56.9M,4) 53.5 (2t1.6) 42.7(21.I) 101 <.r1.2) 61.5 54.8(19.9) 58,4(17.8) 57.0 (20.0) Range 27.5-21.1 31.5=-61.5 25.2-56.9 24.3-58.4 23.9-57.0 (1.4.7w21.2) (17.1 21.4) ('F6.0w20.6) (17.8-21.1) x 6eM 19.i3 t 0.44 50.4 3.3 41.0-?- 4.0 37.8 :t CO 33,7 3.5 (18.9 0.70) (19.5 0.5) (18.4 0.6) (19.7 ~t 0.4) VaEues for r.an.tr4atcra.t normotensive (OS) cpeR are shown in paro.~ntheses.

Linear regression analysis (see FIGs. 4, 6, 7, and 9) was made using the method of least squares. To test the hypothesis that the slopes of the regressions for two data sets were the same, it was verified that each data set could be reasonably well fit to a linear model. The probability (P) that any difference in slope could have occurred by chance was then determined by application of a general linear models procedure for analysis of covariance. All results of ERG and VECP measures were analyzed in this manner and are summarized in Table 2.

Table 2 TI õ- ..a........_ Tz Ta slOpe a= Slope aN'X vs 10P. h 0.21 ~-(3.#J024~? 0.12 u'shicle f3.+U0668 0.~#t2 0.00533 Mtinaxxiizt.z --fl.tlfi:t83 0.09 O.fJUS~E~'i '0:3~. 0.00i7~ 0.06 P-value 0.404 0.311 0,973 N2-P2 tirs.lOP
tlehide -0.04054 0.76 -0.i~x8~ t3.7'6 -0.03155 0.73 ~73(199 0.71 Mexnaxstiae --Q.m68 0.82 -0.0t788 0.54 --~ 0.03 ;~~~al~re 0.032 0.172 P2-N3 vs IOi' Vehlclc --0.1334192 0.97 -0,02027 0.54 -0.04142 0.66 Mexn.aindn.e 0.00057 0.03 -=[3.E0525 0.29 -4.o4596 Ã1.67 RvatÃae 0,0002 0.031 0.2%) P-N vs IOP
Vehlcle --0.04483 0.94 -0.03IDI4 0.37 --QA034 0.80 Me.-fnalatine -0.02407 0.83 -0.E31313 0.36 -il.o5136 0.509 P-value 0.238 0.018 0.966 V-FGI'nipl vs li.7P ..-0.02835 0.89 Vehicle -{k.0750 0.38 Meniantine {]
.#1~0 P-va6ue The method of least squares was used for linear regression analysis of data sets which express histologic (FIG. 16) or morphologic measurements from the two treatment groups (vehicle or memantine) as a function of mean IOP.
This method provided measurements of slope (m) and correlation coefficient (r) for each data set. Analysis of covariance with both treat group and mean IOP as covariates was used to test whether the slopes for regressions of the two treatment groups were equivalent.

