WO2010056710A1

WO2010056710A1 - Compositions and methods for treating eye diseases

Info

Publication number: WO2010056710A1
Application number: PCT/US2009/063981
Authority: WO
Inventors: Spyros Deftereos; Andreas Persidis
Original assignee: Biovista, Inc.
Priority date: 2008-11-11
Filing date: 2009-11-11
Publication date: 2010-05-20

Abstract

The invention described herein includes compositions and methods and uses for treating a patient with one or more inflammatory eye disorders and/or degenerative eye diseases.

Description

COMPOSITIONS AND METHODS FOR TREATING EYE DISEASES

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 USC §119(e) to U.S. Provisional Application Serial No. 61/113,372 filed on November 11, 2008 and U.S. Provisional

Application Serial No. 61/232,586 filed on August 10, 2009, the entire disclosure of each of which is incorporated herein by reference.

TECHNICAL FIELD

The invention described herein relates to the treatment of diseases of the eye. In particular, the invention described herein relates to the treatment of inflammatory eye disorders and degenerative eye diseases.

BACKGROUND AND SUMMARY OF THE INVENTION

Age-related macular degeneration (AMD) begins with characteristic yellow deposits in the macula, the central area of the retina, also called the fovea, and which provides detailed central vision. The yellow spots, also called drusen, form between the retinal pigment epithelium and the underlying choroid. The formation of drusen leads to a thinning and drying out of the macula, and the location and amount of thinning in the retina caused by the drusen reportedly correlates to the amount of central vision loss. It has been also reported that degeneration results in the pigmented layer of the retina and photoreceptors overlying drusen to become atrophic, causing a slow loss of central vision, which may occur over a decade or more. During early stages of the disease, also referred to as age-related maculopathy, most affected people still have good vision. However, in later stages of the disease, affected people with drusen may subsequently develop advanced age-related macular degeneration. Advanced AMD, which is responsible for profound vision loss, is elicited in two forms, dry- AMD and wet- AMD. The risk of advanced disease is reportedly higher when the drusen are large and numerous and associated with a disturbance in the pigmented cell layer under the macula.

Central geographic atrophy, the dry form of advanced AMD, results from atrophy of the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors, both rods and cones, in the central part of the eye. Dry AMD is atrophic or non-neovascular. It has been reported that approximately 85% to 90% of the cases of macular degeneration are dry- AMD.

Neovascular or exudative AMD, the wet form of advanced AMD, causes vision loss due to abnormal blood vessel growth in the choriocapillaries, and through Bruch's membrane. Abnormal blood vessels from the choroidal layer of the eye, known as subretinal neovascularization grow under the retina and macula. These blood vessels tend to proliferate with fibrous tissue, bleed, and then leak fluid and protein under the macula, causing the macula to bulge or move, distorting the central vision. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated. Acute vision loss occurs as transudate or hemorrhage accumulates in and beneath the retina. Permanent vision loss occurs as the outer retina becomes atrophic or replaced by fibrous tissues. In addition, it has been reported that macular degeneration may arise due to one or more defects or dysfunctions, including genetic diseases arising from defects in ATP-binding cassette (ABC) transporters, glutathione (GSH) deficiency, and/or depressed levels of GSH. Without being bound by theory, it is believed herein that such dysfunctions may contribute or lead to excessive free radical reactions, resulting in insufficient GSH.

Stargardt disease is another macular dystrophy that manifests as a recessive form of macular degeneration with an onset during childhood (see for example, Allikmets et al., Science, 277:1805-07 (1997); the foregoing publication, and each other publication cited herein, is incorporated herein by reference). Stargardt disease is characterized clinically by progressive loss of central vision and progressive atrophy of the retinal pigment epithelial (RPE) cells overlying the macula. It has been reported that mutations in the human ABCA4 gene for RmP are responsible for Stargardt disease. Early in the disease course, patients show delayed dark adaptation but otherwise normal rod function. Histologically, Stargardt disease is associated with deposition of lipofuscin pigment granules in RPE cells. Besides Stargardt disease, mutations in ABCA4 have also been reported to result in other eye diseases, such as recessive retinitis pigmentosa, recessive cone-rod dystrophy, and non-exudative age-related macular degeneration. Similar to Stargardt disease, it is believed that those diseases are associated with delayed rod dark-adaptation. Lipofuscin deposition in RPE cells is also seen in AMD, and in some cases of retinitis pigmentosa and cone-rod dystrophy.

