Abstract:
Glutamate causes migration and proliferation of retinal pigment epithelium and/or glial cells, and glutamate antagonists can prevent, treat or reduce retinal pigment epithelium and/or glial migration and the subsequent development of proliferative vitreoretinopathy. Avoidance or management of proliferative vitreoretinopathy can be achieved by administering to the patient a compound capable of reducing glutamate-induced retinal cell migration in a concentration effective to reduce such migration.

Description:
CROSS REFERENCE TO RELATED PATENT APPLICATIONS 
     This patent application is a continuation of U.S. patent application Ser. No. 09/445,832 which was filed on Dec. 13, 1999 now U.S. Pat. No. 6,380,261 as the U.S. National Patent Application of PCT/US98/12414, which was filed on Jun. 15, 1998 and was based on U.S. Provisional Application No. 60/051,962, which was filed on Jun. 30, 1997 in the name of Dreyer. 
    
    
     BACKGROUND OF THE INVENTION 
     This application relates to preventing, controlling reducing and/or treating proliferative vitreoretinopathy. Proliferative vitreoretinopathy (including epiretinal membrane formation) is a potentially devastating ophthalmic condition that can lead to blindness. It can develop after any penetration of the eye—surgical or traumatic. Predisposing conditions therefore include, but are not limited to, penetrating trauma, retinal tears, traction detachments, vitrectomy, and intraocular surgery. Any ophthalmic condition that precipitates or permits migration of retinal pigment is epithelium or glial cells can lead to the development of proliferative vitreoretinopathy. See Machamer (1978) British J. Ophthal. 62:737; Hilton et al. (1983) Ophthalmology 90:121. 
     SUMMARY OF THE INVENTION 
     I have discovered that glutamate causes migration and proliferation of retinal pigment epithelium and/or glial cells. The invention features the use of glutamate antagonists to reduce or control retinal pigment epithelium and/or glial migration and the subsequent development of proliferative vitreoretinopathy. Avoidance or management of proliferative vitreoretinopathy can be achieved by administering to the patient a compound capable of reducing glutamate-induced retinal pigment epithelium and/or glial migration in a concentration effective to reduce such migration. 
     While I do not wish to be bound to any specific theory, I conclude that one or more of the several types of calcium-permeable CNS ion channels mentioned below can be involved in controlling such migration, including: a) the various aspects of the NMDA (N-methyl-D-aspartate) receptor channel complex; b) the voltage-dependent Ca 2+ channels; and c) other channels directly coupled to glutamate (or excitatory amino acid) receptors. Such channels are reviewed in: Sommer, B. and Seeburg, P. H. “Glutamate receptor channels: novel properties and new clones”  Trends Pharmacological Sciences  13:291-296 (1992); Nakanishi, S., “Molecular Diversity of glutamate receptors and implications for brain function”,  Science  248:597-603 (1992). 
     One aspect of the invention generally features a method of treating, preventing, or reducing proliferative vitreoretinopathy in a patient by administering to the patient&#39;s retina an effective amount of a compound that reduces CNS neuronal damage incident to (associated with) calcium ion influx. 
     A second aspect of the invention features treating, preventing, or reducing proliferative vitreoretinopathy in a patient by administering to the patient&#39;s retina an effective amount of at least one of the compounds listed in one or more of Tables 2-5. below. 
     A third aspect of the invention features treating preventing or reducing proliferative vitreoretinopathy in a patient by administering to the patient&#39;s retina an effective amount of a compound that reduces glutamate related retinal cell migration, proliferation, or both. 
     The compound may be one of the so-called NMDA antagonists—i.e., it reduces neuronal damage mediated by the NMDA receptor complex. Alternatively, the compound antagonizes neuronal damage mediated by the voltage-dependent calcium channel. Other useful compounds are those which limit release of glutamate from cells or reduce the intracellular neurotoxic consequences of glutamate interaction with cell membrane glutamate receptors. Preferably, the compound crosses the blood-retinal barrier. 
     The patient may be anyone who has experienced, or is at risk for experiencing, penetrating trauma, retinal tear, traction detachment, vitrectomy, or intraocular surgery. The compound may be administered to the patient topically, orally, or intravitreally, as well as by other routes described below. It may be administered chronically, i.e., over an extended period of a month or even six months or years. 
     The invention preferably will be used to treat patients having proliferative vitreoretinopathy or to treat patients prophylactically to avoid that condition. Preferably, the agent is administered over an extended period (e.g., at least six months and preferably at least one year). Those at risk for developing proliferative vitreoretinopathy include patients who have experienced penetrating trauma, retinal tears, traction detachments, vitrectomy, or intraocular surgery. 
     Particularly preferred compounds are antagonists of the NMDA receptor-channel complex. The term “NMDA receptor antagonists” includes several sub-types of NMDA antagonists including: a) channel blockers—i.e., antagonists that operate uncompetitively to block the NMDA receptor channel; b) receptor antagonists—antagonists that compete with NMDA to act at the NMDA binding site; c) 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; d) agents which inhibit the downstream effects of NMDA receptor stimulation, such as agents that inhibit activation of protein kinase C activation by NMDA stimulation, antioxidants, and agents that decrease phosphatidylinositol metabolism. 
     Other compounds that are useful in the invention include voltage-dependent calcium channel antagonists, e.g. those which exert a substantial direct effect on glutamate toxicity mediated by the L-type voltage dependent Ca++ channel in that they produce a statistically significant result in experiments measuring glutamate induced effects by the general method described in Karschian and Lipton,  J. Physiol . 418: 379-396 (1989) or by other techniques for measuring antagonism of the L-type Ca++ channel known to those in the art. (We contrast the direct effect so measured with the secondary effects of excitoxicity mediated by other channels, which in turn causes flow through the voltage dependent Ca++ channels.) Particular candidate compounds include Class I voltage dependent Ca++ channel antagonists, e.g., phenylalkylamines. 
     Preferably, the compounds used cross the blood-retina barrier and can be administered chronically. Other useful agents act as antagonists of non-NMDA receptors (glutamate receptor types other than the NMDA receptor complex discussed above), and include agents which block inotropic glutamate receptors or interact with metabotropic glutamate receptors (Nakanishi, supra). Still other agents act to limit (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 most preferred compounds are those capable of crossing the blood-retinal barrier; these compounds may be administered orally, intravenously, or topically and cross intervening barriers including the blood-retina barrier to reach the retinal ganglion cells. Compounds that do not freely cross the blood-retina barrier are less preferred; these compounds may be administered intravitreally to the retina. In the case of compounds that have an intermediate ability to cross the blood-retina barrier, the mode of administration will depend on the dosage required and other factors. 
     Among the preferred compounds are amantadine derivatives (e.g., memantine, amantadine, and rimantadine), nitroglycerin, dextorphan, dextromethorphan, and CGS-19755. See generally, the compounds listed in Table 2. 
     The invention is useful for the reduction or prevention (including prophylactic treatment) of damage as a result of proliferative vitreoretinopathy. 
    
