MXPA97009609A - Non-steroid anti-inflammatory drugs for the cito-protection of mesh trabecu - Google Patents

Abstract

The invention relates to the recognition that certain nonsteroidal antiinflammatory agents produce cytoprotective effects on trabecular cells, and therefore, can be used to prevent cell damage and to treat the loss of trabecular cells caused by oxidative damage and other forms of injury to cells. This treatment can reduce the severity of, or prevent, the glaucous

Description

NON-STERQIDAL ANTI-INFLAMMATORY DRUGS FOR THE PROTECTION OF TRABECTJLAR MESH FIELD OF THE INVENTION The present invention is in the field of therapeutics, and is related to methods and reagents for protecting cells from the trabecular meshwork of agents or processes that would otherwise result in the loss of trabecular cells. This invention was supported with government funds (NIH EY 02477 and NIH EY 08905-02). The Government has certain rights over this invention.

BACKGROUND OF THE INVENTION "Glaucoma" is a group of debilitating eye diseases that are the leading cause of blindness subject to positive intervention in the United States of America and other developed nations. The term "glaucoma" currently encompasses a variety of states of ophthalmic diseases that are caused by different disease processes or pathological conditions of the eye. Disease states under the term "glaucoma" generally share the characteristic of having an elevated intraocular pressure ("IOP"), which is a major risk factor in the production of visual field loss and blindness. Of the many different states of ophthalmic disease, Chandler et al. (Glaucoma, Third Edition, Lea and Febliger, Philadelphia (1986)) describe the following forms: primary open-angle glaucoma ("POAG"), progressive low-tension glaucoma, glaucoma of exfoliation and open angle ("OAG"), amilodosis and open angle glaucoma, pigment and pigment dispersion glaucoma, angle closure glaucoma, combined open angle and angle closure glaucoma, malignant glaucoma, glaucoma closure angle after lateral scleral flexion operations for separate retina, angle closure glaucoma due to multiple cysts of the iris and ciliary body, angle closure glaucoma to central retinal vein occlusion, secondary angle closure glaucoma to transient bilateral myopia, glaucoma of perforating lesions, glaucoma due to eye contusion, hemolytic or ghost cell glaucoma, glaucoma asoci with congenital or spontaneous lens dislocations, lens-induced glaucoma, glaucoma in aphasia, glaucoma due to intraocular inflammation, neovascular glaucoma, glaucoma associated with extraocular venous congestion, essential atrophy of the iris with glaucoma, corticosteroid glaucoma, glaucoma after penetrating keratoplasty and characteristically unilateral glaucoma. In almost all cases, the intraocular pressure found in these glaucoma syndromes is the result of an increase in the flow resistance of the aqueous efflux (see, Vaughan, D. and collaborators in: General Ophthamolocry, Appleton &Lange, Norwalk, CT, pages 213-230 (1992)). Primary open-angle glaucoma ("POAG") also called chronic open-angle glaucoma ("COAG") is the most prevalent form of glaucoma. The incidence of this condition in people over the age of forty years is approximately 0.4-0.5 percent. (Leske, MC et al., J. Epidemiol 113: 1843-1846 (1986), Bengtsson, B., Br. J. Ophthamol 73: 483-487 (1989), Strong, NP, Ophthal, Phvsiol, Qpt. 12: 3-7 (1992)). On the other hand, the frequent occurrence of the disease increases with age to more than 6, percent of those of 75 years or older (Strong, NP, Ophthal. Physiol., Qpt. 12: 3-7 (1992) ). Primary open angle glaucoma is characterized by the loss of endothelial cells of the trabecular meshwork, which is associated with the degeneration of the normal structure of the trabecular meshwork. This degeneration leads to the obstruction of the normal capacity for the aqueous humor to leave the eye (see, Vaughan, D. and collaborators in: General Ophthalmolosy, Appleton &Lange, Nor alk, CT, pages 213-230 (1992)) . In ordinary terminology, glaucoma is called "primary" if it is believed that the pathogenic defect occurs orinciDal within the tissue itself, and without an obvious external causal mechanism that can be defined for "secondary" glaucoma (for example, see McGraw-Hill Encvclopedia of Science and Technolocry, sixth edition, Volume 8, page 131 (McGraw-Hill 1987)). Both in primary open angle glaucoma (for which no precise cause is known, although it is believed that toxic substances produced locally / or from the aqueous humor account for the damage / death of trabecular cells), as in pigmentary glaucoma ( frequently classified as a secondary glaucoma since it is thought that the pigment or other waste of the posterior iris produces damage when surrounded by trabecular mesh cells), it is known that there is a marked loss of the endothelial cells of the mesh. It is possible that oxidation products play a role in the production of trabecular meshwork damage in both conditions, as well as ocular iron toxicity, which can also produce glaucoma. It would be very important to protect the endothelial cells of the trabecular meshwork from injuries and death that occur in disease processes. It is believed that a loss in the number of cells of the trabecular meshwork and an alteration in the function of the remaining cells is responsible for the decrease in the normal ability of the aqueous humor to leave the eye, leading to a decreased ease of outflow. (increased resistance to outflow), and high intraocular pressure. It has previously been shown that age itself leads to the progressive loss of human trabecular meshwork cells, which eventually also leads to a compromise of the structure of the mesh over time. In fact, it appears that increased resistance to outflow occurs in the non-glaucomatous elderly population, and a method for preserving the cells in an elderly normal individual, as well as in those with a chronic glaucoma syndrome, would be highly desirable. recognized. For these reasons, it would be desirable to have a means to treat or prevent pathological changes such as loss of endothelial cells of the trabecular meshwork, which is associated with the development and progress of these glaucoma syndromes. The present invention provides these agents and improved therapeutic methods. High intraocular pressure results in progressive visual loss and blindness, if not treated properly and in time. Normal intraocular pressure for humans usually measures 10-20 millimeters of mercury (1.3-2.7 kilopascals), and is maintained by a balance between the inflow and the aqueous outflow.; With rare exceptions, all glaucoma syndromes are associated with an output flow defect. Aqueous humor is produced by the ciliary body in the eye, and passes from the posterior chamber through the papillary space into the anterior chamber. The aqueous humor drains through the trabecular meshwork in Schlemm's canal, through which it leaves the eye. Elevated intraocular pressure is considered a major risk factor in the production of damage to the head of the optic nerve, leading to the loss of visual fields, and eventually to blindness in many patients. Even in so-called "normal tension glaucoma", it is believed that lowering an apparently normal intraocular pressure helps prevent visual loss. In treatments currently available for glaucoma, one attempts to symptomatically lower intraocular pressure by decreasing the amount of inflow (slowing the rate of aqueous formation), or by increasing the ease of outflow. Although the flow of output can be increased by a variety of drugs, as will be noted, the treatments available do not address the fundamental pathogenic processes in primary open-angle glaucoma, pigmentary glaucoma and other syndromes associated with cell loss ( nor are they aimed at the loss of cells from the trabecular meshwork associated with normal aging). Examples of different drug treatments that symptomatically reduce intraocular pressure (see, for example, Babcock, JC, and co-workers; U.S. Patent Number 5,124,154; Epstein, DL, U.S. Patent Number 4,757,089; Doulakas; , J., U.S. Patent Number 4,829,088) include: pilocarpine and efeneprine, which owe their effectiveness to the increase in ease of outflow; as well as timolol and other beta-blockers, carbonic anhydrase inhibitor drugs, and alpha-adrenergic agents, which owe their effectiveness to the decrease in the rate of aqueous formation. Doulakas (US Pat. No. 4,829,088) describes the use of an ophthalmic medicament containing diclofenac-sodium in aqueous solution for the treatment of inflammations of the eye. Diclofenac-sodium is a non-steroidal anti-inflammatory agent ("NSAI") that is believed to be an alternative to corticosteroids (glucocorticoids) for the treatment of some inflammatory symptoms in the eye, and seems especially useful for the symptomatic relief of pain. The aqueous solution is suitable for the local treatment of inflammations of the eye, due to its stability against the chemical decomposition of diclofenac-sodium and to the preservation of properties and tolerance on the part of the eye.

