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:
This Application is a 371 of PCT/US 98/12414 filed Jun. 15, 1998 which claims benefit of Provisional No. 60/051,962 filed Jun. 30, 1997. 
    
    
     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 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) is 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 
                  2. 
                 Channel 
                  3. 
                 Antagonists at 
               
               
                   
                 NMDA 
                   
                 Blockers 
                   
                 Glycine Site 
               
               
                   
                 Antagonists 
                   
                 (Un-Competi- 
                   
                 of the NMDA 
               
               
                   
                 (act at agonist 
                   
                 tive NMDA 
                   
                 Receptor 
               
               
                   
                 binding site) 
                   
                 Antagonists) 
                   
                   
               
               
                   
                 CGS-19755 
                   
                 MK-801 
                   
                 Kyourenate, 7- 
               
               
                   
                 (CIBA- 
                   
                 (Dizocilpine) 
                   
                 chloro- 
               
               
                   
                 GEIGY) 
                   
                 and other 
                   
                 kyourenate, 
               
               
                   
                 and other 
                   
                 derivatives 
                   
                 5,7-chloro- 
               
               
                   
                 piperdine 
                   
                 of dibenzy- 
                   
                 kyourenate, 
               
               
                   
                 derivatives, 
                   
                 ocycloheptene 
                   
                 thio- 
               
               
                   
                 D-2-amino-5- 
                   
                 (Merck) 
                   
                 derivatives, 
               
               
                   
                 phospho- 
                   
                   
                   
                 and other 
               
               
                   
                 valerate, 
                   
                   
                   
                 derivatives. 
               
               
                   
                 D-2-amino-7- 
                   
                   
                   
                 (Merck) 
               
               
                   
                 phosphonohep- 
                   
                   
                   
                   
               
               
                   
                 tanoate (AP7) 
                   
                   
                   
                   
               
               
                   
                 CPP {[3-(2- 
                   
                 Sigma receptor 
                   
                 Indole-2- 
               
               
                   
                 carboxy- 
                   
                 ligands, e.g. 
                   
                 carboxylic acid 
               
               
                   
                 piperazin-4-y- 
                   
                 Dextrorphan, 
                   
                   
               
               
                   
                 propyl-1-phos- 
                   
                 dextro- 
                   
                   
               
               
                   
                 phonic acid]} 
                   
                 methorphan 
                   
                   
               
               
                   
                   
                   
                 and morphinan 
                   
                   
               
               
                   
                   
                   
                 derivatives 
                   
                   
               
               
                   
                   
                   
                 (Hoffman La 
                   
                   
               
               
                   
                   
                   
                 Roche) such 
                   
                   
               
               
                   
                   
                   
                 as cara- 
                   
                   
               
               
                   
                   
                   
                 miphen and 
                   
                   
               
               
                   
                   
                   
                 timeazole 
                   
                   
               
               
                   
                   
                   
                 (which 
                   
                   
               
               
                   
                   
                   
                 also block 
                   
                   
               
               
                   
                   
                   
                 calcium 
                   
                   
               
               
                   
                   
                   
                 channels) 
                   
                   
               
               
                   
                 LY27614, 
                   
                 Ketamine, 
                   
                 DNQX 
               
               
                   
                 CGP39551, 
                   
                 Tiletamine and 
                   
                   
               
               
                   
                 CGP37849, 
                   
                 other cyclo- 
                   
                   
               
               
                   
                 LY233053, 
                   
                 hexanes 
                   
                   
               
               
                   
                 LY233536 
                   
                   
                   
                   
               
               
                   
                 O-phospho- 
                   
                 Phencyclidine 
                   
                 Quinoxaline or 
               
               
                   
                 bornoserine 
                   
                 (PCP) and 
                   
                 oxidiazole 
               
               
                   
                   
                   
                 derivatives, and 
                   
                 derivatives 
               
               
                   
                   
                   
                 pyrazine 
                   
                 including CNQX, 
               
               
                   
                   
                   
                 compounds 
                   
                 NMQX 
               
               
                   
                 MDL100,453 
                   
                 Memantine, 
                   
                 Glycine partial 
               
               
                   
                   
                   
                 amantadine, 
                   
                 agonist (e.g. 
               