    
     Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Selection of Antagonists 
     In view of our discovery that glutamate is associated with proliferative vitreoretinopathy, the invention features antagonists having certain specific characteristics: the ability to cross the blood-retina barrier; and the ability to be administered chronically. Within those guidelines, any suitable antagonist of the glutamate induced excitotoxicity may be used in accordance with the invention. As mentioned, in preferred embodiments, N-methyl-D-aspartate (NMDA) subtype of glutamate receptor-channel complex may be used to reduce or prevent proliferative vitreoretinopathy-related injury. Many antagonists of the NMDA receptor have been identified (Watkins et al., Trends in Pharmacological Sci. 11:25, 1990, hereby incorporated by reference). There are several recognized sub-types of NMDA receptor including: a) channel blockers—i.e., antagonists that operate non-competitively to block the NMDA receptor channel; b) receptor antagonists—antagonists that compete with NMDA, acting at the NMDA binding site; c) 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; d) agents which inhibit the downstream effects of NMDA receptor stimulation such as agents that inhibit activation of protein kinase C activation by NMDA stimulation, antioxidants, and agents that decrease phosphatidylinositol metabolism. 
     Other compounds that are useful in this invention include non-NMDA receptor antagonists, such as agents which block other types of inotropic glutamate receptors or interact with metabotropic glutamate receptors; voltage-dependent calcium channel antagonists (against L, N, T, and P type channels) (Bean, B. P. Annu. Rev. Physiol. 51:367-384 (1989); Hess, P. Annu. Rev. Neurosci. 13:337-356 (1990)), and are described in greater detail below; and agents which act to decrease the release of glutamate, thereby acting upstream in the excitatory neurotoxicity process. 
     Table 1, below, lists various suitable NMDA and non-NMDA receptors which do not operate via the voltage-dependent Ca++ ion channel. Tables 2-4 list antagonists of the voltage dependent Ca++ channel, which can be used by themselves in connection with the first aspect of the invention, and which can also be used in combination with other antagonists in the second aspect of the invention. 
     