Nagy (U.S. Patent No. 4,960,799) discloses aqueous ophthalmic solutions containing diclofenac-sodium. The solutions, which have a pH of about 7.8, comprise per milliliter of solution, about 0.1 to about 5.0 milligrams of (a) pharmaceutically acceptable salt of ortho- (2,6-diclphenyl) aminophenylacetic acid, - (b) about 0.1 to about 10 milligrams of a pharmaceutically acceptable salt of ethylene diamintetraacetic acid; (c) from about 0.5 to about 200 milligrams of a pharmaceutically acceptable solubilizer; (d) from about 0.01 to about 5.0 milligrams of a pharmaceutically acceptable bacteriostatic and (e) the remaining water. Ophthalmic solutions are used for topical administration to the eye, for the control or treatment of ocular inflammation. Cherng-Chyi et al. (Patent of the US Pat. No. 5,110,493) relates to ophthalmic formulations of non-steroidal anti-inflammatory drugs containing a quaternary ammonium preservative and a non-ionic surfactant. The formulations are useful for treating diseases that are either caused by, are associated with, or are accompanied by, inflammatory processes. The foregoing, and others in the well-known class of nonsteroidal anti-inflammatory agents, have been proposed to suppress the signs of inflammatory responses, to avoid particular side effects or surgical trauma, especially to prevent fluid from accumulating in the back of the eye, and the appearance of inflammatory cells and the spilling of vessels in the anterior chamber. It is known that non-steroidal anti-inflammatory agents useful in the treatment of inflammation, inhibit the production of prostaglandin, and also affect other eicosanoid trajectories. It is believed that non-steroidal anti-inflammatory agents are a possible alternative for glucocorticoids, to reduce inflammation and avoid side effects due to these drugs (for example, disguising the risk of deterioration as a result of bacterial or viral infection), but in the In practice, non-steroidal anti-inflammatory agents have proven to be much less effective in the treatment of many different types of ocular inflammation. There is no non-steroidal anti-inflammatory agent that has been proposed to overcome the loss of trabecular cells, associated with normal aging, nor in conditions in which cell loss and cell damage appear to be greater - as in primary open-angle glaucoma, pigmentary glaucoma and some other glaucoma syndromes. The prevention or treatment of trabecular cell loss is particularly important since the control of intraocular pressure in many glaucoma patients eventually becomes a problem, which, even with optimal medical and surgical therapy, can lead to progressive visual loss. . It has also been shown that aging itself leads to a progressive loss of cells from the human trabecular meshwork, which will eventually lead to a compromise of the mesh over time. In fact, it appears that increased resistance to outflow occurs in the non-glaucomatous aging population, and a method for preserving cells in a normal individual in aging, as well as in those with a recognized chronic glaucoma syndrome, would be highly desirable. For these reasons, it would be desirable to have means to treat or prevent pathological changes such as the loss of endothelial cells of the trabecular meshwork, which are associated with the development and progress of these glaucoma syndromes. The present invention provides these agents and improved therapeutic methods.

SUMMARY OF THE INVENTION The invention has to do with the recognition of a loss of trabecular cells and the loss of the normal structure of the trabecular meshwork, contribute to the increased intraocular pressure that characterizes glaucoma. The invention also has to do with the recognition that certain nonsteroidal anti-inflammatory agents (in addition to antioxidants, such as vitamin E) produce cytoprotective effects in trabecular cells. These agents can therefore be used singly, in combination with other non-steroidal anti-inflammatory agents, to prevent or treat the loss of trabecular cells, observed in glaucoma patients. In detail, the invention provides a method for the cytoprotection of the trabecular meshwork, which comprises administering to a human a composition that includes (a) an ophthalmologically effective amount of a non-steroidal cyclooxygenase inhibitor, and (b) a pharmaceutically carrier acceptable, to avoid the loss of trabecular cells. The invention is particularly concerned with the embodiment wherein the non-steroidal anti-inflammatory agent is selected from the group of known cyclooxygenase inhibitors consisting of salicylates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolones, or from the group consisting of diclofenac, indomethacin and fenoprofen.

The invention additionally concerns the embodiment wherein the composition is administered topically (as in an aqueous polymer solution, an aqueous suspension, an ointment or a gel vehicle), or by intraocular injection, oral administration (as with an aqueous solution). , an aqueous suspension, an elixir, a tablet, a pill, or a capsule) and intravenous injection. The invention further provides a method for the cytoprotection of the trabecular meshwork, which comprises administering to a human a composition that includes (a) an ophthalmologically effective amount of diclofenac, and (b) a pharmaceutically acceptable carrier, including a polymer that contains carboxy, lightly cross-linked, in the form of an aqueous polymeric solution, a suspension, an ointment or a gel for topical administration, to avoid the loss of trabecular cells. The invention further provides a method for the cytoprotection of the trabecular meshwork, which comprises administering to a human in need of treatment or prevention of oxidative damage to their trabecular cells, or of damage to trabecular cells by phagocytic or endocytic processes or other causes, a composition that includes (a) an ophthalmologically effective amount of a non-steroidal anti-inflammatory cyclooxygenase inhibitor, and (b) a pharmaceutically inert carrier, to prevent the loss of trabecular cells. The invention also provides a composition for the cytoprotection of the trabecular meshwork, comprising (a) a non-steroidal cyclooxygenase inhibitor of a type, and in an amount, to prevent the loss of trabecular cells, and (b) a carrier pharmaceutically acceptable therefor. In particular, the composition contains diclofenac, indomethacin, or fenoprofen.