               
                   
                   
                   
                 rimanta- 
                   
                 Hoecht-Roussel 
               
               
                   
                   
                   
                 dine and 
                   
                 P-9939) 
               
               
                   
                   
                   
                 derivatives 
                   
                   
               
               
                   
                   
                   
                 CNS 1102 (and 
                   
                   
               
               
                   
                   
                   
                 related bi- and 
                   
                   
               
               
                   
                   
                   
                 tri- substituted 
                   
                   
               
               
                   
                   
                   
                 guanidines) 
                   
                   
               
               
                   
                   
                   
                 Diamines 
                   
                   
               
               
                   
                   
                   
                 Conantokan 
                   
                   
               
               
                   
                   
                   
                 peptide from 
                   
                   
               
               
                   
                   
                   
                 
                   Cocus 
                 
                   
                   
               
               
                   
                   
                   
                 
                   geographus 
                 
                   
                   
               
               
                   
                   
                   
                 Agatoxin-489 
                   
                   
               
               
                  4. 
                 Polyamine Site 
                  5. 
                 Redox Site of 
                  6. 
                 Other Non- 
               
               
                   
                 of NMDA 
                   
                 NMDA 
                   
                 Competitive 
               
               
                   
                 Receptor 
                   
                 Receptor 
                   
                 NMDA 
               
               
                   
                   
                   
                   
                   
                 Antagonists 
               
               
                   
                 Arcaine and 
                   
                 Oxidized and 
                   
                 Hoechst 
               
               
                   
                 related biguani- 
                   
                 reduced 
                   
                 831917189 
               
               
                   
                 dines and 
                   
                 glutathione 
                   
                   
               
               
                   
                 biogenic 
                   
                   
                   
                   
               
               
                   
                 polyamines 
                   
                   
                   
                   
               
               
                   
                 Ifenprodil and 
                   
                 PQQ (pyrrolo- 
                   
                 SKB Carvedilol 
               
               
                   
                 related drugs 
                   
                 quinoline) 
                   
                   
               
               
                   
                 Diethylene- 
                   
                 Compounds 
                   
                   
               
               
                   
                 triamine SL 
                   
                 that generate 
                   
                   
               
               
                   
                 82.0715 
                   
                 Nitric Oxide 
                   
                   
               
               
                   
                   
                   
                 (NO) or 
                   
                   
               
               
                   
                   
                   
                 other oxi- 
                   
                   
               
               
                   
                   
                   
                 dation states 
                   
                   
               
               
                   
                   
                   
                 of nitrogen 
                   
                   
               
               
                   
                   
                   
                 monoxide 
                   
                   
               
               
                   
                   
                   
                 (NO+, NO−) 
                   
                   
               
               
                   
                   
                   
                 including those 
                   
                   
               
               
                   
                   
                   
                 listed in the 
                   
                   
               
               
                   
                   
                   
                 box below 
                   
                   
               
               
                   
                 1,10-diamino- 
                   
                 Nitroglycerin 
                   
                   
               
               
                   
                 decane (and 
                   
                 and 
                   
                   
               
               
                   
                 related inverse 
                   
                 derivative, 
                   
                   
               
               
                   
                 agonists) 
                   
                 Sodium Nitro- 
                   
                   
               
               
                   
                   
                   
                 prusside, and 
                   
                   
               
               
                   
                   
                   
                 other NO 
                   
                   
               
               
                   
                   
                   
                 generating 
                   
                   
               
               
                   
                   
                   
                 listed on p. 5 
                   
                   
               
               
                   
                   
                   
                 of this table 
                   
                   
               
               
                   
                   
                   
                 Nitric oxide 
                   
                   
               
               
                   
                   
                   
                 sythase (NOS) 
                   
                   
               
               
                   
                   
                   
                 Inhibitors: 
                   
                   
               
               
                   
                   
                   
                 Arginine 
                   
                   
               
               
                   
                   
                   
                 analogs 
                   
                   
               
               
                   