Example 2 Functional Measures of Memantine Treatment in Experimental Glaucoma FIG. 1 illustrates a method for estimating mean IOP of the hypertensive (OD) eyes over three time intervals for electrophysiological measures for the monkeys described in Example 1. The data in FIG. 1 were obtained from monkey M94 in Table 1. TO is the first IOP measure after laser treatment at which IOP was elevated above baseline. TO is the same for all animals tested.
The average IOP for all eighteen OD eyes of both treatment groups is summarized in FIG. 2. Laser treatment was followed by an initial decrease and then an increase in IOP. The magnitude of this initial elevation and the IOP is summarized in Table 1 where the mean IOP is listed for each of the three time intervals, T1, T2, and T3 for the hypertensive eyes of all animals in the two treatment groups. At Ti, approximately 3 months after IOP elevation, the range and average values for the two treatment groups are similar. Average mean IOP declines over the following two months (T1 to T2) and the decline is greater in the memantine treated animals at T2. From T2 to T3, average mean pressure decreased slightly in the vehicle treated animals while a greater decrease is seen in the memantine treated animals. Based on these results, it can be concluded that memantine treatment has little or no effect on pressure in normotensive eyes.
Serum and vitreous memantine levels are summarized for animals in the memantine-treated group in Table 3. Serum levels of about 1 micromole were obtained at all time points except at 2 months when values ranged from 0.03 to 0.8 micro. Vitreous memantine levels obtained a the end of the study were also in the range of 1 micro.
Table 3 t'ltreous Moman.ttae Serqm Meamilne (PIM) (1ffl) 16 mas Monkey i 2 mos 4 mos 6 mos 8 m.os mos mos m.as nuos OLf 05 94 0.3 1.9 1.7 1.4 0.6 1.5 l.2 1.2 1.5 1.2 95 0.03 1.6 1.2 1.3 0.8 1.7 1.3 1.5 0.6 0.5 97 0.2 1.8 1.5 1.1 0.9 0.7 1.2 0.9 0.3 0.4 99 0.2 1.6 1.0 1.0 0.7 1.3 1.3 1.0 0.7 0.9 100 0.3 2.1 1.4 1.8 1.1 1.4 1.6 1.5 1.6 1.5 101 0.1. 0.9 1.5 0.8 0.8 0.8 0.7 1.1 0.5 0.8 102 0.8 1.6 2.0 1.2 0.6 0.6 0.9 0.5 0.7 0.7 107 0.8 2.1 1.6 1.1 0.7 1.7 1.4 0.6 1.8 1.7 108 0.3 1.5 1.7 1A 1.2 0.8 1.2 0.7 1.2 1.3 S 0.3 1.7 1.5 1.2 0.8 1.2 1.2 1.0 1,0 1.0 ~ SF.US 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.2 0,2 Range 0.03-0.8 0.9-2.1 1,0-2.0 0.8-1.8 0.6-1.2 0.6-1.7 0.7-1.6 0.5-1.5 0.3-1.8 0.4-1.7 Conventional ERG responses from a normotensive eye of one animal are illustrated in FIG. 3. Panel A illustrates a flash response to a stimulus of 10 microsecond duration delivered at 0 milliseconds (average of 10 responses). The amplitude of the a-wave and the b-wave peak voltage was measured, as shown by the arrows. Panel B illustrates the oscillatory potential (OP) response to the same stimulus used to elicit the flash response in panel A (average of 25 responses). The response amplitude was measured as the RMS
voltage from 10 to 75 milliseconds after the stimulus.
Panel C illustrates the flicker response to a 30 Hz stimulus train of 512 millisecond duration beginning at 0 milliseconds (average of 30 responses). The amplitude was measured as the average peak-to-peak voltage of the last three response cycles (1, 2, 3). For each response measure, the amplitude of the hypertensive eye was normalized with respect to the value obtained from the normotensive eye (OD/OS). These values at time T3 are plotted in FIG. 4 as a function of mean IOP elevation in the hypertensive eye.
Ocular hypertension had little or no effect on flash (FIGs. 4A and 4B) or OP (FIG. 4C) responses and only a small effect on 30 Hz flicker (FIG. 4D) response measures obtained from either treatment group. Similar results were observed at times Tl and T2.
The left hand panels of FIG. 5 illustrate first order (A) and second order (C) multifocal ERG responses obtained from a normotensive eye. In each panel, responses from macular retina (approximately central 16 ) are highlighted in the trace array and averaged to provide the macular responses in the right-hand panels (B, first order; D, second order). The peak-to-peak measures in the first order response (N2-P2, and P2-N3) and second order response (P-N) are correlated with the degree of COHT-induced loss of cells in the retinal ganglion cell layer (Hare et al., Invest.
Opthalmol. Vis. Sci., 42:127-135, 2001). This correlation is illustrated in FIG. 6, where normalized (OD/OS) macular response amplitude measures are plotted as a function of normalized (OD/OS) perifoveal RGC counts for seven animals in the vehicle treated group and eight animals in the memantine-treated group. FIGs. 6B and 6C show that RGC loss is correlated with a decreased amplitude of these response measures. For comparison, the amplitude of the first negative peak (N1) in the first order response is plotted in panel A. Even severe RGC loss had little effect on amplitude measures of this response component. It can be concluded that specific components of the multifocal ERG
response provided a functional measure of injury to RGCs and these same measures may be used to determine the degree of functional loss associated with chronic ocular hypertension.
Results from recordings made at approximately 3 months (T1) after induction of ocular hypertension are summarized in FIG. 7. For the measures illustrated in panels 7B and 7D, response amplitude in the hypertensive eye of vehicle-treated animals is inversely correlated with the mean level of IOP exposure. Or, stated differently, higher IOP is associated with decreased response amplitude. As shown in panel 7A, IOP history has little or no effect on the amplitude of peak N1 for both treatment groups. The slope of the correlation (represented by the linear regression lines) illustrated in panels 7B and 7D provides an expression for the relationship between IOP elevation and these functional measures of injury to RGCs. The effects of memantine, or other neuroprotective agent, to reduce retinal injury would be evident as a decrease in the slope shown in these panels. For example, panels 7B and 7D show that the slop for the memantine treated group is less than the slope for the vehicle treated animals. Results for these three measures at times T1, T2, and T3 are summarized in Table 2.
As shown in the figures and Table 2, IOP elevation is associated with a decrease in response amplitude as reflected in the negative slope. In addition, for times T1 and T2, the slope for all three measures from the memantine treated animals is less than that obtained from the control animals.
FIG. 8 illustrates the average amplitude (nV/degree2) of responses from the hypertensive eye as a function of times T1, T2, and T3. As shown in panel 8A, peak N1 amplitude changes little over time. Panels 8B and 8D
illustrate that peak N2-P2 and peak P-N increase over time.
In panel 8C, vehicle treated animals show a trend for increasing response amplitude for peak P2-N3, and memantine treated animals show little change over time.
Based on these results, it can be concluded that measures of retinal function that are not correlated with RGC injury (N1) show little effect of IOP elevation and little or no change over time. Measures of retinal function which are highly correlated with RGC injury (e.g., N2-P2 and P-N) and severely attenuated by elevated IOP show a tendency to increasing response amplitude over time in both treatment groups.
The VECP requires transmission of the visual signal from the retina to the visual cortex. Thus, injury to retinal ganglion cells and their axons can directly and indirectly affect the VECP. VECP amplitude is positively correlated with the number of surviving cells in the ganglion cell layer of COHT monkey eyes (Hare et al., Eur.
J. Ophthalmol., 1(suppl):30-33, 1999).
Panel A of FIG. 9 illustrates the VECP response obtained from a normotensive (OS) eye. Panel B of FIG. 9 illustrates the normalized n1-p1 amplitudes for both treatment groups as a function of mean IOP. The slope for the memantine-treated group is less than the slope for the vehicle-treated group. Thus, treatment with memantine is associated with a preservation of the VECP response, even in animals with highly elevated IOP. A comparison of the slopes obtained from measures on the VECP responses of both groups is included in Table 2.

