MXPA01004175A - Treatment of disorders of the outer retina - Google Patents

Abstract

Compositions and methods for treating disorders of the outer retina with glutamate antagonists are disclosed.

Description

TREATMENT OF EXTERNAL RETINA DISORDERS FIELD OF THE INVENTION This invention is directed to the use of glutamate antagonists to treat disorders of the external retina.

BACKGROUND OF THE INVENTION The pathogenesis of retinal degenerative diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) is multi-faceted and may be caused by environmental factors in those who are genetically predisposed. One such environmental factor is exposure to light, which has been identified as a contributory factor to the progression of retinal degenerative disorders such as ARMD (Sur Ophthal, 1988, 32, 252-269). The photo-oxidant stress that leads to light damage to retinal cells has been shown to be a useful model for investigating retinal degenerative diseases for the following reasons: the damage is mainly to the photoreceptor and retinal pigment epithelium of the retina External (Invest Ophthal &Vis Sci, 1966, 5, 450-472; Sur Ophthal, 1988, 32, 375-413; Invest Ophthal &Vis Sci, REF: 128789 1996, 31, 1236-1249); they share a common mechanism of cell death, apoptosis (Trans AM Ophthal Soc, 1996, 94, 411-430; Res Common Mol Pathol Pharmacol, 1996, 92, 177-189); light has been implicated as an environmental risk factor for the progression of ARMD and RP (Arch Ophthal, 1992, 110, 99-104, Invest Ophthal &Vis Sci, 1996, 31, 775-782); and therapeutic interventions that inhibit photo-oxidant damage have also been shown to be effective in animal models of hereditary-retinal disease (Proc Nat Acad Sci, 1992, 89, 11249-11253; Nature, 1990, 347, 83-86). Some different classes of compounds have been reported to minimize retinal phytic injury in several animal models: antioxidants, such as, ascorbate (Invest Ophthal &Vis Sci, 1985, 26, 1589-1598), dimethyl thiourea (Invest Ophthal & Vis Sci, 1992, 33, 450-472; Arch Ophthal, 1990, 108, 1751-1752), α-tocopherol (Nippon Ganka Gakkai Zasshi, 1994, 98, 948-954), and β-carotene (Cur Eye Res, 1995, 15, 219-232); calcium antagonists, such as flunarizine, (Exp Eye Res, 1993, 56, 71-78, Arch Ophthal, 1992, 109, 554-622); growth factors, such as, basic fibroblast growth factor, nerve derived nerve factor, ciliary neurotrophic factor, and interleukin-1-β (Proc Nat Acad Sci, 1992, 89, 11249-11253); glucocorticoids, such as, methylprednisolone (Grafis Arch Cl in Exp Oph tha l, 1993, 231, 729-736), dexamethasone (Exp Eye Res, 1992, 54, 583-594); and iron chelating agents, such as, deferrioxamine (Cur Eye Res, 1992, 2, 133-144). To date, excitatory amino acid antagonists have not been evaluated in models of external retinal degeneration as several studies have shown that mainly internal retinal cells are sensitive to the toxicity of excitatory amino acids, while exposure to excitatory amino acids has no effect on the photoreceptors of the external retina and retinal pigment epithelial cells (RPE) (Exp Brain Res, 1995, 106, 93-105; Vis Neurosci, 1992, 8, 567-573). However, when tested in an ischemic reperfusion model induced by mechanical stress, internal retinal function and RPE function were moderately protected by treatment with dextromethorphan but no significant protective effect was measured by external retinal function (Arch. Oph tha l, 1993, 1 1 1, 384-388). Similarly, MK-801 was found to be effective at least 60 days to prevent the extension of laser-induced thermal burn to the retina, but does not significantly prevent photoreceptor loss when evaluated at 3 and 20 days post-treatment. laser exposure (Invest Ophthal &Vis Sci, 1997, 38, 1380-1389). A series of N-methyl-D-aspartate (NMDA) antagonists including eliprodil, ifenprodil, CP-101,606, tibalosin, 2309BT, 840S, and related structural analogs are effective neuroprotectants that are apparent to the toxicity of modulated excitatory amino acids interacting in the polyamine binding site of the NMDA receptor (Journal of Pharmacology and Experimental Therapeutic, 1990, 253, 475-482, British Journal of Pharmacology, 1995, 114, 1359-64, Bioorganic &; Medicinal Chemistry Letters, 1993, 13, 91-94, Journal of Medicinal Chemistry, 1995, 38, 3138-45, Journal of Medicinal Chemistry, 1998, 41, 1172-1184, Journal of Medicinal Chemistry, 1991, 34, 3085-3090 , WO 97/09309 Synthélabo, WO 97/09310 Synthélabo). More specifically ifenprodil, eliprodil, and CP-101,606 have recently been shown to preferentially obstruct the NR1A / NR2B subtype of the polyamine binding site of the NMDA receptor (Neuroscience Letters, 1997, 223, 133-136, Journal of Experimental Therapeutic, 1996, 279, 515-523). The selective interaction of the compounds with the polyamine site of the NMDA receptor subunit is apparent to be responsible at least in part for both the neuroprotective activity and the relatively favorable side effects of the profile of this class of compounds when compared to antagonists. NMDAs that act at different sites on the NMDA receptor, such as MK-801 and PCP. In addition to having activity as NMDA antagonists, certain compounds, such as, eliprodil and ifenprodil, have calcium antagonist activity in both calcium channels, N, P and L. (European Journal of Pha rma col ogy, 1996, 299, 103-112, European Journal of Pha rma col ogy, 1994, 257, 297-301). Other calcium antagonists, such as flunarizine, have also been shown to be protective in damaged models induced by light (Exp Eye Res, 1993, 56, 71-78; Arch Oph tha l, 109, 1991, 554-62).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the prevention of photic retinopathy by means of eliprodil and other glutamate agonists. Figure 2 shows the protection of the retina from collateral damage due to laser treatment.