                   
                   
                 including N- 
                   
                   
               
               
                   
                   
                   
                 mono-methyl- 
                   
                   
               
               
                   
                   
                   
                 L-argine 
                   
                   
               
               
                   
                   
                   
                 (NMA): 
                   
                   
               
               
                   
                   
                   
                 N-amino-L- 
                   
                   
               
               
                   
                   
                   
                 arginine 
                   
                   
               
               
                   
                   
                   
                 (NAA); 
                   
                   
               
               
                   
                   
                   
                 N-nitro-L- 
                   
                   
               
               
                   
                   
                   
                 (NNA); 
                   
                   
               
               
                   
                   
                   
                 N-nitro-L- 
                   
                   
               
               
                   
                   
                   
                 arginine methyl 
                   
                   
               
               
                   
                   
                   
                 ester; N-imino- 
                   
                   
               
               
                   
                   
                   
                 ethyl-L- 
                   
                   
               
               
                   
                   
                   
                 ornithine 
                   
                   
               
               
                   
                   
                   
                 Flavin 
                   
                   
               
               
                   
                   
                   
                 Inhibitors: 
                   
                   
               
               
                   
                   
                   
                 diphenyl- 
                   
                   
               
               
                   
                   
                   
                 iodinium; 
                   
                   
               
               
                   
                   
                   
                 Calmodulin 
                   
                   
               
               
                   
                   
                   
                 inhibitors, 
                   
                   
               
               
                   
                   
                   
                 trifluoperizine 
                   
                   
               
               
                   
                   
                   
                 Calcineurin 
                   
                   
               
               
                   
                   
                   
                 Inhibitors, e.g., 
                   
                   
               
               
                   
                   
                   
                 FK-506 
                   
                   
               
               
                   
                   
                   
                 (inhibits 
                   
                   
               
               
                   
                   
                   
                 calcineurin 
                   
                   
               
               
                   
                   
                   
                 and thus NOS 
                   
                   
               
               
                   
                   
                   
                 diphos- 
                   
                   
               
               
                   
                   
                   
                 phorylase) 
               
               
                   
               
             
          
           
               
                 Inhibitors 
                 Inhibitors 
                   
               
               
                 of Downstream 
                 of Downstream 
                 Non-NMDA 
               
               
                 Effects of NMDA 
                 Effects of NMDA 
                 Receptor Antagonists 
               
               
                   
               
             
          
           
               
                  7. 
                 Agents to 
                  8. 
                 Downstream 
                  9A. 
                 Non-NMDA 
               
               
                   
                 inhibit protein 
                   
                 effects from 
                   
                 antagonists 
               
               
                   
                 kinase C 
                   
                 Receptor 
                   
                 (Competitive) 
               
               
                   
                 activation by 
                   
                 Activation 
                   
                   
               
               
                   
                 NMDA stimu- 
                   
                   
                   
                   
               
               
                   
                 lation 
                   
                   
                   
                   
               
               
                   
                 (involved in 
                   
                   
                   
                   
               
               
                   
                 NMDA 
                   
                   
                   
                   
               
               
                   
                 toxicity) 
                   
                   
                   
                   
               
               
                   
                 MDL 27.266 
                  8a. 
                 To decrease 
                   
                 CNQX, NBQX, 
               
               
                   
                 (Merrill Dow) 
                   
                 phopshati- 
                   
                 YM900, DNQX, 
               
               
                   
                 and triazole- 
                   
                 dylinositol 
                   
                 PD 140532 
               
               
                   
                 one derivatives 
                   
                 metabolism 
                   
                   
               
               
                   
                 Monosialo- 
                   
                 kappa opioid 
                   
                 AMOA (2-amino- 
               
               
                   
                 gangliosides 
                   
                 receptor 
                   
                 3[3-9carboxy- 
               
               
                   
                 (eg GM1 
                   
                 agonist: 
                   
                 methoxyl-5- 
               
               
                   
                 of Fidia Corp.) 
                   