FIG. 10 illustrates VECP amplitude measures as a function of RGC count. As evident from FIG. 10, three animals in each treatment group suffered a loss of about 72%
or more of the RGCs and the slope for an effect of RGC loss on VECP response is less for the memantine treated animals compared to the vehicle treated animals. These results indicate that VECP responses of apparently normal amplitude were obtained from all three memantine treated eyes, which lost more than 30% of their RGCs.
Measures obtained at time T3 from all normotensive (OS) eyes of the memantine-treated and vehicle-treated animals were compared to determine whether daily oral dosing of memantine (4 mg/kg) for 16 months had an adverse effect on visual pathway function. Results are shown in FIG. 11.
Mean peak amplitude measures for the flash, OP, and flicker ERG responses are shown in panel A of FIG. 11 (values obtained from the memantine-treated group are normalized with respect to the vehicle-treated group). FIG. 11, panel C shows a similar comparison of time-to-peak values for the same response measures represented in panel A. There were no significant differences in the amplitude or timing of any measure of conventional responses from the two treatment groups. Panels B and D of FIG. 11 illustrate the results for measures of amplitude and timing of peaks in the first order macular multifocal response. No significant differences were observed between the two treatment groups for any measure of the conventional responses.
FIG. 12 illustrates vitreal glutamate concentrations for vehicle and memantine-treated groups. On average, glutamate levels for hypertensive and normotensive eyes for memantine treated animals were similar. Vitreal glutamate levels in the vehicle treated animals was slightly higher for hypertensive eyes compared to normotensive eyes.
Components of the multifocal ERG response reflect the activity of RGCs in humans and monkeys (Sutter et al., Vis.
Res., 3:419-436, 1999; Hare et al., Documenta Ophthalmologica, 105:189-222, 2002; Hood et al., Vis.
Neurosci., 16:411-416, 1999; and Frishman et al., Doc.
Ophthalmol., 100:231-251, 2000).
The results presented herein indicate that eyes having high mean IOPs suffered severe deficits in RGC function that were apparent by 3 months after induction of ocular hypertension (FIGs. 6 and 7). The RGC injury can be distinguished from contribution of an ischemic insult based on the observation that amplitude measures of the flash ERG
a-wave, b-wave, and OP responses were unaffected by elevated IOP (FIG. 4).
For eyes with the highest IOPs, the amplitudes of RGC
dependent components of the multifocal ERG response were typically larger in memantine-treated animals when compared to responses obtained from control animals with similar IOPs (FIG. 7 and Table 3). These observations may indicate that in these eyes, the rate of injury to RGCs was slowed by memantine treatment. A model potentially explaining the apparent loss in treatment effect is illustrated in FIG. 13.
In FIG. 13, the number of surviving RGCs is plotted as a function of time after induction of ocular hypertension.
RGCs are lost at a rate represented by the slope of the plot. Treatment with memantine reduces the rate of RGC
injury/loss, but the magnitude of any difference in the level of injury in the two eyes can vary with the measurement time point. Thus, the observation that modest levels of protection can be obtained at early time points, and the failure of an effect of memantine treatment to preserve ERG responses obtained at the end of the experiment may be related to a relatively steep rate of injury as suggested by the severe levels of injury observed at the early measures in animals having the highest IOP elevation.
At least one unexpected result from the present results was that the VECP responses were well preserved in memantine treated animals (FIG. 9, panel B and FIG. 10). As discussed herein, at this time point (T3), the ERG measures of RGC

injury were similar for memantine-treated animals and vehicle-treated animals. One potential explanation for these results is that memantine treatment promotes a greater survival of RGC subtypes whose activity is not reflected in the ERG measures but which makes a relatively large contribution to the generation of the VECP. Another potential explanation is that memantine treatment enhances the ability of surviving RGCs to drive activity in the visual cortex, for example, memantine treatment can be associated with plastic changes occurring at more central levels of the visual pathways, such as in the lateral geniculate nucleus (LGN) of the thalamus, or one or more regions of the visual cortex. Examples of plasticity may include an enhanced axonal sprouting and/or formation of new synapses on target neurons whose inputs may have been reduced or lost from the ocular injury or RGC injury.
In short, the present results demonstrate that systemic treatment with memantine, a compound that does not appear to lower intraocular pressure, was safe and effective for reducing a functional loss of central nervous system visual activity associated with chronic ocular hypertension, such as glaucoma.