DETAILED DESCRIPTION OF THE INVENTION I. General Description of the Invention The cells of the human trabecular meshwork are endothelial-like cells that line the outflow annals through which the aqueous humor of the eye exits. As indicated above, it has been proposed that the trabecular meshwork plays an important role in the normal outflow of aqueous fluid, and it has been assumed that it is the largest site of resistance to outflow in glaucomatous eyes. It is believed that increased resistance to outflow through the trabecular meshwork results in the high intraocular pressure observed in primary open-angle glaucoma and other major glaucoma syndromes. The present invention is related to an acknowledgment that the health and viability of the cells that provide the endothelial lining of the trabecular meshwork structure are essential in the preservation of the integrity of the outflow channels. A loss in the number and / or function of these cells results in the development of pathological changes that lead to collapse or coating of outflow path structures, or otherwise compromise the normal function of this structure . The result of these changes is the increased resistance to outflow observed in primary open-angle glaucoma and other forms of glaucoma (eg, pigmentary glaucoma). The present invention is therefore directed to methods for treating cells of the trabecular meshwork, subject to cell loss, in order to maintain the number of trabecular cells. In the present reference is made to the treatments that protect the viability of cells of the trabecular meshwork of agents or processes that would otherwise cause the loss of trabecular cells, as "cytoprotective" treatments. As used herein, a treatment is said to have a "minor to no" effect if it results in an increase in cytoprotection in relation to a treatment that has a "minimal" effect if it results in a increase in cytoprotection in relation to untreated controls, from 10 to 20 percent. It is said that a treatment has a "substantial" effect if it results in an increase in cytoprotection in relation to untreated controls, between 20 and 50 percent. A treatment is said to have a "major" effect if it results in an increase in cytoprotection relative to untreated controls of more than 50 percent.

II. The Cito-Protection of Trabecular Cells The cytoprotective treatments of the present invention can be used to protect trabecular cells against loss caused by a diverse set of harmful agents or processes. Examples of these agents and processes include agents that cause oxidative damage, and cell-mediated processes (such as phagocytosis and endocytosis of toxic materials) that have a negative effect on the cells of the trabecular meshwork.

A. Agents and Processes that Cause Loss of Trabecular Cells 1. Oxidative Lesion Human trabecular meshwork cells encounter relatively high concentrations of hydrogen peroxide and other reactive oxygen species. It has been proposed that the stress by these factors results in a decreased function of the human trabecular meshwork, which involves the loss of cells from the trabecular meshwork, and loss of the normal architecture of the outflow, thereby preventing the flow of outflow of aqueous humor (Polansky, JR et al., in: Principies and Prac ice of Ophthalmolocry, pages 226-247, WB Saunders and Company, Philadelphia (1994)). Experiments to test this proposal initially showed injury only if relatively high (ie> 1 mM) levels of hydrogen peroxide were employed, and if defensive enzymes were inhibited (Bhuyan, KC et al., Biochem. Biophys. : 641 (1977); Bhuyan, KC et al., In "Biochemical and Clinical Aspects of Oxygen", Caughey, WS (ed.) Page 795 (1981); Spector, A. et al., Exper. Eye Res 33: 673 ( 1981); Giblin, FJ et al., Invest. Ophthalmol, Vis. Sci. 24: 1283-1287 (1983)). However, it was later discovered that lower levels of hydrogen peroxide (ie 0.05-0.1 mM) can produce remarkable effects on the cells of the trabecular meshwork, if exposure to hydrogen peroxide was maintained for 1-2 hours, more rather than using only a brief exposition (Polansky, JR et al., CLAO Suppl. 16: S23 (1990)). One aspect of the present invention has to do with the recognition that the reduced capacity of the outflow of the mesh, which is observed in glaucomatous patients, is caused in part by toxic oxidizing agents in the aqueous humor. These agents induce an oxidative injury or oxidative stress to the trabecular meshwork. Since the mesh is not in direct light, the main causes of oxidative damage are stable oxidative species, such as hydrogen peroxide or lipidihydroperoxides, or their decomposition products (Polansky, JR et al., In: Principies and Practice of Ophthalmology, pages 226-247, WB Saunders and Company, Philadelphia (1994), - Bhuyan, KC et al, Biochem Biophvs, Acta 497: 641 (1977), Bhuyan, KC et al, in "Biochemical and Clinical Aspects of Oxygen ", Caughey, WS (ed.) Pages 785-796 (1981); Spector, A. et al., Exper. Eye Res 33: 673-881 (1981); Giblin, FJ et al., Invest. Ophthalmol. Vis. Sci. 22: 330-335 (1982); Babizhayev, MA et al., Invest. Ophthalmol, Vis. Sci. 67: 371 (1989)). In this regard, substantial levels of hydrogen peroxide (approximately 0.03 M) are present in the normal aqueous fluid, and alterations in normal physiology can significantly increase these levels (Giblin, F.J. et al., Invest.

Ophthalmol. Vis. Sci. 22: 330-335 (1982); Kahn, M.G. and collaborators, Invest. Ophthalmol. Vis. Sci. 24: 1283-1287 (1983)). It has been proposed that normal animals detoxify hydrogen peroxide by coupled reactions involving glutathione peroxidase, glutathione reductase and hexose monophosphate derivation (Giblin, F.J. and collaborators, Invest. Ophthalmol, Vis. Sci. 22: 330-335 (1982)). It is also believed that catalase controls the concentration of hydrogen peroxide. The processes that impair the ability of the trabecular meshwork to control peroxide concentration increase the likelihood of oxidative damage (Kahn, M.G. et al., Invest. Ophthalmol, Vis. Sci. 24: 1283-1287 (1983).; Nguyen, K.P.V. and collaborators, Invest. Ophthalmol. Vis. Sci. 29: 976-981 (1988)). The trabecular meshwork plays a substantial role in the removal of excess hydrogen peroxide from the aqueous (Nguyen, K.P.V. et al., Invest. Ophthalmol, Vis. Sci. 29: 976-981 (1988)). 2 . Cell-Mediated Injury The cells of the human trabecular meshwork are capable of actively attacking the debris that blocks the outflow channels by both phagocytosis and endocytosis (Polanskv, J. R. et al. in: Principies and Practice of Ophthalmology, pages 226-247, W.B. Saunders and Company, Philadelphia (1994)). As used herein, phagocytosis is the capture and re-adsorption of larger cells or fragments of cellular waste. In contrast, endocytosis is the capture and readsorption of minor fragments of cellular waste, macromolecular complexes, pigment, and so on. The phagocytic / endocytic capacities of cells in the human trabecular meshwork allow them to act as a "self-cleaning filter" (Rohen, JW et al., Graefes Arch. Clin. Exper. Ophthalmol., 175: 143 (1968); Ringvold, A and collaborators, Virchows Arch, TPathol, Anat. 1, 353: 110 (1971), Shabo, AL and co-workers, Amer., J. Ophthalmol, 71:25 (1972)). Although these processes occur naturally, it is believed that phagocytosis of toxic materials released into the anterior chamber causes damage and cell loss. In the course of certain secondary glaucomas (ie, glaucoma associated with pigment dispersion), the cells of the trabecular meshwork are subjected to an excessive phagocytic and / or endocytic attack of materials that become toxic, leading to cell damage and loss. It is believed that pigment endocytosis associated with cell membrane fragments has a toxic effect on cells of the human trabecular meshwork, and this effect seems greater if the membranes have been oxidized in preliminary studies (Polansky, JR et al., In: Principies). and Practice of Ophthalmology, pages 226-247, WB Saunders and Company, Philadelphia (1994)).