Figure 3 shows the prevention of laser burn damage of the collateral retina by means of eliprodil and its enantiomers. The present invention is directed to glutamate antagonists that have been discovered to be useful in the treatment of external retinal disorders, particularly: age-related macular degeneration; retinitis pigmentosa and other forms of inherited-retinal retinal diseases; retinal detachment and tears; macular wrinkle; ischemia that affects the external retina; damage associated with laser therapy (reticule, focal and panretinal) that includes photodynamic therapy (PDT); trauma; light-induced or surgical iatrogenic retinopathy (retinal translocation, subretinal surgery or vitrectomy); and preservation of retinal transplants. As used herein, the external retina includes the RPE, photoreceptors, Muller cells (for extension were found in the outer retina), and the outer plexiform layer. The compounds are formulated by local or systemic ocular delivery. In our paradigms of light damage, antioxidants are either ineffective (alpha-tocopherol) or marginally effective in high doses (ascorbate, vitamin E analogues). Similarly, some calcium antagonists (flunarizine, nicardipine) are moderately effective while others (nifedipine, nimodipine, barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride) have no effect on the prevention of functional or morphological changes induced by light. However, it has been discovered that NMDA antagonists are effective in the treatment of external retinal disorders. As used herein, the term "glutamate antagonist" means the antagonist of the NMDA receptor channel complex. NMDA receptor antagonists include channel blockers (agents that operate incompetence to block the NMDA receptor channel); receptor antagonists (agents that take part with the NMDA or glutamate at the NMDA binding site, agents that act on the glycine coagonist site or any of the various modulation sites (eg zinc, magnesium, redox or polyamine) External retinal disorders encompass the environmentally acute or chronic induced degenerative conditions (trauma, ischemia, photo-oxidant stress) of the outer retina (retinal pigment epithelial cells "RPE cells") in genetically predisposed individuals. , but not limited to, macular degeneration related to age, retinitis pigmentosa and other forms of hereditary retinal disease, retinal detachment, tears, macular wrinkle, ischemia that affects the external retina, damage associated with laser therapy (reticule, focal and panretinal) that includes photodynamic therapy (PDT), trauma, light induced or surgical iatrogenic retinopathy (transloca retinal surgery, subretinal surgery or vi trectomy), and preservation of retinal transplants. Preferred glutamate antagonists inhibit excitotoxicity by binding at the polyamine site and have calcium antagonist and / or sodium antagonist, and / or neurotrophic activity. The glutamate antagonists that have been found to be effective in particular have the following structure.