Example 3 O-ahthalmic Anatomical Measures of Memantine Treatment in Experimental Glaucoma FIG. 14 is a graph of the average IOP history for laser-treated hypertensive (OD) eyes of vehicle-treated and memantine-treated monkeys described above. FIG. 14 is similar to FIG. 1 except that FIG. 14 includes indications of HRT measurements. FIG. 15 is an illustration of the location of retinal samples used for histologic analysis.
Each sample was 3 mm square and cut with the use of a transparent template from fixed flat-mounted retina-RPE-choroid. The perifoveal (PF) sample was centered on the fovea. Samples 1 to 3 were located on the horizontal and vertical meridians from 3.5 to 6.5 mm from the fovea, while samples 4 to 7 were located on the oblique meridians from 8.5 to 11.5 mm from the fovea. Sections were cut from either the inferior edge (sample PF) or the edge facing the fovea (samples 1 to 7) as indicated by the heavy border.
The dashed circle indicates the position of the optic nerve head (ONH).
FIG. 16 provides photographs of the optic disc and histologic sections from a vehicle-treated animal (M91, see Table 5).
Table 5 IOP ('t,xxnt klg) Monkey lfaschne toP Pea..t~~-, (MM HR) (rardus).. tt. YM
Ve~xicte-ire.[tecl ~~<7~
96 22.1(22.8) 50.0 (2I.5) 39.9 (19.5) 3$.4(19.5) 104 19.1(13.5) 61.o .5 (23.5) 116,1 (2 t.0) 39.6(19.5) 91 18.8(18.7) 55.0 51.0 (19.0) 53..0 (1fi1.5) 49.6 (20.0) 93 19.0(19.0) 55.9 53.4(16.5) 52.2 (19.5) 53.0 (20.5) 92 18.7(19.1) 61.5 51.1(18.0) 53.3 (20.5) 54.7 (24.0) R ume 18.7-22.1 50.0ri61.5 38.7-511.5 39.9w53.3 38.4-54.7 (1$.7-218) (I6.5-23-5) (18.5-21.0) (19.5w20.5) t SE1L1 19.5 t 0.64 58.7 -r' 2.1 49.8 t 2.8 48.5 2.5 47.0 =!- 3.4 (19.8 0,76) (19.7 12) (19.9 0.4) (19.9 0.2) 1klexnantÃn,e-tr.eated axsimats 102 1.3 (18.7) 55.0 Y2.7 (.16.0) 281 (18,0) 26.5 (15.5) .97 21,1(21.0) 47M 43=3(ii7.U) 37.7 ('18.5) 34.3 (1}.5) 94 18.5 G8..5) 53.0 43.6(18.0) 37.5 (175) 36.5 00.0) 95 21.1 (i4.7> 60.0 5(1.9 (215) 51.6 (:21.00) 45=E3 (23.5) I01 20.8 (21..2) 61.5 54.8(18.5) 58.(} 09.S) 56.6 (x9.5) Range 18.5-21.1 47.0-61.5 32.7-56.9 28.1-58.0 26.5-.56.6 (14.7-29..2) (17.5-21.0) (35.5-.23.5) X 5E1Vi 20.1 -!- 0.53 55.3 '-" 2.6 9.6.3 4.3 42,6 " 53 39.8 t 5.1 (1$.8 1.1) (17.8 1.0) (18,9 ;..r 0A) (18.2 t 0.2) 'V'a1ues for contralateral normotensive (05) ~.t y+es are stxowa in paa=et3theses.