B. Cytoprotective Agents A second aspect of the present invention has to do with the recognition that non-steroidal anti-inflammatory agents ("NSAI") are able to combat the effect of this injury, either due to oxidation or other causes , and, by the same, avoid or treat (ie, decrease or minimize) the loss of cells of the trabecular meshwork. These agents are capable of breaking the pathogenic processes that cause the reduced ease of outflow and the high intraocular pressure of glaucoma. These agents, therefore, can be used to treat chronic glaucoma or pigmentary glaucoma, which are induced or aggravated by the loss of cells from the trabecular meshwork. Non-steroidal anti-inflammatory agents have been used in the eye primarily to treat inflammatory conditions and pain (see, for example, U.S. Patent Nos. 4,960,799, 4,829,088, 5,110,493). This includes their application as topical agents in the eye, where they demonstrate their ability to suppress inflammatory responses and to avoid particular side effects of surgical trauma (in the pupil, avoiding surgical meiosis), fluid accumulation in the back of the eye after of cataract surgery (macular edema after surgery) and the appearance of inflammatory cells and effusion of vessels in the anterior chamber. Furthermore, it seems that the topical application of non-steroidal anti-inflammatory agents in the eye relieves some of the itching due to allergic conjunctivitis. These conditions fit with the normal and expected effects of non-steroidal anti-inflammatory agents on inflammation and pain. In view of the known mechanisms of action of non-steroidal anti-inflammatory agents to decrease the production of prostaglandin (and other eicosanoids), it is very surprising that these agents can provide a cytoprotective effect on the cells of the trabecular meshwork, and avoid cell loss It is especially surprising that a pre-treatment of the cells with these agents would prevent a subsequent injury, even if the drug is not present in the fluid that surrounds the cells at the time of injury. The concept has previously been proposed that non-steroidal anti-inflammatory agents can be used in the treatment of "inflammatory glaucoma" (ie, inflammations in the anterior part of the eye (anterior uveitis)). In this glaucoma syndrome, it is thought that the inflammatory cells of acute inflammation contribute to an elevated intraocular pressure that can become very dangerous if left untreated. It was proposed, but never proved, that this glaucoma syndrome can be treated by decreasing inflammation with non-steroidal anti-inflammatory agents. Since non-steroidal anti-inflammatory agents have not been found to have a greater effect in the treatment of inflammatory glaucoma, they are not generally used for this condition. Rather, corticosteroids are the drugs of choice to treat inflammation in patients with inflammatory glaucoma; These drugs are used together with palliative measures that help to maintain low intraocular pressure, until the inflammatory processes are controlled.

III. Preferred Agents of the Invention The preferred agents of the present invention comprise non-steroidal anti-inflammatory agents that are capable of preventing or decreasing damage to, or loss of, trabecular cells, which is caused by a variety of mechanisms, including oxidative injury to the tissues of the eye, and especially the trabecular meshwork. A class of non-steroidal anti-inflammatory agents that can be used in accordance with the methods of the present invention are the "eicosanoid inhibiting agents". Eicosanoid inhibiting agents include those compounds that inhibit prostaglandin and other eicosanoids or cyclooxygenase trajectories that are believed to affect intraocular pressure. Compounds considered within the classification of eicosanoid inhibitors include certain non-steroidal anti-inflammatory agents. The ability of a drug to suppress the activity of cyclooxygenase and the synthesis of eicosanoids in model systems does not seem to predict the observed cytoprotective effects. J. Lombardino has documented non-steroidal anti-inflammatory agents in Nonsteroidal Anti-inflammatory Drugs, Wiley-Interscience. New York, (1985). Examples of compounds of this class of anti-inflammatory drugs include, but are not limited to the following: aspirin, benoxaprofen, benzofenac, bucilloxic acid, butibufen, carprofen, cycloprofen, cinmetacin, clidanac, clopirac, diclofenac, etodolac, fenbufen, fenclofenac, fenclorac , fenoprofen, fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen, furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, isoxepac, ketoprofen, lactorolac, lonazolac, metyazinic, miroprofen, naproxen, oxaprozin, oxepinac, fenacitin, pirprofen, pirazolac, protizinic acid, sulindac, suprofeno, tiaprofénico acid, tolmetina, and zomepirac. Non-steroidal eicosanoid inhibitor compounds can be prepared in the form of pharmaceutically acceptable salts, esters and other prodrugs. The derived salts include relatively non-toxic, inorganic or organic acid addition salts, or alkaline earth metal salts of the therapeutic compounds, which can be prepared in situ during the isolation and final purification of the compounds, or by means of reacting separately the free base with a suitable organic or inorganic acid. Where the compounds include a basic functionality such as amine or alkylamine, the representative salts include hydrochloro, sulfate, acetate, maleate, lauryl sulfate, and the like. Where an acidic functionality is present, salts such as sodium, calcium, potassium, and magnesium salts can be formed. Additional examples of nonsteroidal anti-inflammatory agents include non-narcotic analgesic / nonsteroidal anti-inflammatory compounds such as (1) propionic acid derivatives, (2) acetic acid derivatives, (3) phenamic acid derivatives, (4) biphenylcarboxylic acid derivatives and (5) we oxygenate. Although some of these agents are presently used primarily as anti-inflammatory agents, and others are used primarily as analgesics, in fact all of the compounds contemplated have both analgesic and anti-inflammatory activity, and can be used at appropriate dose levels for any purpose, in different compositions. The compounds in groups (1) to (4) typically contain a carboxylic acid function; however, these acids are sometimes administered in the form of their pharmaceutically acceptable acid addition or alkali metal salts, for example, sodium salts. Propionic acid derivatives include, but are not limited to ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, thioxaprofen, suprofen, alimoprofen, thiaprofenic acid, fluprofen and bucilloxic acid. It is intended that structurally related propionic acid derivatives, which have similar analgesic and antiinflammatory properties, are also encompassed by this group. Therefore, as defined herein, the "propionic acid derivatives" are non-narcotic analgesic / non-steroidal anti-inflammatory drugs having a free -CH (CH 3) COOH or -CH 2 CH 2 COOH group (which optionally may be in the form of a pharmaceutically acceptable salt group, for example, -CH (CH 3) COO ~ Na +, typically linked directly or via a carbonyl function to a ring system, preferably to an aromatic ring system. defined herein include, but are not limited to, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, thiopinac, zidometacin, acemetacin, fentiazac, clidanac, and oxpinac. structurally related acetic acid, which have similar analgesic and anti-inflammatory properties, are also covered by this group, therefore, as defined herein, the "acetic acid derivatives" are non-narcotic analgesic / nonsteroidal anti-inflammatory drugs having a free -CH 2 COOH group (which may optionally be in the form of a pharmaceutically acceptable salt group, eg, -CH-COO ~ Na +), typically linked directly to a ring system, preferably to an aromatic or heteroaromatic ring system. The phenamic acid derivatives, as defined herein, include, but are not limited to, mefenamic acid, meclofenamic acid, flufenamic acid, nifluic acid, and tolfenamic acid. It is intended that structurally related fenamic acid derivatives, which have similar analgesic and antiinflammatory properties, are also encompassed by this group. Therefore, as defined herein, "phenamic acid derivatives" are non-narcotic analgesic / non-steroidal anti-inflammatory drugs that contain the basic structure which can carry a variety of substituents, and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, for example, -COO "NA +. The biphenylcarboxylic acid derivatives as defined herein include , but are not limited to diflunisal and flufenisal.It is also intended that structurally related biphenylcarboxylic acid derivatives having similar analgesic and antiinflammatory properties be included in this group, thus, the "biphenylcarboxylic acid derivatives" as defined by the invention. used in the present, are non-narcotic, analgesic / non-steroidal, anti-inflammatory drugs, which contain the basic structure which can carry a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, for example, -COO "NA +. Oxicams as defined herein include, but are not limit to, piroxicam, sudoxicam, isoxicam, and CP-14,304.It is also intended to include in this group the structurally related oxicams that have similar analgesic and antiinflammatory properties.A preferred member of this group is piroxicam. way, the "oxicamos" as defined in the present, are non-narcotic, analgesic / non-steroidal, anti-inflammatory drugs, which have the general formula: O 'wherein R is an aryl or heteroaryl ring system. Also included within the non-steroidal eicosanoid inhibitors, or nonsteroidal anti-inflammatory agents of the present invention, certain cyclooxygenase inhibitors are described as described in Flach, A.J., Survey Qphthalmolocry 36: 259-284 (1992). Cyclooxygenase inhibitors are nonsteroidal anti-inflammatory drugs that have been made available as eye drops for treatment or inflammation. These inhibitors can be grouped into six different classes: salicylates, fenamates, indoles, phenylalkanoic acid and pyrazolones. The specific drugs within the respective groups are summarized below.