       
         
               
               
               
             
           
               
                   
               
             
             
               
                 NMDA Antagonists 
                 NMDA Antagonists 
                 NMDA Antagonists 
               
               
                   
               
               
                 1. Competitive NMDA Antagonists (act 
                 2. Channel Blockers (Un-Competitve 
                 3. Antagonists at Glydne Site of the 
               
               
                 at agonist binding site) 
                 NMDA Antagonists) 
                 NMDA Receptor 
               
               
                 CGS-19755 (CIBA-GEIGY) and other 
                 MK-801 (Dizocilpine) and other 
                 Kynurenate, 7-chloro-kynurenate, 5,7- 
               
               
                 piperdine derivatives, D-2-amino-5- 
                 derivatives of dibenzyocycloheptene 
                 chloro-kynurenate, thio-derivatives, and 
               
               
                 phosphovalerate, D-2-amino-7- 
                 (Merck) 
                 other derivatives. (Merck) 
               
               
                 phosphosoheptanoate (AP7) 
               
               
                 CPP {[3-2-carboxypiperazin-4-y-propyl- 
                 Sigma receptor ligands, e.g. Dextrorphan, 
                 Indole-2-carboxylic acid 
               
               
                 1-phosphonic acid]} 
                 dextromethorphan and morphiasn 
               
               
                   
                 derivatives (Hoffman La Roche) such as 
               
               
                   
                 caramiphen and rimcazole (which also 
               
               
                   
                 block calcium channels) 
               
               
                 LY 274614, CGP39551, CGP37849, 
                 Ketamine, Tiletamine and other 
                 DNQX 
               
               
                 LY233053, LY233536 
                 cyclohexanes 
               
               
                 O-phosphohomoserine 
                 Phencyclidine (PCP) and derivatives, and 
                 Quinoxaline or oxidiazole derivatives 
               
               
                   
                 pyrazine compounds 
                 including CNQX, NBQX 
               
               
                 MDL100,453 
                 Memantine, amantadine, rimantadine and 
                 Glycine partial agonist (e.g. Hoecht- 
               
               
                   
                 derivatives 
                 Roussel P-9939 
               
               
                   
                 CNS 1102 (and related bi- and tri- 
               
               
                   
                 substituted guanidines) 
               
               
                   
                 Diamines 
               
               
                   
                 Conantokan peptide from Conus 
               
               
                   
                 geographus 
               
               
                   
                 Agatoxis-489 
               
               
                 4. Polyamine Site of NMDA Receptor 
                 5. Redox Site of NMDA Receptor 
                 6. Other Non-Competitve NMDA 
               
               
                   
                   
                 Antagonists 
               
               
                 Arcaine and relate biguanidines and 
                 Oxidized and reduced glutathione 
                 Hoechst 831917189 
               
               
                 biogenic polyamines 
               
               
                 Ifenprodil and related drugs 
                 PQQ (pyrroloquinoline quinone) 
                 SKB Carvedilol 
               
               
                 Diethylenetriamine SL 82,0715 
                 Compounds that generate Nitric Oxide (NO) 
               
               
                   
                 or other oxidation states of nitrogen monoxide 
               
               
                   
                 (NO+, NO-) including those listed in the box 
               
               
                   
                 below 
               
               
                 1,10-diaminodecane (and related inverse 
                 Nitroglycerin and derivatatives, Sodium 
               
               
                 agonists) 
                 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-argenine 
               
               
                   
                 (NAA):N -nitro-L-arginine (NNA); N - 
               
               
                   
                 nitro-L-arginine methyl ester; N-iminoethyl- 
               
               
                   
                 L-ormithine 
               
               
                   
                 Flavin Inhibitors; diphenyliodinium; 
               
               
                   
                 Calmodulia inhibitors, trifluoperizine 
               
               
                   
                 Calcineurin Inhibitors, e.g., FK-506 (inhibits 
               
               
                   
                 caleineurin and thus NOS diphosphorylase) 
               
               
                   
               
               
                 Inhibitors of Downstream 
                 Inhibitors of Downstream 
                 Non-NMDA Receptor 
               
               
                 Effects of NMDA 
                 Effects of NMDA 
                 Antagonists 
               
               
                   
               
               
                 7. Agents to inhibit protein kinase C 
                 8. Downstream effects from Receptor 
                 9A. Non-NMDA antagonists 
               
               
                 activation by NMDA stimulation 
                 Activation 
                 (Competitive) 
               
               
                 (Involved in NMDA toxicity) 
               
               
                 MDL 27,266 (Merrill Dow) and triazole- 
                 8a. To decrease phopshatidylinositol 
                 CNQX, NBQX, YM900, DNQX. 
               