The disc images were obtained approximately 5 months after elevation of IOP (near HRT measurement time point T2) at which point the mean IOP history for the hypertensive eye was approximately 50 mm Hg. A single image from the stereo pair for the hypertensive (OD) and normotensive (OS) eye is present in the top panels of FIG. 16. The OD eye shows an atrophic appearance of the disc and nasal deflection of vessels. Below each fundus photograph is a micrograph of a section from the PF sample region of that eye. In the OS
eye, it is evident that the RGC layer contains six or seven layers of RGC nuclei. In the OD eye, the RGC layer contains one layer of nuclei indicating a substantial loss of RGCs in the hypertensive eye. The RGC loss appears to be selective since little or no reduction was observed in the outer nuclear layer (ONL) or inner nuclear layer (INL).
As shown in FIG. 17, counts for cells in the central ganglion cell layer of OD eyes were highly correlated with mean IOP. Similar effects were observed from peripheral retinal areas. Thus, it appears that memantine treatment does not protect the eye from RGC cell loss resulting from increased IOP when all of the retinal regions are grouped.
However, for a subgroup of animals having a moderate mean IOP (26 to 39 mm Hg), memantine treatment appeared to be associated with regionally selective cell loss. For example, inferior regions of the retina showed less cell loss in memantine treated animals than inferior retinal regions of vehicle-treated animals, as shown in FIG. 18. A
summary of the cell counts for the eyes represented in FIG.
18 is provided in Table 4. Table 4 also shows that the distribution of mean IOP values obtained over the time course from TO to death is similar among the two groups of animals.
Table 4 Inferior SuperIor PeripBtra.l Pcrimacala PerIfaveal Total Cell Counts Ccll Counts Cel! Counct Cell Counts Cell Counts Celt Counts (SamPle 2,6,7) (Sample 1,4,5) (Sampte 4,5,6;'?3. '(Sample 1,2,3) (PF) (Sample 1 7,PB) iOP
MonkeyOD/OS OD/OS OD/O5 OD/OS OD/()S O0/OS (aua iig) VC11[C1C
96 0,83 0.87 0.91 0.71 0.92 0.87 37.4 98 0.78 0,77 0.77 0.84 0.96 0.90 31.2 106 0.69 0.92 0.73 0.96 0.69 0.74 28.9 105 0,84 1.04 0.79 0.92 1.08 1.05 27.3 Average 0.78 0.90 0.80 0.86 0.91 0.88 31.2 SEM 0.04 0.06 0.04 0.06 0.08 0.06 2.20 Memautine 94 0.97 1.16 0.89 1.12 0.63 0.78 35.3 97 0.88 0.74 0.71 0.82 0.91 0.86 29.3 107 0.89 0,85 0.92 0.84 0.88 0,89 29,2 99 11.00 1.00 0.97 0.99 0.91 0.89 26.2 Avenge 0.94 0.94 0.87 0.94 0.83 0,86 30.0 SEM 0.03 0.09 0.06 0.07 0.07 0.03 1.9 P=vatue 0.01 0.69 0.36 0.38 0.49 0.69 0.15 ' Compacison of two trentmeut groups: twoo-ta3le@ studetu d=test.

In view of the above, it is apparent that for eyes with moderate IOP elevation, memantine treatment was associated with a significant preservation of cells in the RGC layer of the inferior retina.
To determine whether memantine treatment was associated with histologic signs of retinal toxicity, counts of cells in the ganglion cell layer of all OS eyes from the two treatment groups were studied. FIG. 19 shows that RGC
counts from the memantine treated group were not significantly different from the vehicle treated group.
This was observed for counts from all individual sample regions and the sum of counts from all samples. Examination of the stained tissue sections from normotensive eyes of both groups showed no evidence of an effect of memantine treatment on the density or appearance of any other retinal cell layer/cell type.
Stereo fundus photographs obtained from both eyes of all animals at approximately 5, 10, 14, 20, 48, arid 60 weeks after IOP elevation were examined for evidence of media opacities, disc hemorrhages, vascular nonperfusion, or overt signs of ischemic insult to the optic nerve head and surrounding retina. The only vascular anomaly observed was the nasal deflection of large vessels at the disks of the eyes with advanced cupping. In both treatment groups, eyes having the highest IOP elevations (see Table 5) showed evidence of moderate to severe optic nerve atrophy with considerable loss of neuroretinal rim. Axonal loss in the nerve fiber layer was observed at the superior and inferior peripapillary retina.
Table 5 provides data from optic nerve head topographic measurements derived from confocal laser tomographic scans at about 3, 5, and 10 months after induction of chronic ocular hypertension. Nerve head morphology was characterized by a series of measurements summarized in Table 6, which reflect properties of either the physiological cup or neuroretinal rim.
Table 6 Mesnantim- Veiis.ir.l+M
S.tape$ r" S1tbpe r* P V'alaae-Cup x [z+ea.su res Mean cup depth t'i 0.0S0 0.85 0.206 0.61 0.282 i2 0.033 0.94 0.356 0.85 0.018 0 0.008 0.06 0.250 0:94 0.057 Cup volumc below suxf-Are tI U.o67 0,72 0.438 0.54 0.314 t2 0.038 0.87 0.756 0.74 0.059 t3 U.M) i).62 0.524 0.136 01019 GF3R tl 0.012 0.66 0.023 0.59 0.580 t2 0.008 0.52 0.033 0.77 0.217 0 ().4103 0.19 t?.029 0.83 0.116 Cup area tl 0.E155 0.98 0.305 0.56' 0.294 t2 0.071 090 0.547 0.84 0.023 0 0.072 ().75 0.57Ã3 0.94 0.004 Cup shape ti -0.073 (3.{38 -0.101 0.95 0.201 t2 --0.052 0.9$ -0.1-47 0.90 0.029 t3 -0.050 0.98 -0.076 0.89 0.261 Meutraretinal .xxnz measures liisn area tl -0.040 0.99 -0:041 0.88 0.955 t2 --t?.U31 0.99 -0.049 0.99 0.010 t3 --Ã1.033 0.95 -0.059 0.95 0.08:5 Rim/disc t1 -0,031 0.96 --ti.{3;3t) 0.87 0.554 t2 -0.024 p .95~ 0..98 0.006 ti -{).026 0.94 --0.039 0.,94 0.039 Rim volume xi -0.057 094 -0.037 0.90 0.328 t2 -0.(335 0. 92 -0.031 0.97 0.800 0 --032 4.93 --0.039 0.95 0.553 1iNFi. thickness rl. -0.035 0.92 --0.024 0.50 0.637 C2 --0.017 0.69 --tl.042 0.64 0.409 0 -0.029 (3.134 --fl.(l6(} 0.94 0.125 liNFL crm secdprt ti -0.04-2 ().91 -0.024 0.50 0.497 t2 --0.021 0.74 -0.1139 0.50 0.564 t3 -0.033 (}.84 -d).062 0.93 0.195 " DetenufRied from linear xegxes.qiorz analysis.
Determined from attaysis =a.t =cavkarixlrcv.
YatueÃ; represent measum' fzdui =W[.tive aSainzWs .i.it each txeatment gracip for wla3cii RRT measur,es were made.