Diabetic retinopathy is the result of microvascular retinal changes. Hyperglycemia-induced pericyte death and thickening of the basement membrane lead to incompetence of the vascular walls. These damages change the formation of the blood-retinal barrier and also make the retinal blood vessels become more permeable. Small blood vessels, such as those in the eye, have been reported to be especially vulnerable to poor blood sugar control. Thus, the over-accumulation of glucose and/or fructose common to a diabetic condition damages the tiny blood vessels in the retina. The initial stage of the disease is also called nonproliferative diabetic retinopathy (NPDR). NPDR generally elicits as cotton wool spots, microvascular abnormalities, or superficial retinal hemorrhages. During the initial stage of the disease, most people reportedly do not notice any changes in their vision. However, some develop macular edema, which occurs when the damaged blood vessels leak fluid and lipids onto the macula. The fluid makes the macula swell, and blurs vision. As the disease progresses, severe nonproliferative diabetic retinopathy enters an advanced, or proliferative, stage. In addition, the subsequent lack of oxygen in the retina causes fragile, new, blood vessels to grow along the retina and in the clear, gel-like vitreous humor that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause tractional retinal detachment. In that disease, the new blood vessels can also grow into the angle of the anterior chamber of the eye and cause neovascular glaucoma.

Currently, there are few treatment options for those suffering from inflammatory eye disorders and degenerative eye diseases, including either form of AMD, Stargardt Disease, diabetic retinopathy, and the like. Accordingly, there is a need to develop new regimens for the treatment of these eye diseases. It has been discovered herein that substituted benzisoselenazoles, and pharmaceutically acceptable salts thereof, are useful in treating inflammatory eye disorders and degenerative eye diseases, including but not limited to age-related macular degeneration, Stargardt disease, diabetic retinopathy, and the like. In one embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, and pharmaceutically acceptable salts thereof, such as ebselen, and analogs and derivatives thereof, and pharmaceutically acceptable salts of the foregoing.

It is to be understood that as used herein, the term "benzisoselenazole" refers to a core ring structure that is optionally substituted with other functional groups, including but not limited to, halo, amino, hydroxyl, oxo, thio, thiono, nitro, and cyano, and alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, arylheteroalkyl, heteroarylalkyl, and heteroarylheteroalkyl, each of which is optionally substituted. It is also to be understood that benzisoselenazoles include any and all hydrates, or other solvates of the parent compound. It is also to be understood that benzisoselenazoles include prodrug derivatives of each of the foregoing. It is also to be understood that the benzisoselenazoles described herein may be amorphous as well as in any and all morphological forms.

It has also been discovered herein that adenosine reuptake inhibitors, and pharmaceutically acceptable salts thereof, are useful in treating inflammatory eye disorders and degenerative eye diseases, including but not limited to age-related macular degeneration, Stargardt disease, and the like. It has also been discovered herein that inhibitors of adenosine deaminase, an enzyme that converts adenosine into inosine, and pharmaceutically acceptable salts thereof, are useful in treating inflammatory eye disorders and degenerative eye diseases, including but not limited to age-related macular degeneration, Stargardt disease, and the like. In one embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more adenosine reuptake inhibitors and/or adenosine deaminase inhibitors, such as substituted amino pyrimidopyrimidines, and pharmaceutically acceptable salts thereof. In another embodiment, the pharmaceutical compositions and methods include therapeutically effective amounts of one or more optionally substituted tetraamino pyrimido[5,4-d]pyrimidines, and pharmaceutically acceptable salts thereof. In another embodiment, the pharmaceutical compositions and methods include a therapeutically effective amount of dipyridamole (persantine), or an analog or derivative thereof, including pharmaceutically acceptable salts of the foregoing.

It is to be understood that as used herein, the term "amino pyrimidopyrimidine" refers to a core ring structure that is optionally substituted with other functional groups, including but not limited to, halo, amino, hydroxyl, oxo, thio, thiono, nitro, and cyano, and alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, arylheteroalkyl, heteroarylalkyl, and heteroarylheteroalkyl, each of which is optionally substituted. It is also to be understood that amino pyrimidopyrimidines include any and all hydrates, or other solvates of the parent compounds. It is also to be understood that amino pyrimidopyrimidines include prodrug derivatives of each of the foregoing. It is also to be understood that the amino pyrimidopyrimidines described herein may be amorphous as well as in any and all morphological forms.