IV. Methods of Administration The agents of the present invention can be formulated in accordance with known methods for preparing pharmaceutically acceptable compositions, by means of which these materials, or their functional derivatives, having the desired degree of purity are combined, in mixtures with a physiologically acceptable carrier, excipient, or stabilizer. These materials are not toxic to recipients at the doses and at the concentration in which they are used. A composition is said to be "pharmaceutically acceptable" if a recipient patient can tolerate its administration. An agent is physiologically significant if its presence results in a change that can be detected in the physiology of a recipient patient. Preferably, these compositions are administered topically in a vehicle of aqueous polymer solution, aqueous suspension, ointment or gel. Suitable carriers and their formulation, including other human proteins, for example, human serum albumin, are described, for example in Remington's Pharmaceutical Sciences (16th edition, Osol, A., Ed., Mack, Easton PA (1980)) . If the composition is to be soluble in water, it can be formulated in a pH regulator such as phosphate or other organic acid salt at a pH of about 7 to 8. If the solution is only partially soluble in water, it can be prepared as a microemulsion by means of formulating it with a nonionic surfactant such as Tween, Pluronics, or PEG, for example, Tween 80, in an amount of, for example, 0.04-0.05 percent (w / v), to increase its solubility. The term "water soluble" as applied to polysaccharides and polyethylene glycols is intended to include colloidal solutions and dispersions. In general, the solubility of the cellulose derivatives is determined by the degree of substitution of the ether groups, and the stabilizing derivatives useful herein should have a sufficient amount of these ether groups per anhydroglucose unit in the cellulose chain to yield the water soluble derivatives. Generally, a degree of substitution by ether of at least 0.35 ether groups per anhydroglucose unit is sufficient. Additionally, the cellulose derivatives may be in the form of alkali metal salts, for example, the salts of Li, Na, K, or Cs. Optionally, other ingredients such as antioxidants can be added, for example, ascorbic acid; polypeptides of low molecular weight (less than about ten residues), for example, polyrginine or tripeptides; proteins, such as serum albumin, gelatin, or hydrophilic polymers such as polyvinyl pyrrolidone; amino acids, such as glycine, glutamic acid, aspirin, or arginine, - monosaccharides, disaccharides and other carbohydrates including cellulose, or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; and sugar alcohols such as mannitol or sorbitol. Additional pharmaceutical methods can be used to control the duration of the action. Sustained or controlled release preparations can be achieved through the use of polymers to complex or absorb the molecule (s) of the composition. Controlled administration can be exercised by selecting the appropriate macromolecules (eg, polyesters, polyamino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, or protamine sulfate) and the concentration of macromolecules as well as incorporation methods to control the release. Sustained-release formulations can also be prepared, and include the formation of microcapsular particles and articles that can be implanted. To prepare the sustained release compositions, the composition of the molecule (s) is preferably incorporated into a biodegradable matrix or microcapsule. A suitable material for this purpose is a polylactide, although other polymers of poly- (or? -hydroxycarboxylic acids), such as poly-D - (-) 3-hydroxybutyric acid (EP 133,988A) can be used. Other biodegradable polymers include poly (lactones), poly (orthoesters), polyamino acids, hydrogels, or poly (orthocarbonates) and poly (acetals). The polymeric material may also include polyesters, poly (lactic acid) or ethylene vinyl acetate copolymers. For examples of sustained release compositions, see U.S. Patent Number 3,773,919, EP 58,481A, U.S. Patent Number 3,887,699, EP 158,277A, Canadian Patent Number 1176565, Sidman, U. , et al., Biopolymers 22: 547 (1983), and Langer, R., et al., Chem. Tech. 12:98 (1982). Alternatively, instead of incorporating the molecule (s) of the composition into the polymer particles, it is possible to entrap these materials within microcapsules prepared for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or microcapsules of gelatin and poly (methylmetacylate) microcapsules, respectively, or in colloidal drug release systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions. These techniques are described in Remington's Pharmaceutical Sciences (1980). In an alternative embodiment, the liposome formulations and methods that allow intracellular uptake of the molecule will be employed. Suitable methods are known in the art, see for example, Chicz, R.M., and co-workers (PCT Application WO 94/04557), Jaysena, S.D., and collaborators (PCT Application WO 93/12234), Yarosh, D.B. (U.S. Patent No. 5,190,762), Callahan, MV, and co-workers (U.S. Patent No. 5,270,052) and Gonzalezro, RJ (PCT Application WO 91/05771), all of which are incorporated in the present as a reference. The pharmaceutical compositions of the present invention can be sterilized, such as by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). The compositions can be stored in lyophilized form or as a liquid solution. It will be understood that the use of some of the excipients, carriers, or stabilizers mentioned above, will result in the formation of salts of the molecules. The compositions of the present invention can be applied topically as on the skin, or on the cornea. When applied topically, the molecule (s) of the composition can be properly combined with other ingredients, such as carriers and / or adjuvants. There are no limitations on the nature of these other ingredients, except that they must be pharmaceutically acceptable and effective for their proposed administration, and they can not degrade the activity of the active ingredients of the composition. Examples of suitable carriers include ointments, gels, or suspensions, with or without purified collagen. The compositions can also be impregnated in transdermal patches, and bandages, preferably in liquid or semi-liquid form. To obtain a gel formulation, the molecule (s) of the formulated composition can be mixed in a liquid composition with an effective amount of a water-soluble polysaccharide or a synthetic polymer such as polyethylene glycol, to form A gel of appropriate viscosity that would be applied topically The polysaccharide that can be used includes, for example, cellulose derivatives such as etherified cellulose derivatives, including alkyl celluloses, hydroxyalkyl celluloses, and al-quilhydroxyalkyl celluloses, for example, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; starch and fractionated starch, agar, alginic acid and alginates; gum arabic, pullulan; agarose; carragahenan, dextrans, dextrins, fructans, inulin, mannans; xylans, arabians; cytosans; glycogens, glycans, and synthetic biopolymers; as well as gums such as xanthan, guar gum; carob gum; gum arabic; tragacanth gum; and karaya gum, - and the derivatives and mixtures thereof. The preferred gelation agent herein is one that is inert to biological systems, non-toxic, easy to prepare, and not too fluid or viscous, and will not destabilize the molecule (s) sustained within it. Preferably, the polysaccharide is an etherified cellulose derivative, more preferably one that is well defined, purified, and enrolled in USP, for example, methylcellulose and the hydroxyalkyl cellulose derivatives, such as hydroxypropyl cellulose, hydroxyethyl cellulose. , and hydroxypropyl methylcellulose. The most preferred one herein is methylcellulose. The polyethylene glycol useful for gelation is typically a mixture of low and high molecular weight polyethylene glycols to obtain the proper viscosity. For example, a mixture of a polyethylene glycol of molecular weight of 400-600 with one of a molecular weight of 1500 would be effective for this purpose, when mixed in the proper ratio to obtain a paste. The compositions of the present invention may also be formulated for parenteral administration by injection, rapid infusion, nasopharyngeal absorption (intranasopharyngeal), der absorption, or orally. The compositions may be administered alternatively, intramuscularly, or intravenously. Compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate. Occlusive carriers, accessories or bandages may be used to increase tissue permeability and improve antigen absorption. Liquid dosage forms for oral administration may include a liposome solution containing the liquid dosage form. Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents that are commonly used in the art, such as purified water. In addition to the inert diluents, these compositions may also include wetting agents, emulsifying and suspending agents, or sweetening, flavoring, coloring or flavoring agents. Alternative oral formulations include an aqueous solution, aqueous suspension, elixir, tablet, or capsule. If methylcellulose is used in the gel, it preferably comprises about 2-5 percent, more preferably about 3 percent of the gel, and the molecule (s) of the composition is present in an amount of about 300- 1000 μg per milliliter of gel. The dose that will be used depends on the factors described above. As a general proposal, the molecule (s) of the composition are formulated and released to the target site or tissue at a dose that can establish a maximum dose in the tissue that is effective but not unnecessarily toxic. In the most preferred embodiment, the molecules of the invention will be provided to the cornea or the surface of the eye, and will be allowed to be absorbed through the cornea into the anterior chamber of the eye. In Zun, L.S. (Emercr. Med Clin North Amer. 6: 121 (1988)), Lee, V.H. (J. Ocular Pharmacol., 6: 157 (1990)), Ellis, P.P. (Ocular Theraoeutics and Pharmacoloay, 7th ed. Mosby, (1987)), Jannesen, H.J. (U.S. Patent Number 5,200,453), Chandrasekaran S .K. , and collaborators (PCT Application Number WO89 / 06964), and (Vaughan, D., et al., in General Ophthamology, Appleton and Lange, Norwalk, CT, pages 213-230 (1992)), describe the methods that can be used to achieve this ocular drug release. More preferably, however, this administration of the drug will be achieved by combining effective amounts of the agents of the invention with any of the sustained release ophthalmic delivery systems described by Davies, JP, and co-workers (U.S. Pat. from North America Number 5,192,535, incorporated herein by reference). These sustained-release topical ophthalmic medicament delivery systems comprise an aqueous suspension at a pH of from about 3 to about 6.5 and an osmic pressure of from about 10 to about 400 mOsM containing from about 0.1 percent to about 6.5 percent. percent by weight, based on the total weight of the suspension, of a carboxyl-containing polymer prepared by the polymerization of one or more carboxyl-containing monoethylenically unsaturated monomers and less than about 5 percent by weight of a cross-linking agent, these percentages by weight of the monomers, based on the total weight of the polymer of the monomers. Desirably, the monomer is prepared by suspension polymerization or emulsion of the monomer with the crosslinking agent at a particle size of not more than about 50 μm, preferably not more than about 30 μm, in equivalent spherical diameter. The suspension has an initial viscosity of from about 1,000 to about 30,000 centipoise (cp) and can be administered in the eye in drop form at that initial viscosity. The polymer has an average particle size of no more than about 50 μm, preferably no more than about 30 μm, in equivalent spherical diameter. In general, these polymers will vary in molecular weight which is estimated to be from about 250,000 to about 4,000,000, and preferably from about 500,000 to about 2,000,000.