FIG. 20 shows results obtained for measurements of the cup at approximately 5 months (T2) after elevation of IOP.
FIG. 21 shows results of measurements of the neuroretinal rim obtained at the same time. In each of these plots, a steeper slop represents a greater effect of ocular hypertension on that measure. As shown in FIG. 20, IOP
elevation was associated with a relatively greater effect in vehicle treated animals compared to the effect observed in memantine-treated animals. As shown in FIG. 21, measurements of the neuroretinal rim showed a more similar effect of IOP elevation in the two treatment groups. A
summary of results from topographic measurements is presented in Table 6. The results presented in FIGs. 20 and 21 show that ocular hypertension has profound effects on measurements of the optic nerve head. In memantine treated animals, ocular hypertension is associated with much less effect on measurements of the cup than seen in the vehicle treated animals, whereas effects of ocular hypertension on measurements of the neuroretinal rim are more similar in the two treatment groups. Non-normalized values for measurements obtained from the hypertensive eyes of the five animals in each treatment group were plotted at the three measurement time points in FIG. 22 for measurements of the cup, and FIG. 23 for measurements of the neuroretinal rim.
The left panels of FIG. 22 show results for measurements of cup volume below the surface (A), cup shape (B), and cup area to disc ratio (C). The right panels show results for the same measurements from memantine treated animals.
Memantine treated animals' had, on average, smaller measurements of cup volume and relative cup area compared to the control animals. Most pressure-related changes in cup morphology had occurred by approximately 3 months after IOP
elevation. As shown in FIG. 23, memantine treated animals had, on average, larger measurements for rim area, rim volume, and RNFL thickness.
Optic disc size remained stable over the three measurement time points. For example, the disc size didn't vary by more than 7% over these times.
These results demonstrate that systemic administration of memantine for prolonged periods of time is not associated with histologic retinal toxicity, which is consistent with the results of the electrophysiology data described above.

Example 4 Central Nervous System Anatomical Measures of Memantine Treatment in Experimental Glaucoma After perfusion of the animals described in Example 1, the brains were removed from the skulls and were fixed by immersion in 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) for at least 48 hours. The left lateral geniculate nucleus (LGN) of the thalamus was blocked in the coronal plane and cryoprotected by immersion in compositions containing glycerol, dimethyl sulfoxide (DMSO), and phosphate buffer for several days. The blocks were frozen in isopentane cooled by a mixture of 100% alcohol and dry eye. Coronal sections (50 micrometers) of the entire LGN
were cut serially on a sliding microtome. Every seventh section was mounted onto a glass slid and stained with cresyl violet.
Parvalbumin immunocytochemistry was performed on tissue sections using a monoclonal antibody (clones PA-235, Sigma, St. Louis, MO) and conventional techniques.
Histological examination of the tissue sections and the determination of neuronal size and numbers were performed using conventional techniques.
The neurons showed a normal size distribution in memantine-treated and vehicle-treated groups for each of the three layers. To assess cell area changes in glaucoma, the mean neuron area for each LGN layer of each vehicle and memantine treated animal with glaucoma was compared to the mean neuron area for the corresponding LGN layer in normal animals without glaucoma. The percent neuron shrinkage was calculated from the difference between mean neuron area of the normal group and mean neuron area of the vehicle or memantine treated glaucoma animals, divided by the mean neuron area in the normal group. The mean neuron areas for the normal group for layer 1, layer 4, and layer 6 were 238.5 12.4 gm2 (mean SD) , 202.6 20.8 mZ, and 219.7 35.8 mz, respectively.
As discussed herein, in these experimental animals, there was no significant difference in mean IOP or maximum IOP between memantine-treated and vehicle-treated groups.
In addition, there was no significant difference in mean percent optic nerve fiber loss between the two groups.
For vehicle-treated animals, cell bodies of parvalbumin-immunoreactive neurons in layers 1, 4, and 6 appeared shrunken and ovoid compared to parvalbumin-immunoreactive neurons in memantine-treated animals.
Overall, the memantine treated animals exhibited larger size parvalbumin immunoreactive neurons in layers 1, 4, and 6 compared to vehicle-treated control animals. However, the difference in layer 6 neurons was not statistically significant.
The mean LGN neuron numbers in the memantine treated animals and the vehicle treated control animals were not significantly different.
In view of these results, it can be concluded that in chronic ocular hypertension, such as experimental glaucoma, memantine reduces transsynaptic atrophy in the LGN neurons.