               
                 one derivatices 
                 metabolism 
                 PD140532 
               
               
                 Mososialoganglioxides (eg GMI of Fidin 
                 kappa opioid receptor agonist: 
                 AMOA (2-amino-3[3-9carboxymethoxyl- 
               
               
                 Corp.) and other ganglioside derivatives 
                 U50488(Upjohn) and dynorphan 
                 5-methoxylisoxazol-4-yl]propionate] 
               
               
                 LIGA20, LIGA4 (may also effect calcium 
               
               
                 extrusion via calcium ATPase) 
               
               
                   
                 kappa opioid receptor agonist: PD117302, 
                 2-phosphophonoethyl phenylalanine 
               
               
                   
                 CI-977 
                 derivatives, i.e. 5-ethyl, 5-methyl, 5- 
               
               
                   
                   
                 trifluoromethyl 
               
               
                   
                 8b. To decrease hydrogen peroxide and 
               
               
                   
                 free radical injury, eg antioxidants 
               
               
                   
                 21-aminosteroid (lazaroids) such as 
                 9B. Non-NMDA Non competitve 
               
               
                   
                 U74500A, U75412E and U74006F 
                 antagonists 
               
               
                   
                 U74389F, FLE26749, Trolox (water 
                 GYK152466 
               
               
                   
                 soluble alpha tocophenol), 3,5-dialkoxy-4- 
               
               
                   
                 hydroxy-benzylamines 
               
               
                   
                 Compounds that generate Nitric Oxide 
                 Evans Blue 
               
               
                   
                 (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) Inhibition: 
               
               
                   
                 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 
                   
                 Drugs to derease intracellular 
               
               
                 Metabotropic Glutamate 
                   
                 calcium following glutamate 
               
               
                 Receptors 
                 Decrease glutamate release 
                 receptor stimulation 
               
               
                   
               
               
                 10a. Blockers of Metabotropic 
                 11. Agents to decrease glutamate release 
                 12a. Agents to decrease Intracellular calcium 
               
               
                 Glutamate Receptors 
                   
                 release 
               
               
                 AP3 (2-amino-3-phosphonoprionic acid) 
                 Adenosine, and derivatives, e.g. 
                 Dantrolene (sodium dantrium): Ryanodine (or 
               
               
                   
                 cyclohexyladenosine 
                 ryanodine + caffiene 
               
               
                 10b. Agonists of Metabotrpic 
                 CN51145 
                 12b. Agents Inhibiting intracellular Calcium- 
               
               
                 Glutamate Receptors 
                   
                 ATPase 
               
               
                 (1S, 3R)-1-Amino-cyclopentane-1,3- 
                 Conopeptides: SNX-111, SNX-183, SNX- 
                 Thaprigargin, cyclopiazosic acid, BHQ ([2,5- 
               
               
                 dicarboxylic acid [(1S.3R)-ACPD], 
                 230 
                 di-(tert butyl)-1,4-benzohydroquinose; 2,5-di- 
               
               
                 commonly ref as ‘trans’-ACPD 
                   
                 (tert-butyl)-1,4benzohydroquinose]) 
               
               
                   
                 Omega-Aga-IVA, toxin from venom of 
               
               
                   
                 funnel web spider 
               
               
                   
                 Compounds that generate Nitric Oxide 
               
               
                   
                 (NO) or other oxidation states of nitrogen 
               
               
                   
                 monoxide (NO+, NO−) including those 
               
               
                   
                 listed in the box below 
               
               
                   
                 Nitroglyccerin, and derivatives, Sodium 
               
               
                   
                 Nitroprusside, and other NO generating 
               
               
                   
                 listed on p.5 of this table 
               
               
                   
                 Nitric oxide synthase (NOS) Inhibitors: 
               
               
                   
                 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 
               
               
                   
                 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-1 (also known as 
               
               
                   
                 SIN1 or molsidomine) 
               
               
                   
                 Ion-nitrosyl complees (e.g., 
               
               
                   
                 nitrosyl-iron complexes, 
               
               
                   
                 with iron in the Fe2+ state) 
               
               
                   
                 Nicorandil 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
             
           
               
                   
                 TABLE 2 
               
               
                   
                   
               
               
                   
                 Antagonists of the Voltage Dependent Calcium Channels (N, 
               
               
                   
                 L. T, P and other types) 
               
               
                   
                   
               
             
             
               
                   
                 dihydropyridines (e.g., nimodipine) 
               
               
                   
                 phenylalkylamines (e.g., verapamil, (S)-emopamil, D-600, 
               
               
                   
                 D-888) 
               
               
                   
                 benzothiazepines (e.g., diltiazem and others) 
               