                 U50488 
                   
                 methoxylisox- 
               
               
                   
                 and other gang- 
                   
                 (Upjohn) 
                   
                 azol-4-yl] 
               
               
                   
                 lioside 
                   
                 and dynorphan 
                   
                 propionate) 
               
               
                   
                 derivatives 
                   
                   
                   
                   
               
               
                   
                 LIGA20, 
                   
                   
                   
                   
               
               
                   
                 LIGA4 
                   
                   
                   
                   
               
               
                   
                 (may also 
                   
                   
                   
                   
               
               
                   
                 effect calcium 
                   
                   
                   
                   
               
               
                   
                 extrusion 
                   
                   
                   
                   
               
               
                   
                 via calcium 
                   
                   
                   
                   
               
               
                   
                 ATPase) 
                   
                   
                   
                   
               
               
                   
                   
                   
                 kappa opioid 
                   
                 2-phospho- 
               
               
                   
                   
                   
                 receptor 
                   
                 phonoethyl 
               
               
                   
                   
                   
                 agonist: 
                   
                 phenylalamine 
               
               
                   
                   
                   
                 PD117302, 
                   
                 derivatives, i.e. 
               
               
                   
                   
                   
                 CI-977 
                   
                 5-ethyl, 5-methyl, 
               
               
                   
                   
                   
                   
                   
                 5-trifluoromethyl 
               
               
                   
                   
                  8b. 
                 To decrease 
                   
                   
               
               
                   
                   
                   
                 hydrogen 
                   
                   
               
               
                   
                   
                   
                 peroxide and 
                   
                   
               
               
                   
                   
                   
                 free radical 
                   
                   
               
               
                   
                   
                   
                 injury, eg 
                   
                   
               
               
                   
                   
                   
                 antioxidants 
                   
                   
               
               
                   
                   
                   
                 21- 
                 9B. 
                 Non-NMDA 
               
               
                   
                   
                   
                 aminosteroid 
                   
                 Non competitive 
               
               
                   
                   
                   
                 (lazaroids) 
                   
                 antagonists 
               
               
                   
                   
                   
                 such as 
                   
                   
               
               
                   
                   
                   
                 U74500A, 
                   
                   
               
               
                   
                   
                   
                 U75412E and 
                   
                   
               
               
                   
                   
                   
                 U74006F 
                   
                   
               
               
                   
                   
                   
                 U74389F, 
                   
                 GYK152466 
               
               
                   
                   
                   
                 FLE26749,  
                   
               
               
                   
                   
                   
                 Trolex (water 
                   
                   
               
               
                   
                   
                   
                 soluble alpha 
                   
                   
               
               
                   
                   
                   
                 tocophenol), 
                   
                   
               
               
                   
                   
                   
                 3,5-dialkoxy-4- 
                   
                   
               
               
                   
                   
                   
                 hydroxy- 
                   
                   
               
               
                   
                   
                   
                 benzylamines 
                   
                   
               
               
                   
                   
                   
                 Compounds 
                   
                 Evans Blue 
               
               
                   
                   
                   
                 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 Nitro- 
                   
                   
               
               
                   
                   
                   
                 prusside, and 
                   
                   
               
               
                   
                   
                   
                 other NO 
                   
                   
               
               
                   
                   
                   
                 generating 
                   
                   
               
               
                   
                   
                   
                 listed on p. 5 
                   
                   
               
               
                   
                   
                   
                 of this 
                   
                   
               
               
                   
                   
                   
                 table 
                   
                   
               
               
                   
                   
                   
                 Nitric oxide 
                   
                   
               
               
                   
                   
                   
                 synthase (NOS) 
                   
                   
               
               
                   
                   
                   
                 Inhibitors: 
                   
                   
               
               
                   
                   
                   
                 Arginine 
                   
                   
               
               
                   
                   
                   
                 analogs in- 
                   
                   
               
               
                   
                   
                   
                 cluding 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- 
                   
                   
               
               
                   
                   
                   
                 ornithine 
               
               
                   
               
             
          
           
               
                 Agents Active at 
                   
                 Drugs to decrease 
               
               
                 Metabotropic 
                   
                 intracellular calcium 
               
               
                 Glutamate 
                 Decrease 
                 following glutamate 
               
               
                 Receptors 
                 glutamate release 
                 receptor stimulation 
               