Example 5 Treatment of Glaucoma With an Antiexcitoxic Agent A 48 year old male undergoing a routine eye examination is told by his ophthalmologist that he appears to have some early signs of glaucoma. The patient is surprised since he has not experienced any vision loss or increased ocular pain. The physician suggests that the patient try a prophylactic therapy to attempt to mitigate against further vision loss. The physician selects an oral memantine formulation among many potential antiexcitoxic formulations.
The patient is advised to take one tablet twice a day and to return for an examination in six months.

Six months later, upon further examination, a determination can be made whether the treatment was successful. An increase in intraocular pressure and/or a decrease in visual field can be indicative that the ocular symptoms of glaucoma are advancing. However, functional brain imaging of the visual cortex, such as by using an FMRI
or functional PET scan, can be used to measure electrical activity in the visual cortex. Comparing the activity to a control, such as the cortical activity prior to drug therapy, can be used to evaluate whether the treatment is ultimately successful. Similar cortical activity readings can indicate that the patient has not experienced further vision loss and the treatment is successful.

The present invention also includes the use of a therapeutic agent, such as an anti-excitotoxic agent, in the manufacture of a medicament for treating an ophthalmic condition by administering the therapeutic agent to an individual who is not aware of a visual field loss. In addition, the present invention also includes the use of a therapeutic agent, such as an anti-excitotoxic agent, in the manufacture of a medicament for treating an ophthalmic condition associated with retinal neurodegeneration by administering the therapeutic agent to an individual to reduce a decrease in a central nervous system response associated with retinal neurodegeneration.

All patents, applications, publications and references cited herein are incorporated by reference in their entireties.

While this invention has been described with respect to various specific examples and embodiments, it is to be understood that the invention is not limited thereto and that it can be variously practiced within the scope of the following claims.

Claims (58)

1. A method for treating an ophthalmic condition or mitigating against an ophthalmic condition, comprising:
administering a therapeutic agent to an individual at a time when the individual is not aware of visual field loss associated with the ophthalmic condition, the therapeutic agent being effective in treating the ophthalmic condition or mitigating against the ophthalmic condition.

2. The method of claim 1, wherein the therapeutic agent is substantially not effective in reducing intraocular pressure.

3. The method of claim 1, wherein the therapeutic agent is an anti-excitotoxic agent.

4. The method of claim 1, wherein the therapeutic agent comprises a glutamate receptor inhibitor.

5. The method of claim 1, wherein the therapeutic agent comprises,an NMDA receptor antagonist.

6. The method of claim 1, wherein the therapeutic agent comprises at least one admantane derivative, salts thereof, and mixtures thereof.

7. The method of claim 1, wherein the therapeutic agent comprises at least one agent selected from the group consisting of memantine, amantadine, rimantadine, salts thereof, and mixtures thereof.

8. The method of claim 1, wherein the therapeutic agent is administered to the individual at a time when the individual has less than about 80% of visual field loss.

9. The method of claim 1, wherein the therapeutic agent is administered to the individual at a time when the individual has less than about 40% of visual field loss.

10. The method of claim 1, wherein the therapeutic agent is administered to the individual at a time when the individual has less than about 20% of visual field loss.

11. The method of claim 1, wherein the therapeutic agent is administered to the individual at a time when the individual has less than about 10% of visual field loss.

12. The method of claim 1, wherein the therapeutic agent is effective in treating an ophthalmic condition which comprises increased intraocular pressure.

13. The method of claim 1, wherein the ophthalmic condition is a retinal neurodegenerative condition.

14. The method of claim 1, wherein the ophthalmic condition is glaucoma.

15. The method of claim 14, wherein the ophthalmic condition is asymptomatic or symptomatic glaucoma.

16. The method of claim 1, wherein the ophthalmic condition comprises a condition other than glaucoma.

17. The method of claim 1, wherein the therapeutic agent is chronically administered.

18. The method of claim 1, wherein the therapeutic agent is administered by a delivery route selected from the group consisting of systemic delivery, topical delivery, intraocular delivery, oral delivery, and combinations thereof.

19. The method of claim 1, wherein administration of the therapeutic agent is effective as a prophylactic to reduce further deterioration of the individual's vision resulting from the ophthalmic condition.

20. The method of claim 1, wherein administration of the therapeutic agent is effective in reducing visual field loss of the individual.

21. The method of claim 1, wherein the administration is effective in reducing a decrease in a visually-evoked cortical potential in response to stimulation of an eye, the decrease being a response resulting from the ophthalmic condition.

22. The method of claim 1, wherein the administration of the therapeutic agent is effective in promoting neuronal growth in at least one visual neuronal pathway of the central nervous system of the individual.