It has also been discovered herein that one or more substituted benzisoselenazoles, including ebselen, and analogs and derivatives thereof, and pharmaceutically acceptable salts of the foregoing, administered in combination with one or more adenosine reuptake inhibitors, and pharmaceutically acceptable salts thereof, and/or one or more inhibitors of adenosine deaminase, and pharmaceutically acceptable salts thereof, are useful in treating inflammatory eye disorders and degenerative eye diseases. In one embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more adenosine reuptake inhibitors or inhibitors of adenosine deaminase, such as substituted amino pyrimidopyrimidines, including dipyridamole, or pharmaceutically acceptable salts thereof. In another embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more adenosine mimics. In another embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or a pharmaceutically acceptable salt thereof, in combination with one or more histone deacetylases (HDAC) inhibitors. In another embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more anti- VEGF compounds. In another embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more anti- TNF compounds. In another embodiment, pharmaceutical compositions and methods are described herein for treating inflammatory eye disorders and degenerative eye diseases that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more HMG-CoA reductase inhibitors.

It is to be understood that combinations of the foregoing cotherapies are also described herein, including but not limited to pharmaceutical compositions and methods that include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, and/or one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as substituted amino pyrimidopyrimidines including dipyridamole, or pharmaceutically acceptable salts thereof, and/or one or more HDAC inhibitors, and/or one or more anti-VEGF compounds, and/or one or more anti-TNF compounds, and/or one or more HMG-CoA reductase inhibitors.

In another embodiment, compounds and compositions are described herein for use in the manufacture of a medicament for treating an inflammatory eye disorder, a degenerative eye disease, or a combination thereof. In one embodiment, the medicaments include therapeutically effective amounts of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof. In another embodiment, the medicaments include therapeutically effective amounts of one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as substituted amino pyrimidopyrimidines including dipyridamole, or pharmaceutically acceptable salts thereof. In another embodiment, the medicaments include therapeutically effective amounts of one or more substituted benzisoselenazoles, and one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics. In another embodiment, the medicaments include therapeutically effective amounts of one or more substituted benzisoselenazoles, and/or one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, and/or one or more HDAC inhibitors, and/or one or more anti-VEGF compounds, and/or one or more anti-TNF compounds, and/or one or more HMG-CoA reductase inhibitors.

DETAILED DESCRIPTION

In one embodiment, methods for treating inflammatory eye disorders and degenerative eye diseases, and combinations thereof, are described herein. In one embodiment, the methods described herein include the step of administering a therapeutically effective amount of one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof to a patient in need of relief from or suffering from one or more inflammatory eye disorders, degenerative eye diseases, and/or combinations thereof.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering a therapeutically effective amount of one or more compounds of formula (I)

and/or pharmaceutically acceptable salts thereof, wherein R^A is independently selected in each instance and represents hydrogen, or one or more aryl substituents; and Q is oxygen or sulfur. In one variation, each R^A is hydrogen. In another variation, Q is oxygen. In another variation, each R^A is hydrogen, and Q is oxygen.

In another embodiment, R^A represents 1-3 substituents each independently selected from a radical -(CH₂)_mZ, where m is an integer from 0-6 and Z is selected from halogen, hydroxy, alkanoyloxy, including C₁-C₆ alkanoyloxy, optionally substituted aroyloxy, alkyl, including C₁-C₆ alkyl, alkoxy, including C₁-C₆ alkoxy, cycloalkyl, including C₃-Cs cycloalkyl, cycloalkoxy, including C₃-Cs cycloalkoxy, alkenyl, including C₂-C₆ alkenyl, alkynyl, including C₂-C₆ alkynyl, haloalkyl, including C₁-C₆ haloalkyl, haloalkoxy, including C₁-C₆ haloalkoxy, halocycloalkyl, including C₃-Cg halocycloalkyl, halocycloalkoxy, including C₃-Cg halocycloalkoxy, amino, C₁-C₆ alkylamino, (C₁-C₆ alkyl)(Ci-C₆ alkyl)amino, alkylcarbonylamino, N-(C₁-C₆ alkyl)alkylcarbonylamino, aminoalkyl, C₁-C₆ alkylaminoalkyl, (C₁-C₆ alkyl)(Ci-C6 alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(C₁-C₆ alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or Z is selected from -CO₂R⁴ and -CONR⁵R⁶, where R⁴, R⁵, and R⁶ are each independently selected in each occurrence from hydrogen, C₁-C₆ alkyl, and aryl-Ci-C₆ alkyl.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering a therapeutically effective amount of ebselen (also referred to as PZ 51 or DR3305), or an analog or derivative thereof, or a pharmaceutically acceptable salt of the foregoing.