Y, X = OH, H m = 0-3 n, p = 1, 2 R1 = H, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy, alkanoyloxy from 1 to 16 carbon atoms, benzoyloxy or when R2 = OH or methoxy in the 4 position and R3 = H then R1 = hydroxymethyl, carbamoyl or alkoxycarbonyl of 1 to 4 carbon atoms; R2 = H, halogen, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms; R3, R4 = H, alkyl of 1 to 4 carbon atoms; and R5 = H, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy, alkanoyloxy of 1 to 16 carbon atoms, benzoyloxy. These compounds include all isomers and pharmaceutically acceptable salts. In preferred embodiments the glutamate antagonist is 2- [4- (4-fluorobenzyl) -piperidino] -1- (4-chlorophenyl) ethanol (eliprodil) and / or its R or S isomers. Certain compounds of this invention have also been shown to have a neurotrophic effect, see U.S. Patent No. 5,547,963.

Since it has been shown that the nerve growth factor inhibits retinal degeneration in a mouse strain genetically predisposed to retinal degeneration (Grafis Arch Cl in and Exp Oph tha l, 1996, 234 s uppl emen t 1, S96- 100) the neurotrophic activity of the compounds of this invention can provide an additional therapeutic effect. In general, for degenerative diseases, the compounds of this invention are administered orally with daily doses of these compounds ranging from 0.01 to 500 milligrams. The preferred total daily doses vary between 1 and 100 milligrams. Without oral administration, such as intravitreal, topical ocular, t-transdermal, parenteral, intraocular, untival subset, or retrobulbar injection, iontophoresis or biodegradable slow-release polymers or liposomes may require adjustment of the total daily dose needed to provide an amount Therapeutically effective compound. The compounds may also be distributed in ocular irrigating solutions used during surgery, see U.S. Patent No. 5,604,244 for irrigation solution formulations. This patent is incorporated herein by reference.

The concentrations should vary from 0.001 μM to 10 μM, preferably from 0.01 μm to 5 μM. The compounds can be incorporated in various types of ophthalmic formulations for topical delivery to the eye. They can be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form sterile, aqueous suspensions or ophthalmic solutions. Ophthalmic solution formulations can be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. In addition, the ophthalmic solution may include an ophthalmologically acceptable surfactant to aid in dissolving the compound. Ophthalmic solutions may contain a thickener, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. To prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a condom in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations can be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the formulations published for analogous ophthalmic preparations; Condoms and tonicity agents can be incorporated. If dosed topically, the compounds are preferably formulated as suspensions or topical ophthalmic solutions, with a pH of about 4 to 8. The compounds will normally be contained in these formulations in an amount of 0.001% to 5% by weight, but preferably in an amount of 0.01% to 2% by weight. Thus, for topical presentation, 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the routine discretion of an expert clinician. The preferred compound, eliprodil (or its R or S isomers), which is orally bioavailable, demonstrates a low incidence of adverse effects in administration, and effectively crosses the blood-brain barrier (Drugs of the Fuure, 1994, 1 9, 905-909) indicating that Effective concentrations are expected in the target tissue, the retina. The compound is described in U.S. Patent No. 4,690,931, the contents of which are incorporated herein by reference. Eliprodil was evaluated by our paradigm of light-induced damage, a model of retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Unexpectedly, eliprodil, an excitatory amino acid antagonist, demonstrates marked potency and efficacy as a cytoprotective agent. Both the photoreceptor and the RPE cells were completely protected from functional changes induced by light and morphological lesions.