Aqueous suspensions containing the polymer particles prepared by suspension or emulsion polymerization, the average particle size of which is appreciably greater than about 50 μm in equivalent spherical diameter, are less comfortable when administered in the eye than suspensions that are In another embodiment, the equivalent spherical diameters of which are, on average, below about 50 μm are identical in composition containing polymer particles. Furthermore, on the average 50 μm size, the advantage of substantially increased viscosity after administration is not realized. The slightly crosslinked suspension can be administered in drop form, after contacting the lower pH suspension with the eye tear fluid of higher pH, the suspension can be rapidly gelatinized to a suspension substantially greater than the viscosity of the suspension as it was originally administered in the form of a drop. In accordance with the above, the resulting more viscous gel can remain in the eye for a prolonged period of time so that it can release its non-steroidal anti-inflammatory agent for a prolonged period of time. A preferred drug delivery system employs a polymer that is preferably prepared from at least about 50 weight percent, more preferably at least 90 weight percent, of one or more carboxyl-containing monoethylenically unsaturated monomers. Acrylic acid is the preferred carboxyl-containing monoethylenically unsaturated monomer, but other, unsaturated, polymerizable carboxyl-containing monomers can be used, such as methacrylic acid, ethacrylic acid, β-methacrylic acid (crotonic acid), cis-a acid -methylcrotonic (angelic acid), trans-oylmethylcrotonic acid (tiglic acid), a-butylcrotonic acid, o-phenylacrylic acid, a-benzyl-acrylic acid, c-cyclohexyl acrylic acid, β-phenyl-acrylic acid ( cinnamic acid), coumaric acid (o-hydroxy cinnamic acid), p-hydroxy-coumaric acid (umbellic acid), and the like, in addition to or in place of, acrylic acid. Carbopol 976 and polycarbophil (Davis, et al., U.S. Patent No. 5,192,535) are examples of suitable polymers. These polymers are crosslinked by using a small percentage, ie, less than about 5 percent, such as from about 0.5 percent or from about 0.1 percent to about 5 percent, and preferably from about 0.2 percent to about 1 percent, based on the total weight of the monomers present, of a polyfunctional crosslinking agent. The crosslinking agents of these compositions include non-polyalkenyl difunctional polyether crosslinking monomers, such as divinyl glycol; 2,3-dihydroxyhexa-1, 5-diene; 2,5-dimethyl-1,5-hexadiene; divinyl benzene; N, N-diallylacrylamide; N, N-diallylmethacrylamide and the like. A preferred crosslinking agent is divinyl glycol. Also included are polyalkenyl polyether crosslinking agents containing two or more alkenyl ether groupings per molecule, preferably alkenyl ether groupings containing groups of H2C = C < terminal, prepared by the etherification of a polyhydric alcohol containing at least four carbon atoms and at least three hydroxyl groups with an alkenyl halide such as allyl bromide or the like, for example, polyallyl sucrose, polyallyl pentaerythritol, or the like; see, for example, Brown, U.S. Patent Number 2,798,053. Macromeric, non-hydrophilic, diolefinic surfactants having molecular weights of from about 400 to about 8,000 can also be used, such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanato-hydroxyalkyl acrylate or methacrylate reaction products. , and reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkyl methacrylates, and the like, as crosslinking agents; see, for example, Mueller et al., Patents of the United States of North America Nos. 4,192,827 and 4,136,250. In a preferred method for preparing sustained release topical ophthalmic delivery systems, suspensions prior to the desired viscosity of from 1,000 to about 30,000 centipoises were prepared and packaged for administration to the eye in drop form. In a preferred method of administration, the above suspensions, which contain the medicament, are administered in the eye to the initial viscosity in the form of a drop to cause the suspension administered, upon contact with the tear fluid of the eye of the highest pH , rapidly gelatinizes in situ at a viscosity substantially greater than the viscosity of the suspension as originally administered in drop form. The more viscous gel remains in the eye for a prolonged period of time so that it releases the drug, trapped in the more viscous gel formed in the eye, in a sustained manner. It may be desirable to replace up to about 40 weight percent of the mono-ethylenically unsaturated carboxyl-containing monomers with one or more of the monoethylenically unsaturated monomers containing no carboxyl, which contain only physiologically and ophthalmologically harmless substituents. Preferably the desired osmotic pressure is achieved by using a physiologically and ophthalmologically acceptable salt in an amount of from about 0.01 percent to about 1 weight percent, based on the total weight of the suspensions. A preferred salt is sodium chloride. Generally, the dose necessary to provide an effective amount of the composition will vary depending on factors such as the age of the recipient, condition, sex, and extent of disease, if any, and other variables, and someone skilled in the art can. adjust and determine. The effective amounts of the compositions of the invention may vary from 0.01-1,000 milligram / milliliter per dose or application, although smaller or larger amounts may be used. For ophthalmic suspensions, the effective amounts will preferably be from about 0.0001 percent to about 10 weight percent, and more preferably from about 0.01 percent to about 5 weight percent, based on the total weight of the suspension. For example, to provide cytoprotection of the trabecular meshwork of a human, and to prevent the loss of trabecular cells, the composition of an ophthalmologically effective amount of a non-steroidal cyclooxygenase inhibitor, and a pharmaceutically acceptable carrier, contains between about 0.001 percent and approximately 10 percent by weight amount of the non-steroidal cyclooxygenase inhibitor. The same compositions can be used to provide cytoprotection of the trabecular meshwork in humans in need of treatment or prevention of oxidative damage to their trabecular cells, or damage to trabecular cells by phagocytic or endocytic processes. More preferably, for any of those uses, the composition is administered to provide a concentration or inhibitor of less than about 1 x 10"M (and preferably between about 1 x 10-9 M and about 1 x 105M) in the aqueous humor of the eye. Having now generally described the invention, it will be more readily understood by reference to the following examples, which are provided by way of illustration, and of which it is not intended to be limiting of the present invention, unless otherwise specified.