Illustrative analogs and derivatives of ebselen are described in H. Sies, Free Rad. Biol. Med., (1993), 14, 313-323), which also describes an illustrative synthesis of ebselen and analogs and derivatives thereof, homologs of ebselen, such as 2H-3,4-dihydro-l,2- benzoselenazin-3-ones, as described by Pierre V. Jacquemin et al. in Tetrahedron Letters, (1992), Vol. 33, No. 27, 3863-3866, organoselenium derivatives thereof as described by I. A. Cotgreave et al., Biochem. Pharmacol, (1992), 43, 793-802 and C. M. Andersson et al., Free Rad. Biol. Med., (1994), 16, 17-28 and S. R. Wilson et al., J. Am. Chem. Soc, (1989), 111, 5936-5939 and V. Galet et al., J. Med. Chem., (1994), 37, 2903-2911), benzisoselenazoline and benzisoselenazine analogs thereof as described in WO-A-95/27706, and derivatives of ebselen as described by A. Wendel et al.; Biochem. Pharmacol; (1984); 33; 3241-3245 and S. D. Mercurio and G. F. Combs; Biochem. Pharmacol; (1986); 35; 4505-4509. Each of the foregoing publications is incorporated herein by reference.

Compounds of formula (I), including ebselen, may be prepared according to US Patent No. 5,008,394, the disclosure of which is incorporated herein by reference. Additional compounds of formula (I) may be prepared by routine modification of the processes described herein and in the publications incorporated herein, and by using conventional synthetic techniques.

In another embodiment, pharmaceutical compositions are described herein that include therapeutically effective amounts of one or more of the foregoing compounds, including the compounds of formula (I), and the pharmaceutically acceptable salts of any of the foregoing. In one variation, the pharmaceutical compositions and/or medicaments described herein include one or more pharmaceutically acceptable carriers, diluents, and/or excipients, and combinations thereof.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering a therapeutically effective amount of one or more adenosine mimics and/or one or more adenosine reuptake inhibitors. In another embodiment, the one or more adenosine mimics and/or one or more adenosine reuptake inhibitors include amino pyrimidopyrimidines, and pharmaceutically acceptable salts thereof. In another embodiment, the one or more adenosine mimics and/or one or more adenosine reuptake inhibitors include optionally substituted tetraamino pyrimido[5,4- d]pyrimidines, and pharmaceutically acceptable salts thereof.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering a therapeutically effective amount of one or more compounds of formula (II)

and/or pharmaceutically acceptable salts thereof, wherein

Z¹ and Z² are independently selected in each instance from NR₂, OR, (CH₂)_n- SO₂R, and (CH₂)_n-Pθ₃R₂; where R is independently selected in each instance from hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, and the like; or, when any of Z¹ and/or Z² is NR₂, then R and R are independently taken together with the attached nitrogen to form an optionally substituted independently selected heterocycle; and n is an integer between 0 and 4. In another embodiment, at least one Z¹ or Z² is NR₂.

In another embodiment, each of Z² is a nitrogen containing heterocyclyl attached at nitrogen. In another embodiment, each of Z² is an optionally substituted piperidin-1-yl. In another embodiment, each of Z² is an optionally substituted benzylamino. In another embodiment, each of Z¹ is a bis (optionally substituted alkyl)amino. In another embodiment, each of Z¹ is a bis(hydroxyalkyl)amino. In another embodiment, each of Z¹ is a bis(alkoxyalkyl)amino. In another embodiment, each of Z¹ is an alkoxyalkyloxy. In another embodiment, each of Z¹ is a heterocyclylalkyloxy. Illustrative analogs and derivatives, and pharmaceutically acceptable salts thereof, of dipyridamole include, but are not limited to, dipyridamole monoacetate, mopidamole, and salts thereof, NU3026 (2,6-bis(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy-4,8- bispiperidinopyrimido[5,4-d]pyrimidine), NU3059 (2,6-bis(2,3-dimethyoxypropoxy)-4,8- bispiperidinopyrimido[5,4-d]pyrimidine), NU3060 (2,6-bis[N,N-bis(2-methoxyethyl)amino]- 4,8-bispiperidinopyrimido[5,4-d]pyrimidine), NU3076 (2,6-bis(diethanolamino)-4,8-bis(4- methoxybenzylamino)pyrimido[5,4-d]pyrimidine), R-E 244 (l -( (2,7-bis{2-methy[-4- morpholinyi)- (>^■■ phenyl- 4-pteridinylV24iydrGxyethyl )amino)-2--propanori. and pharmaceutically acceptable salts of any of the foregoing, arid the like.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering a therapeutically effective amount of a compound of formula (III)

and/or a pharmaceutically acceptable salt thereof, including but not limited to acetate and monoacetate salts.