EXAMPLE 1 Photo-oxidative Induced Retinopathy Phototic retinopathy results from excessive excitement of the retinal pigment epithelium and neurorretin by absorption of visible or nearby ultraviolet radiation. The severity of the lesion is dependent on wavelength, irradiation, duration of exposure, species, ocular pigmentation and age. The damage may result from peroxidation of cell membranes, inactivation of mitochondrial enzymes such as cytochrome oxidase, or increased intracellular calcium. The cell damage resulting from photo-oxidant stress leads to cell death by apoptosis (Shahinfar, S., Ed ard, DP and Tso, MO (1991).) A pathological study of photoreceptor cell death in retinal photic lesion. 10: 47-59; Abler, AS, Chang, CJ, Fu, J, and Tso, MO (1994) .Fotic lesion activates apoptosis of photoreceptor cells Investigative Ophthalmology &Visual Science, 35 (Suppl): 1517) . The oxidative stress of induced apoptosis has been implicated as a reason for many ocular pathologies, including iatrogenic retinopathy, macular degeneration, retinitis pigmentosa and other forms of inherited-degenerative disease, ischemic retinopathy, retinal tear, retinal detachment, glaucoma and retinal neovascularization (Chang , CJ, Lai, WW, Edward, DP, and Tso, MO (1995), Apoptotic Photoreceptor Cell Death after Traumatic Retinal Detachment in Humans, Archives of Ophthalmology, 113: 880-886, Portera-Cailliau, C, Sung, C. H., Nathans, J. and Adler, R. (1994). Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa, Proceedings of National Academy of Science (U.S.A.), 91: 974-978; Buchi, E. R. (1992). The cell death in the retina of the rat after a reperfusion attack by induced pressure ischemia: a microscopic study of electrons. I. Cell layer of the ganglion and inner nuclear layer, Experimental Eye Research, 55: 605-613; Quigley, H.A., Nickells, R.W., Kerrigan, L.A., Pease, M.E., Thibault, D.J. and Zack, D.J. (1995). Cell death of the retinal ganglion in experimental glaucoma and after axotomy occurs by apoptosis, Investiga tive Ophthalmology & Visual Science, 36: 774-786). The phytic induced retinal damage has been observed in mice (Zigman, S., Groff, J., Yulo, T. and Vaughan, T. (1975) .The response of mouse eye tissues to exposure to UV light close continuous, Investigative Ophthalmology &Visual Science, 14: 710-713), rats (Noell, WK, Walker, VS, Kang, BS, and Berman, S. (1966) .The retinal damage by light in rats, Investigative Ophthalmology &Visual Science, 5: 450-473; Kuwabara, T., and Gorn, RA (1968), Retinal Damage by Visible Light: A Microscopic Electron Study, Archives of Ophthalmology, 79: 69-78; Labial, MM (1976) Survival of some photoreceptor cells in albino rats following long-term exposure to continuous light, Investigative Ophthalmology &Visual Science, 15: 64-70), Rabbit (Lawwill, T. (1973) The effects of prolonged exposure of the rabbit retina to light at low intensity, Investigative Ophthalmology &Visual Science, 12: 45-51), Squirrel (Collier, R. J. and Zigman, S. (1989). The comparison of retinal photochemical lesions after exposure to near or short wavelength visible UV radiation, In M. M. Labial, R. E. Anderson, and J. G. Hollyfield (Eds.), Inherited and Environmentally Induced Retinal Degenerations. Alan R. Liss. Inc., New York; Collier, R., W., Waldron and Zigman, S. (1989). The temporal sequence of changes to the gray • squirrel retina after exposure to nearby UV, Investigative Ophthalmology & Visual Science, 30: 631-637), non-human primates (Tso, M. O. M. (1973), Phthic maculopathy in rhesus monkeys, a microscopic study of light and electrons, Investigative Ophthalmology &Visual Science, 12: 17-34; Ham, W. T., Jr. , Ruffolo, J. J., Jr. , Mueller, H. A. and Guerry, D., III (1980). The nature of retinal radiation damage: dependence on wavelength, energy level and time of exposure, Vision Research, 20: 1105-1111; Sperling, H. G. Jonson, C. and Harwerth, R. S. (1980), Differential spectral phytic damage to primate cones, Vision Research, 20: 1117-1125; Sykes, S.M., Robison, W.G., Jr. , Waxler, M. and Kuwabara, T. (1981). Damage to monkeys' retina by broad spectrum fluorescent light, Investigative Ophthalmology & Visual Science, 20: 425-434; Lawwill, T. (1982). Three main pathological processes caused by light in the primate's retina: A search by mechanisms, Transactions of the American Ophthalmology Society, 80: 517-577), and man (Marshall, J., Hamilton, AM and Bird, AC (1975 The histopathology of ruby and argon laser lesions in the retina of monkeys and humans, British Journal of Ophthalmology, 59: 610-630, Green, WR and Robertson, DM (1991). human eye, American Journal of Ophthalmology, 112: 520-27). In humans, chronic exposure to environmental radiation has also been implicated as a risk factor for age-related macular degeneration (Young, RW (1988).) Solar radiation and age-related macular degeneration, Survey of Ophthalmology, 32: 252-269; Taylor, H. West, Muñoz, B., Rosenthal, F. S., Bressler, S. B. and Bressler, N. M. (1992). The long-term effects of visible light in the eye, Archives of Ophthalmology, 110: 99-104; Cruickshanks, K. J., Klein, R. and Klein, E. K. (1993). Sunlight and macular degeneration related to age. The Beaver Dam Eye Study, Archives of Ophthalmology, 111: 514-518). To determine whether eliprodil and other glutamate antagonists can rescue photo-oxidant attack retinal cells, male Sprague Dawley rats were randomized to experimental drug or vehicle groups. In Experiment I, the rats were dosed with various glutamate antagonists, including: MK-801; eliprodil; and memae and in Experiment 2, the potency of eliprodil was compared with the potency of its isomers. In both experiments, the rats received three intra-peritoneal injections (IP) of any vehicle or drug at 48, 24, and 0 hours prior to a light exposure for 6 hours at speci fi edly filtered blue light (~ 220 fe). Control rats were housed in their house cage under normal cyclic light exposure. The elect rorret inogram (ERG) is a non-aggressive clinical measure of the eye's electrical response to a flash of light. Wave a and wave b are two components of the ERG that are diagnostic of retinal function. The wave a reflects out the function of the retina and is generated by interactions between the photoreceptor and the pigment epithelial cells while the b wave reflects the function of the internal retina, particularly the Muller cells. The ERG was recorded after a five day recovery period from the anesthetized rats adapted to darkness (Ke t a ine-HCl, 75 mg / Kg, Xylazine, 6 mg / Kg). The electrical response of the eyes to a flash of light was produced by observing a total field (ganzfeld). The ERGs for a series of flashes of light that increase in intensity were digitalized to analyze temporal characteristics of the relationship of the waveform and the response to the voltage intensity (Vlogl).