23. The method of claim 22, wherein the at least one visual neuronal pathway is an extraocular neuronal pathway.

24. The method of claim 1, wherein the administration of the therapeutic agent is effective in treating an early stage retinal neurodegenerative disorder.

25. The method of claim 1, wherein the therapeutic agent is an NMDA receptor inhibitor, and wherein chronic administration of the NMDA receptor inhibitor is effective in enhancing transfer of visual signals from surviving retinal ganglion cells of the individual to at least one central visual region of the central nervous system.

26. The method of claim 1, wherein the administration of the therapeutic agent is effective in suppressing a reduction in visual field of the individual for a time period in a range of about one month to about ten years after initial administration of the therapeutic agent to the individual.

27. The method of claim 26, wherein the time period is in a range of about one month to about five years.

28. The method of claim 27, wherein the time period is in a range of about one month to about three years.

29. The method of claim 28, wherein the time period is in a range of about one month to about one year.

30. A method for treating an ophthalmic condition, comprising:
administering a therapeutic agent to an individual with an ophthalmic condition associated with retinal neurodegeneration, wherein the administering of the therapeutic agent is effective in reducing a decrease in a central nervous system response associated with the retinal neurodegeneration.

31. The method of claim 30, wherein the therapeutic agent is substantially not effective in reducing intraocular pressure.

32. The method of claim 30, wherein the therapeutic agent is an anti-excitotoxic agent.

33. The method of claim 30, wherein the therapeutic agent comprises a glutamate receptor inhibitor.

34. The method of claim 30, wherein the therapeutic agent comprises an NMDA receptor antagonist.

35. The method of claim 30, wherein the therapeutic agent comprises at least one admantane derivative, salts thereof, and mixtures thereof.

36. The method of claim 30, wherein the therapeutic agent comprises at least one agent selected from the group consisting of memantine, amantadine, rimantadine, salts thereof, and mixtures thereof.

37. The method of claim 30, wherein the ophthalmic condition comprises increased intraocular pressure.

38. The method of claim 30, wherein ophthalmic condition is a retinal neurodegenerative condition.

39. The method of claim 30, wherein the ophthalmic condition is asymptomatic or symptomatic glaucoma.

40. The method of claim 30, wherein the ophthalmic condition is a condition other than glaucoma.

41. The method of claim 30, wherein the therapeutic agent is chronically administered.

42. The method of claim 30, wherein the therapeutic agent is administered by a delivery route selected from the group consisting of systemic delivery, topical delivery, intraocular delivery, oral delivery, and combinations thereof.

43. The method of claim 30, wherein the administration of the therapeutic agent is effective in reducing a decrease in a visually-evoked cortical potential in response to stimulation of an eye, the decrease being a response from the ophthalmic condition.

44. The method of claim 43, wherein the reducing is relative to a decrease in a visually-evoked cortical potential of a different individual having a substantially identical ophthalmic condition and not administered the therapeutic agent.

45. The method of claim 30, wherein the administration of the therapeutic agent is effective in promoting neuronal growth in at least one visual neuronal pathway of the central nervous system of the individual.

46. The method of claim 45, wherein the neuronal growth occurs in an extraocular visual neuronal pathway.

47. The method of claim 30, wherein the administration of the therapeutic agent is effective in treating an early stage retinal neurodegenerative disorder.

48. The method of claim 30, wherein the therapeutic agent is an NMDA receptor inhibitor, and wherein chronic administration of the NMDA receptor inhibitor is effective in enhancing transfer of visual signals from surviving retinal ganglion cells of the individual to at least one central visual region of the central nervous system

49. The method of claim 1 or claim 30, wherein the therapeutic agent is administered to the individual at a time prior to an abnormal increase in glutamate concentration in the vitreous of the eye.

50. The method of claim 49, wherein the therapeutic agent is administered to the individual when the individual has a sub-toxic intraocular concentration of glutamate.

51. The method of claim 1 or claim 30, wherein the therapeutic agent is administered to the individual prior to undergoing any anti-glaucoma treatment.

52. The method of claim 1 or claim 30, wherein the therapeutic agent is administered to an individual who has not undergone an ophthalmic filtering operation.

53. The method of claim 1 or claim 30, wherein the administering is effective in preserving a visually-evoked cortical response without substantially reducing retinal ganglion cell loss resulting from the ophthalmic condition.

54. The method of claim 1 or claim 30, wherein the therapeutic agent is chronically administered and the administration is effective in enhancing transfer of electrical signals from surviving retinal ganglion cells to at least one central visual region of the central nervous system.

55. The method of claim 1 or claim 30, wherein the administration of the therapeutic agent is effective in enhancing an adaptive response to injury within the central nervous system.

56. The method of claim 1 or claim 30, wherein the administration of the therapeutic agent is effective in preventing a detectable decrease in visual field.

57. The method of claim 1 or claim 30, wherein the therapeutic agent is an adamantane-based neuroprotective amine.

58. The method of claim 1 or claim 30, wherein the therapeutic agent is selected from the group consisting of memantine, salts thereof, or mixtures thereof.