               
                   
               
             
          
           
               
                 10a. 
                 Blockers of 
                 11. 
                 Agents to 
                 12a. 
                 Agents to 
               
               
                   
                 Metabotropic 
                   
                 decrease 
                   
                 decrease 
               
               
                   
                 Glutamate 
                   
                 glutamate 
                   
                 intracellular 
               
               
                   
                 Receptors 
                   
                 release 
                   
                 calcium release 
               
               
                   
                 AP3 (2-amino- 
                   
                 Adenosine, and 
                   
                 Dantrolene 
               
               
                   
                 3-phosphono- 
                   
                 derivatives, 
                   
                 (sodium 
               
               
                   
                 prionic acid) 
                   
                 e.g. cyclo- 
                   
                 dantrium); 
               
               
                   
                   
                   
                 hexyladenosine 
                   
                 Ryanodine (or 
               
               
                   
                   
                   
                   
                   
                 ryanodine + 
               
               
                   
                   
                   
                   
                   
                 caffiene) 
               
               
                 10b. 
                 Agonists of 
                   
                 CNS1145 
                 12b. 
                 Agents 
               
               
                   
                 Metabotropic 
                   
                   
                   
                 inhibiting 
               
               
                   
                 Glutamate 
                   
                   
                   
                 intracellular 
               
               
                   
                 Receptors 
                   
                   
                   
                 Calcium- 
               
               
                   
                   
                   
                   
                   
                 ATPase 
               
               
                   
                 (1S,3R)-1- 
                   
                 Conopeptides: 
                   
                 Thapsigargin, 
               
               
                   
                 Amino-cyclo- 
                   
                 SNX-111, 
                   
                 cyclopiazonic 
               
               
                   
                 pentane-1,3- 
                   
                 SNX-183, 
                   
                 acid, BHQ 
               
               
                   
                 dicarboxylic 
                   
                 SNX-230 
                   
                 ([2,5-di- 
               
               
                   
                 acid [(1S,3R)- 
                   
                   
                   
                 (tert butyl)-1,4- 
               
               
                   
                 ACPD], 
                   
                   
                   
                 benzohydro- 
               
               
                   
                 commonly ref 
                   
                   
                   
                 quinone; 
               
               
                   
                 as ‘trans’- 
                   
                   
                   
                 2,5-di-(tert 
               
               
                   
                 ACPD 
                   
                   
                   
                 butyl)-1,4 
               
               
                   
                   
                   
                   
                   
                 benzohydro- 
               
               
                   
                   
                   
                   
                   
                 quinone]) 
               
               
                   
                   
                   
                 Omega-Age- 
                   
                   
               
               
                   
                   
                   
                 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 
                   
                   
               
               
                   
                   
                   
                 Nitroglycerin 
                   
                   
               
               
                   
                   
                   
                 and 
                   
                   
               
               
                   
                   
                   
                 derivatives, 
                   
                   
               
               
                   
                   
                   
                 Sodium Nitro- 
                   
                   
               
               
                   
                   
                   
                 prusside, 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-ornithine 
                   
                   
               
               
                   
                   
                   
                 Additional NO- 
                   
                   
               
               
                   
                   
                   
                 generating 
                   
                   
               
               
                   
                   
                   
                 compounds 
                   
                   
               
               
                   
                   
                   
                 Isosorbide 
                   
                   
               
               
                   
                   
                   
                 dinitrate  
                   
               
               
                   
                   
                   
                 (isordil) 
                   
                   
               
               
                   
                   
                   
                 S-nitrosocapto- 
                   
                   
               
               
                   
                   
                   
                 pril (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 molsi- 
                   
                   
               
               
                   
                   
                   
                 domine) 
                   
                   
               
               
                   
                   
                   
                 Ion-nitrosyl 
                   
                   
               
               
                   
                   
                   
                 complexes 
                   
                   
               
               
                   
                   
                   
                 (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/ 
                 R-58735 
               
               
                   
                 cinnarizine 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.