Results Effect of exposure to blue light in doses dosed with vehicle: Exposure to blue light for 6 hours results in a significant decrease in the response amplitude of ERG (ANOVA, p <0.001; Bonferroni, p <0.05) compared to the controls when measured after a recovery period of 5 days (Figure 1-A). The maximum wavelengths a and wave b are reduced by more than 70% in rats dosed with vehicle compared with the controls. In addition, the threshold responses were lower and evoked at brightening flash intensities.

Experiment 1: Preven of photic retinopathy with glutamate antagonists: Rats dosed with MK-801, eliprodil or memae shown in the dose protection dependent on external and internal retinal function against photo-oxidant-induced retinopathy: 1. ) MK-801. MK-801 provides significant protection of external and internal retinal function against light-induced retinal degradation in rats dosed at 20 mg / kg. In addition, the response amplitudes, waveforms, and threshold responses were not significantly different from the control. The wave-to-peak response amplitudes averaged 734.05 μV (SEM = 36.79 μV) of the controls and 537.93 μV (SEM = 34.42 μV) of rats dosed with 20 mg / kg (See Figure 1-A). Similarly, the maximum b-wave response amplitudes were not significantly different and averaged 1807 μV (SEM = 74.32 μV) of the controls and 1449. 77 μV (SEM = 68.12 μV) of rats dosed with MK-801 No significant protection of retinal function was measured in rats dosed with MK-801 in doses of 2 or 10 mg / kg.