Compounds of formulae (II) and (III), including dipyridamole, may be prepared by conventional processes, and by the processes described in U.S. Pat. No. 3,031,450 and GB 1,051,218, the disclosures of which are incorporated herein by reference.

In another embodiment, pharmaceutical compositions are described herein that include therapeutically effective amounts of one or more of the foregoing compounds, including the compounds of formulae (II) and/or (III), and the pharmaceutically acceptable salts of any of the foregoing. In one variation, the pharmaceutical compositions and/or medicaments described herein include one or more pharmaceutically acceptable carriers, diluents, and/or excipients, and combinations thereof.

As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched. It is to be understood that alkyl is advantageously of limited length, including C₁-C₂₄, C₁-C₁₂, C₁-Cg, C₁-C₆, and C₁-C₄. It is appreciated herein that shorter alkyl groups add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior. As used herein, the term "cycloalkyl" includes a chain of carbon atoms, which is optionally branched, and where at least a portion of the chain in cyclic. It is to be understood that chain forming cycloalkyl is advantageously of limited length, including C₃- C₂₄, C₃-C₁₂, C₃-Cg, C₃-C₆, and C₃-C₄. It is appreciated herein that shorter alkyl groups add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior. As used herein, the term "heteroalkyl" includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium. As used herein, the term "heterocyclyl" including heterocycle includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched, where at least a portion of the chain is cyclic. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium. Illustrative heteocycles include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic and aromatic heterocyclic groups, each of which may be optionally substituted. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups, each of which may be optionally substituted. Illustrative carbocyclic aromatic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. Illustrative heterocyclic aromatic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.

As used herein, the term "amino" includes the group NH₂, alkylamino, and dialkylamino, where the two alkyl groups in dialkylamino may be the same or different, i.e. alkylalkylamino. Illustratively, amino includes methylamino, ethylamino, dimethylamino, methylethylamino, and the like. In addition, it is to be understood that when amino modifies or is modified by another term, such as aminoalkyl, or acylamino, the above variations of the term amino are included therein. Illustratively, aminoalkyl includes H₂N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl, and the like. Illustratively, acylamino includes acylmethylamino, acylethylamino, and the like. As used herein, the term "optionally substituted amino" includes derivatives of amino as described herein, such as, but not limited to, acylamino, urea, and carbamate, and the like.

The term "optionally substituted" as used herein includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.

The term "optionally substituted aryl" as used herein includes the replacement of hydrogen atoms with other functional groups on the aryl that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.

Illustrative substituents include, but are not limited to, a radical -(CH₂)_mZ, where m is an integer from 0-6 and Z is selected from halogen, hydroxy, alkanoyloxy, including C₁-C₆ alkanoyloxy, optionally substituted aroyloxy, alkyl, including C₁-C₆ alkyl, alkoxy, including C₁- C₆ alkoxy, cycloalkyl, including C₃-Cg cycloalkyl, cycloalkoxy, including C₃-Cg cycloalkoxy, alkenyl, including C₂-C₆ alkenyl, alkynyl, including C₂-C₆ alkynyl, haloalkyl, including C₁-C₆ haloalkyl, haloalkoxy, including C₁-C₆ haloalkoxy, halocycloalkyl, including C₃-Cg halocycloalkyl, halocycloalkoxy, including C₃-Cg halocycloalkoxy, amino, C₁-C₆ alkylamino, (C₁-C₆ alkyl)(Ci-C₆ alkyl)amino, alkylcarbonylamino, N-(C₁-C₆ alkyl)alkylcarbonylamino, aminoalkyl, C₁-C₆ alkylaminoalkyl, (C₁-C₆ alkyl)(Ci-C₆ alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(C₁-C₆ alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or Z is selected from -CO₂R⁴ and -CONR⁵R⁶, where R⁴, R⁵, and R⁶ are each independently selected in each occurrence from hydrogen, C₁-C₆ alkyl, and aryl-Ci-C₆ alkyl. The term "prodrug" as used herein generally refers to any compound that when administered to a biological system generates a biologically active compound as a result of one or more spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination thereof. In vivo, the prodrug is typically acted upon by an enzyme (such as esterases, amidases, phosphatases, and the like), simple biological chemistry, or other process in vivo to liberate or regenerate the more pharmacologically active drug. This activation may occur through the action of an endogenous host enzyme or a non- endogenous enzyme that is administered to the host preceding, following, or during administration of the prodrug. Additional details of prodrug use are described in U.S. Pat. No. 5,627,165; and Pathalk et al., Enzymic protecting group techniques in organic synthesis, Stereosel. Biocatal. 775-797 (2000). It is appreciated that the prodrug is advantageously converted to the original drug as soon as the goal, such as targeted delivery, safety, stability, and the like is achieved, followed by the subsequent rapid elimination of the released remains of the group forming the prodrug.