EXAMPLE 1 Oxidative Stress in Human Trabecular Mesh Cells Confluent monolayers of human trabecular mesh cells were prepared using conventional methods (Polansky, J.R., and collaborators, Invest. Ophthalmol, Vis. Sci. 18: 1043 (1979); Alvarado, J.A., and collaborators, Invest. Ophthalmol. Vis. Sci. 23: 464 (1982); Polansky, J.R., et al., Proc. Int. Soc. Eve Res. 3:76 (1980); Polansky, J.R., and collaborators, in: Principies and Practice of Ophthalmology, pages 226-247, W.B. Saunders & Company, Philadelphia (1994). The monolayers were exposed to varying concentrations of hydrogen peroxide and other oxidants for their effects on the morphology and growth of the human trabecular mesh cell, after trypsinization. The morphological changes included an increase in detached cells and the appearance of dark granules in the cytoplasm if the hydrogen peroxide levels were maintained at approximately 0.3-1 mM for 1-2 hours. A shorter exposure or a decreased concentration was required to inhibit the growth of the trabecular meshwork cells. When non-steroidal anti-inflammatory agents are provided to cells that undergo oxidative damage, they were found to produce cytoprotective effects when they avoided these changes. It appears that the protective effects are relatively cell type based on comparisons between human trabecular meshwork cells, ciliary epithelium, and retinal pigment epithelial cells.

EXAMPLE 2 Effect of Peroxide on Protein Secretion by Cultivated Trabecular Mesh Cells The effect of hydrogen peroxide concentration on the ability of cultured trabecular mesh cells to secrete protein was investigated. As described in Example 1, human trabecular mesh cells were cultured. The cells were then given with aspirin, vitamin E, basic fibroblast growth factor (bFGF), ibuprofine, or tylenol (all at 10"5 M) for a period of three days, then the medium was changed and the cells were exposed at 0.3 mM hydrogen peroxide for 1 hour After a recovery period of 24 hours, the amount of secreted protein was measured by testing the extracellular radioactivity after a 2-hr 35 S-methionine incorporation. The results of this experiment showed that hydrogen peroxide has a profound inhibitory effect on the ability of human trabecular mesh cells to secrete protein.This inhibitory effect could be avoided by the presence of aspirin, vitamin E, ibuprofin or tylenol, but not by the basic fibroblast growth factor.

EXAMPLE 3 Effect of Nonsteroidal Anti-inflammatory Agents on Rb Taking by Human Trabecular Mesh Cells Under Oxidative Stress The effect of non-steroidal anti-inflammatory agents on the ability of human trabecular mesh cells exposed to oxidative damage to incorporate the Rb. Human trabecular cells were treated on both three and one days, before oxidative stress with aspirin, diclofenac, Vitamin E acetate, fenoprofen, flurbiprofen, ibuprofen, indomethacin, phenacetin, tolmetin, and acetammonifen. The solutions were prepared as 50 mM solutions in ethanol, further diluted in culture medium and added as 100X dilutions. Oxidative stress was made by rinsing first with phosphate buffered saline (PBS) and then adding phosphate buffered saline or 0.6 mM of H2 ° 2 diluted with phosphate buffered saline. The cells were then placed in an incubator covered with water. After 1 hour, the cells were changed to their normal culture medium. The next day, the culture medium was removed and replaced with RbCL (1 μCi / ml) diluted in phosphate buffered saline solution with 1 gram / liter of glucose. After incubation at 37 ° C for 20 minutes, the rubidium (Rb) solution was removed, the cells were rinsed twice with ice-cold phosphate buffered saline and then the cells were dissolved with 0. l M of NaOH. The dissolved cells were then counted using a titration counter. Table 1 gives the amount of rubidium incorporation for lμm and 10μm drug treatments.; the control had no drug. Table 1 86 provides the Rb uptake of treated cells relative to that of the control, expressed as a percentage of the control. As shown, human trabecular meshwork cells previously treated with diclofenac, fenoprofen, flurbiprofen, indomethacin and tolmetin, had essentially the ability to incorporate rubidium.