Eliprodil The significant preservation of retinal function was also measured with rats dosed with eliprodil (racemic mixture) (20 mg / kg) compared to vehicles (Figures 1-A). The a and b waves of ERG were 57% and 53% of the normal and 2.4 and 2.2 times higher than the rats dosed with vehicle, respectively. The registered ERGs of rats dosed with eliprodil (2 or 10 mg / kg) were not significantly different from the vehicles and about 32% of normal.

Memantine As shown in Figure 1-A, no significant protection of external and internal retinal function was measured with rats dosed with memantine (2 mg / kg). Memantine provides significant protection of external and internal retinal function against light-induced retinal degeneration in rats dosed at 20 mg / kg compared to rats dosed with vehicle. However, the ERG responses were significantly lower than normal in rats dosed at 20 mg / kg.

Experiment 2: Comparison of eliprodil with the isomer R and S: 1.) Eliprodil. Eliprodil (racemic) provides significant protection of external and internal retinal function against light-induced retinal degeneration in rats dosed with and 40 mg / kg (Figure 1-B). The wave-to-peak response amplitudes in rats dosed with eliprodil with 20 and 40 mg / kg were 2.4 and 2.25 times higher, respectively, than for rats dosed with vehicle. After a recovery period of 5 days, the amplitudes of wave response to maximum averaged 395.82 μV (SEM = 46.4 μV) of rats dosed with 20 mg / kg and 419.85 μV (SEM = 63.88 μV) of rats dosed with 40 mg / kg. No significant difference in retinal function was detected between any dosing group and these amplitudes were approximately 60% of normal.

.) R-eliprodil. As noted in Figure 1-B, the R-eliprodil was twice as potent as eliprodil (racemic). No significant protection of external and internal retinal function was measured after a recovery period of 5 days in rats dosed with R-eliprodil at 20 mg / kg. The maximum a and b wave responses were 38% and 36% of normal, respectively. However, R-eliprodil provides significant protection of external and internal retinal function against light-induced retinal degeneration in rats dosed at 40 mg / kg (Figure 1-B). The response amplitudes were approximately 2 times higher than the rats dosed with vehicle and 50% of normal. The maximum a and b wave response amplitudes averaged 397.25 μV (SEM = 77.14 μV) and 812.87 μV (SEM = 160.13 μV), respectively. No significant retinal protection was measured in rats dosed with the highest doses of R-eliprodil, 80 mg / kg. The maximum a and b wave responses were approximately 40% of normal. 3. ) S-eliprodil. No significant difference in the response amplitude of ERG was measured between rats dosed with S-eliprodil (5 mg / kg) compared to rats dosed with vehicle. However, as noted in Figure 1-B, S-eliprodil was twice as potent as eliprodil (racemic). The significant protection of external and internal retinal function was measured after a recovery period of 5 days in rats dosed with S-eliprodil as low as 10 mg / kg compared to vehicles. The maximum a and b wave responses were 64% and 76% of normal, respectively. Significant protection of external and internal retina function against light-induced retinal degeneration compared to vehicle-dosed rats was also measured in rats dosed at 20 mg / kg. The response amplitudes were approximately 2 times higher than the rats dosed with vehicle and approximately 62% of normal after a recovery period of 5 days. The maximum a and b wave response amplitudes averaged 418.04 μV (SEM = 56.18 μV) and 1015.95 μV (SEM = 141.49 μV), respectively.

Abstract: All glutamate antagonists evaluated from this series of compounds provide significant rescue of photoreceptor and RPE cells in this model of photically induced retinopathy. Complete protection was measured in rats dosed with MK-801. The S-enantiomer is the most potent retinoprotective agent in this series of glutamate antagonists.