               
                   
                 bepridil and related drugs 
               
               
                   
                 diphenylbutylpiperdines 
               
               
                   
                 diphenylpiperazines (e.g., flunarizine/cinnarizine 
               
               
                   
                 series) 
               
               
                   
                 HOE 166 and related drugs 
               
               
                   
                 fluspirilene and related drugs 
               
               
                   
                 toxins and natural compounds (e.g., snail toxins - 
               
               
                   
                   (ωconotoxin GVIA and GVIIA, maitotoxin, taicatoxin, 
               
               
                   
                   tetrandine, hololena toxin, plectreurys toxin, 
               
               
                   
                   funnel-web spider venom and its toxin fraction, 
               
               
                   
                   agatoxins including ω-agatoxin IIIA and ω-agatoxin 
               
               
                   
                   IVA. 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 DIHYDROPYRIDINE CALCIUM CHANNEL ANTAGONISTS 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 nifedipine 
                 KW3049 
               
               
                   
                 niludipine 
                 oxodipine 
               
               
                   
                 PY108-068 (darodipine) 
                 CD349 
               
               
                   
                 mesudipine 
                 TC81 
               
               
                   
                 GX 1048 
                 YM-09730-5 or (4S)DHP 
               
               
                   
                 floridine 
                 MDL72567 
               
               
                   
                 nitrendipine 
                 Ro18-3981 
               
               
                   
                 nisoldipine 
                 DHP-218 
               
               
                   
                 nimodipine 
                 nilvadipine 
               
               
                   
                 nicardipine 
                 amlodipine 
               
               
                   
                 felodipine 
                 8363-S 
               
               
                   
                 PN200-110 (Isradipine) 
                 iodipine 
               
               
                   
                 CV4093 
                 azidopine 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 OTHER CALCIUM CHANNEL ANTAGONISTS 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 diclofurime 
                 D-600 
               
               
                   
                 pimozide 
                 D-888 
               
               
                   
                 prenylamine 
                 Smith Kline 9512 
               
               
                   
                 fendiline 
                 ranolzine 
               
               
                   
                 perhexiline 
                 lidoflazine 
               
               
                   
                 mioflazine 
                 CERM-11956 
               
               
                   
                 flunarizine/cinnarizine 
                 R-58735 
               
               
                   
                 series 
                 R-56865 
               
               
                   
                 verapamil 
                 amiloride 
               
               
                   
                 dilfiazine 
                 phenytoin 
               
               
                   
                 dipropervine 
                 thioridazine 
               
               
                   
                 (S)-emopamil 
                 tricyclic antidepressents 
               
               
                   
                   
               
             
          
         
       
     
     In Vitro Assay 
     An antagonist may be tested for utility in the method of the invention by monitoring its effect on proliferative retinopathy as follows. 
     Cultured fibroblasts will be injected into the vitreous of the rabbit eye. After two weeks, the degree of vitreopathy can be assessed histologically. At the time of the initial insult, the animals will be treated with the compound under consideration. 
     Such models are well known. A few examples (hereby incorporated by reference) included Kiumura et al.  Human Gene Therapy , 7:799-808 (1996); Sakamoto et al.,  Ophthalmology  102:1417-1421 (1995); Handa et al.  Experimental Eye Research  62:689-696 (1996); Berger et al. 37: 2318-1325 (1996); de Souza et al.  Ophthalmologica  209: 212-216 (1995); Nakagawa et al.  Ophthalmology  &amp;  Visual Science  36:2388-2395 (1995); Steinhorst et al.  Archive for Clinical  &amp;  Experimental Ophthalmology  232:347-354 (1994). 
     Use 
     An effective receptor antagonist will cause a decrease in proliferative vitreoretinopathy. As described above, the preferred compounds which cross the blood-retinal barriers are preferably administered topically or orally in known, physiologically acceptable vehicles including tablets, liquid excipients and suspensions. Those skilled in the art will appreciate how to formulate acceptable therapeutics. 
     Antagonists may be compounded into a pharmaceutical preparation, using pharmaceutical compounds well-known in the art; the exact formulation and dosage of the antagonist compound depends upon the route of administration. Generally, the effective daily dose of the antagonists will range from 0.01 to 1000 mg/kg. 
     OTHER EMBODIMENTS 
     Other embodiments are within the following claims. In the method of the invention, a useful compound may be administered by any means that allows the compound access to the retina. The compounds useful in the method include antagonists of excitatory amino acid receptors (both NMDA and non-NMDA subtypes) that act to reduce retinal cell migration or proliferation or reduce binding of glutamate to the NMDA receptor. The antagonists can act at a modulatory site or a co-agonist site or by blocking the chain of events initiated by receptor activation. 
     Other embodiments are within the following claims.