EXAMPLE Effect of Different Concentrations of Nonsteroidal Anti-inflammatory Agents on the Taking of Rb by Human Trabecular Mesh Cells Subject to Oxidative Stress The effect of anti-inflammatory or steroidal agents on the capacity of cultured trabecular mesh cells was investigated, to incorporate the Rb. Human trabecular cells were treated on both three and one days, before oxidative stress with aspirin, diclofenac, Vitamin E acetate, fenoprofen, flurbiprofen, ibuprofen, indomethacin, and acetaminophen. The solutions were prepared as 50 mM solutions in e-tanol, further diluted in culture medium and added as 100X dilutions. Oxidative stress was made by rinsing first with phosphate buffered saline (PBS) at 37 ° C and then adding phosphate buffered saline or 0.6 mM H202 diluted with phosphate buffered saline. The cells were then placed in an incubator covered with water at 37 ° C. After 1 hour, the cells were changed to their normal culture medium. The following day, the culture medium was removed and replaced with 86RbCL (lμCi / ml) diluted in phosphate buffered saline solution with 1 gram / liter of glucose. After incubation at 37 ° C for 20 minutes, the rubidium (Rb) solution was removed, the cells were rinsed twice with ice-cold phosphate buffered saline and then the cells were dissolved with 0.1 M NaOH. The dissolved cells were then counted using a titration counter. Table 2 shows the results of the experiment. Table 2 shows the 86Rb uptake of the treated cells expressed as a percentage of control cells. As shown in Table 2, the rubidium intake for the previous treatments of 1 μM of diclofenac and flurbiprofen were at essentially the same levels. However, substantial differences were found for the previous treatments with 0.1 and 0.01 μM of diclofenac and flurbiprofen. It was a particularly unexpected finding that diclofenac worked at a very low dose in the trials, suggesting that substantially lower doses of topical (and perhaps even systemic) diclofenac, as well as other non-steroidal agents, can prevent the progression of elevated intraocular pressure due to loss of and / or damage to, trabecular mesh cells.

Although the invention has been described in connection with specific embodiments thereof, it will be understood that further modifications may be made and it is intended that this application cover any variations, uses, or adaptations of the invention by following, in general, the principles of the invention. the invention and including such deviations from the present disclosure as those which come to be within the knowledge or usual practice within the art to which the invention pertains and as they may be applied to the essential features set forth hereinbefore and as follows in the scope of the appended claims.

Claims (32)

NOVELTY OF THE INVENTION Having described the above invention is considered as a novelty, and therefore, it is claimed as property contained in the following: CLAIMS

1. A method for the cytoprotection of the trabecular meshwork, which comprises administering to a human a composition that includes (a) an ophthalmologically effective amount of a non-steroidal cyclooxygenase inhibitor, and (b) a pharmaceutically acceptable carrier, to prevent loss of trabecular cells.

The method, according to claim 1, wherein the cyclooxygenase inhibitor is selected from the group consisting of salicylates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolones.

3. The method according to claim 1, wherein the non-steroidal cyclooxygenase inhibitor is selected from the group consisting of diclofenac, indomethacin, and fenoprofen.

4. The method according to claim 1, wherein the composition is administered topically in an aqueous polymer solution, an aqueous suspension, an ointment, or a gel vehicle.

5. The method according to claim 1, wherein the composition comprises between about 0.001 percent and about 10 percent by weight of the cyclooxygenase inhibitor.

The method, according to claim 6, wherein the composition comprises between about 0.001 percent and about 0.009 percent by weight of the inhibitor.

The method, according to claim 1, wherein the composition is administered to provide an inhibitor concentration of less than about 1 x 10"M in the aqueous humor of the eye 8.

The method, in accordance with the claim 7, wherein the composition is administered to provide an inhibitor concentration of between -9, -5 about 1 x 10 M and about 1 x 10 M in the aqueous humor of the eye 9.

The method, according to claim 1 , wherein the composition is administered by a method selected from the group consisting of intraocular injection, oral administration and intravenous injection 10.

The method, according to claim 10, wherein the composition is administered orally, and wherein the composition is an aqueous solution, an aqueous suspension, an elixir, a tablet, a tablet or a capsule 11.

A method for the cytoprotection of the trabecular mesh, which and comprises administering to a human a composition comprising (a) an ophthalmologically effective amount of diclofenac, and (b) a pharmaceutically acceptable carrier, including a carboxy-containing, lightly cross-linked polymer, in the form of an aqueous polymeric solution, a suspension, an ointment or a gel for topical administration, to avoid the loss of trabecular cells.

The method, according to claim 11, wherein the diclofenac is present in the formulation in an amount from about 0.001 percent to about 10 percent by weight of the composition.

The method, according to claim 12, wherein the diclofenac is present in the formulation in an amount from about 0.001 percent to about 0.009 percent by weight of the composition.

The method, according to claim 13, wherein the composition is administered in an amount sufficient to provide an ophthalmically effective amount of diclofenac, which does not exceed 1 x 10"5 M in the aqueous humor of the eye.

A method for the cytoprotection of the trabecular meshwork, which comprises administering to a human in need of treatment or prevention of oxidative damage to their trabecular cells, or of damage to trabecular cells by phagocytic or endocytic processes, a composition that includes ( a) an ophthalmologically effective amount of an anti-inflammatory cyclooxygenase inhibitor, non-steroidal, and (b) a pharmaceutically inert carrier, to prevent the loss of trabecular cells.

16. The method according to claim 15, wherein the non-steroidal antiinflammatory cyclooxygenase inhibitor is selected from the group consisting of salicylates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolones.

The method, according to claim 15, wherein the non-steroidal anti-inflammatory cyclooxygenase inhibitor is selected from the group consisting of diclofenac, indomethacin and fenoprofen.

18. The method according to claim 15, wherein the non-steroidal antiinflammatory cyclooxygenase inhibitor is diclofenac.

The method, according to claim 15, wherein the composition is topically administered in an aqueous polymer solution, an aqueous suspension, an ointment, or a gel vehicle.

The method, according to claim 15, wherein the composition comprises between about 0.001 percent and about 10 percent by weight of the eicosanoid inhibitor.

The method, according to claim 20, wherein the composition comprises between about 0.001 percent and about 0.009 percent by weight of the inhibitor.

22. The method according to claim 21, wherein the composition is administered to provide a concentration of the inhibitor of less than about 1 x 10"M in the aqueous humor of the eye

23. The method, in accordance with the claim 22, wherein the composition is administered to provide a concentration of the inhibitor of between about 1 x 10 -9 M and about 1 x 10 -5 M in the aqueous humor of the eye

24. The method, in accordance with the claim 15, wherein the composition is administered by a method selected from the group consisting of intraocular injection, oral administration and intravenous injection

25. The method, according to claim 24, wherein the composition is administered orally, and in wherein the composition is an aqueous solution, an aqueous suspension, an elixir, a tablet, a tablet or a capsule.

26. A composition for the cytoprotection of the trabecular meshwork, comprising (a) a non-sidal cyclooxygenase inhibitor of one type, and in an amount, to prevent damage or loss of trabecular cells, and (b) a pharmaceutically carrier acceptable for it.

27. The composition according to claim 26, wherein the cyclooxygenase inhibitor is diclofenac, indomethacin, or fenoprofen.

28. The composition, according to claim 27, wherein the cyclooxygenase inhibitor is diclofenac.

29. The composition, according to claim 28, wherein the diclofenac is present in an amount between 0.001 and about 0.009 weight percent.

30. The method of claim 15, wherein the human is in need of treatment or prevention of oxidative injury to their trabecular cells.

31. The method of claim 30, wherein the oxidative injury is caused by hydrogen peroxide or lipidihydroperoxide.

32. The method of claim 15, wherein the human is in need of treatment or prevention of damage to their trabecular cells by phagocytic or endocytic processes.