EXAMPLE 2 Extended Damage by Retinal Laser Burn The eye is exposed to high energy laser radiation during retinal photocoagulation therapy (reticule, focal and panretinal) or during photodynamic therapy. This type of therapy is frequently used during the. treatment of choroidal neovascularization, proliferative stages of diabetic retinopathy, retinopathy of prematurity, or to repair cavities or retinal detachments. The destruction of the tissue that leads to the deterioration of vision is associated with this laser therapy. The Macular Photocoagulation Study found that 20% of eyes treated by subfoveal macular choroidal neovascularizations (CNV) and 18% of eyes treated by juxtafoveal CNV suffer severe visual losses of six or more lines as a direct result of laser treatment. . It is believed that this loss of vision results directly from the expansion of the laser-induced injury to the surrounding normal neurosensorial retina and RPE. Singlet oxygen and other reactive oxygen species as well as cytokines are generated in the area of laser burn and the purpose of migrating laterally to cause collateral retinal damage. Retinal morphological changes in this area are similar to changes in our photo-oxidant retinopathy paradigm. The objective of this study was to quantitatively change the size of laser burn in rats dosed with vehicle or dosed with eliprodil to determine if the therapeutic agents would minimize the extended damage from laser burn. Pigmented Long Evans rats randomly assigned to control dosed groups with drug or vehicle. Rats were predosed (IP) 64, 48, 24, and 2 hours before laser treatment and 3, 19, and 25 hours after receiving 2 to 4 laser burns from an argon laser (dot size = 200 microns) , energy intensity = 100 mW, and duration of exposure = 0.1 seconds). After a recovery period of 48 hours, the eyes were fixed, dehydrated and embedded in plastic resin. The histological evaluation of laser burns was carried out by mounting the retina in a flat part and dividing the tissue in a tangential plane for the nerve fiber layer. Using this technique, the area of injury in the outer nuclear layer could be calculated using an image analysis system.

Results: Histological assessment of retinal burns 48 hours after laser exposure showed that the lesions were usually confined to the choriocapillaris, retinal pigment epithelium and external retina. The center of the laser burn was made by: complete closure of all capillaries, arterioles and venules; perforation of Bruch's membrane; pycnosis and necrosis of all photoreceptor nuclei; and destruction of internal and external segments. The extension of the peripheral retinal lesion consists of shortening of the outer segments, swelling of the internal segment, agglutination of melanin granules in the RPE and choroid, and vacuolization of the RPE. In the eyes dosed with vehicle and control, the laser burned areas averaged 50.6.27.07 and 55.243.65 μ2, respectively (Figures 2, 3).

Eliprodil Treatment with eliprodil (racemic) significantly reduces the retinal burned area by approximately 60% (Figures 2, 3) compared to the vehicle. The average burned area in rats dosed with eliprodil was 22,406 μ2 (SEM = 3559.3 μ2). No reduction in the size of the burn due to laser injury was measured in rats dosed with 10 mg / kg. The areas of laser burn injury averaged 55,411.67 μ2 (SEM = 2555.47 μ2) in this group of rats.

R-eliprodil. Dosing with R-eliprodil (40 mg / kg) resulted in lesion areas that were 28% smaller than lesions in vehicle-dosed rats. Laser burn injury areas in rats dosed with R-eliprodil averaged 36,016 μ2 (SEM = 4779.49 μ2) and were significantly different than lesions with vehicle or non-injected doses (Figure 3). The dosage with R-eliprodil (20 mg / kg) resulted in areas of laser injury that were 16% smaller than the lesions measured in vehicle-dosed rats but were not significantly different. 3. ) S-eliprodil. The areas of laser burn injury in rats dosed with S-eliprodil (20 mg / kg) averaged 43.098.5 μ2 (SEM = 2992.94 μ2). The area of injury was 15% smaller than the lesion areas in rats dosed with vehicle, but they were not significantly different from the vehicle controls (Figure 3).

Summary: Both the R isomer and the racemic mixture of eliprodil provide significant reduction of collateral retinal damage around the laser burn. Eliprodil (racemic) was found to be twice as potent and twice as effective in this model of laser burn extension as compared to R-eliprodil. Both of these molecules have nanomolar binding affinities for the NMDA receptor, compared to S-eliprodil, which is devoid of significant efficacy in this model and has millimolar affinity with the NMDA receptor. The following formulations are representative and not limiting.

EXAMPLE 3 EXAMPLE 4 EXAMPLE 5 EXAMPLE S EXAMPLE 7 Equivalent to 5 mg of Eliprodil as a free base. EXAMPLE 8 'Equivalent to 50 mg of Eliprodll as a free base.

EXAMPLE 9 Equivalent to 10 mg of Eliprodil as a free base. EXAMPLE 10 1 Equivalent to 20 mg of Eliprodil as a free base.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A composition for the treatment of external retinal disorders, characterized in that it comprises a pharmaceutically effective amount of a glutamate antagonist.
2. 2. The composition according to claim 1, characterized in that the glutamate antagonist is a polyamine site antagonist.
3. 3. The composition according to claim 1, characterized in that the glutamate antagonist is a compound of the formula: Y, X = OH, H m = 0-3 n, p = 1, 2 R1 = H, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy, alkanoyloxy from 1 to 16 carbon atoms, benzoyloxy or when R2 = OH or methoxy in the 4 position and R3 = H then R1 = hydroxymethyl, carbamoyl or alkoxycarbonyl of 1 to 4 carbon atoms; R2 = H, halogen, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms; R3, R4 = H, alkyl of 1 to 4 carbon atoms; and R5 = H, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy, alkanoyloxy of 1 to 16 carbon atoms, benzoyloxy, in a pharmaceutically acceptable carrier.
4. 4. The composition according to claim 3, characterized in that the compound is eliprodil.
5. 5. The composition according to claim 3, characterized in that the compound is the R or S isomer of eliprodil.
6. 6. The composition according to claim 1, characterized in that the disorder is selected from the group consisting of: macular degeneration related to age; retinitis pigmentosa and other forms of inherited degenerative retinal diseases; retinal detachment and tears; macular wrinkle; ischemia that affects the external retina; damage associated with laser therapy (reticule, focal and panretinal) that includes photodynamic therapy (PDT); trauma; light-induced or surgical iatrogenic retinopathy (retinal translocation, subretinal surgery or vi trectomy); and preservation of retinal transplants.
7. 7. The composition according to claim 6, characterized in that the compound is eliprodil.
8. 8. The composition according to claim 7, characterized in that the compound is the R or S isomer of eliprodil.
9. 9. Use of a glutamate antagonist for the manufacture of a drug to treat external retinal disorders.
10. 10. The use according to claim 9, characterized in that the glutamate antagonist is a polyamine site antagonist.
11. 11. The use according to claim 9, characterized in that the glutamate antagonist is a compound of the formula: Y, X = OH, H m = 0-3 n, p = 1, 2 R1 = H, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy, alkanoyloxy from 1 to 16 carbon atoms, benzoyloxy or when R2 = OH or methoxy in the 4 position and R3 = H then R1 = hydroxymethyl, carbamoyl or alkoxycarbonyl of 1 to 4 carbon atoms; R2 = H, halogen, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms; R3, R4 = H, alkyl of 1 to 4 carbon atoms; and R5 = H, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy, alkanoyloxy of 1 to 16 carbon atoms, benzoyloxy, in a pharmaceutically acceptable carrier.
12. 12. The use according to claim 11, characterized in that the compound is eliprodi 1.
13. 13. The use according to claim 12, characterized in that the compound is the R or S isomer of eliprodil.
14. 14. The use of a compound according to claim 9 for the manufacture of a medicament for treating the disorder selected from the group consisting of: age-related macular degeneration; retinitis pigmentosa and other forms of inherited degenerative retinal diseases; retinal detachment and tears; macular wrinkle; ischemia that affects the external retina; damage associated with laser therapy (reticule, focal and panretinal) that includes photodynamic therapy (PDT); trauma; iatrogenic retinopathy induced by light or surgical (retinal trans location, subretinal surgery or rectal vein a); and preservation of retinal transplants.
15. 15. The use according to claim 14, characterized in that the compound is eliprodil or its R or S isomer. TREATMENT OF EXTERNAL RETINA DISORDERS SUMMARY OF THE INVENTION Compositions and methods are described for treating disorders of the external retina with glutamate antagonists.