Prodrugs may be prepared from the compounds described herein by attaching groups that ultimately cleave in vivo to one or more functional groups present on the compound, such as -OH-, -SH, -CO₂H, -NR₂. Illustrative prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Illustrative esters, also referred to as active esters, include but are not limited to 1-indanyl, N-oxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, β-acetoxyethyl, β-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, (1 -aminoethyl)carbonyloxymethyl, and the like; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl, β-ethoxycarbonyloxyethyl, and the like; dialkylaminoalkyl groups, including di-lower alkylamino alkyl groups, such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl) pent-2-enyl, 2-(ethoxycarbonyl)but-2-enyl, and the like; and lactone groups such as phthalidyl, dimethoxyphthalidyl, and the like.

Further illustrative prodrugs contain a chemical moiety, such as an amide or phosphorus group functioning to increase solubility and/or stability of the compounds described herein. Further illustrative prodrugs for amino groups include, but are not limited to, (C₃- C₂o)alkanoyl; halo-(C₃-C₂o)alkanoyl; (C₃-C₂o)alkenoyl; (C₄-C₇)cycloalkanoyl; (C₃-C₆)- cycloalkyl(C₂-Ci₆)alkanoyl; optionally substituted aroyl, such as unsubstituted aroyl or aroyl substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (CrQ^alkyl and (CrC^alkoxy, each of which is optionally further substituted with one or more of 1 to 3 halogen atoms; optionally substituted aryl(C₂- Ci₆)alkanoyl, such as the aryl radical being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen,

each of which is optionally further substituted with 1 to 3 halogen atoms; and optionally substituted heteroarylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl moiety and 2 to 10 carbon atoms in the alkanoyl moiety, such as the heteroaryl radical being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (CrQ^alkyl, and (Ci-C₃)alkoxy, each of which is optionally further substituted with 1 to 3 halogen atoms. The groups illustrated are exemplary, not exhaustive, and may be prepared by conventional processes.

It is understood that the prodrugs themselves may not possess significant biological activity, but instead undergo one or more spontaneous chemical reaction(s), enzyme- catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination thereof after administration in vivo to produce the compound described herein that is biologically active or is a precursor of the biologically active compound. However, it is appreciated that in some cases, the prodrug is biologically active. It is also appreciated that prodrugs may often serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half- life, and the like. Prodrugs also refer to derivatives of the compounds described herein that include groups that simply mask undesirable drug properties or improve drug delivery. For example, one or more compounds described herein may exhibit an undesirable property that is advantageously blocked or minimized may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug application, such as low oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, pain at injection site, and the like), and others. It is appreciated herein that a prodrug, or other strategy using reversible derivatives, can be useful in the optimization of the clinical application of a drug.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering a therapeutically effective amount of one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts thereof.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more HDAC inhibitors. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more inhibitors of vascular endothelial growth factor (VEGF) expression, also referred to as anti-VEGF compounds. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more inhibitors of tumor necrosis factor (TNF) expression, also referred to as anti-TNF compounds. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more HMG-CoA reductase inhibitors, also referred to as statins.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts thereof, in combination with one or more HDAC inhibitors. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts thereof, in combination with one or more anti-VEGF compounds. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts thereof, in combination with one or more anti-TNF compounds. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts thereof, in combination with one or more HMG-CoA reductase inhibitors, also referred to as statins.

In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts of any of the foregoing, in combination with one or more HDAC inhibitors. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts of any of the foregoing, in combination with one or more anti-VEGF compounds. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts of any of the foregoing, in combination with one or more anti-TNF compounds. In another embodiment, the methods described herein for treating inflammatory eye disorders and degenerative eye diseases, include the step of administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, and/or inhibitors of adenosine deaminase, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, or pharmaceutically acceptable salts of any of the foregoing, in combination with one or more HMG-CoA reductase inhibitors, also referred to as statins. Illustrative HDAC inhibitors include, but are not limited to, valproic acid, vorinostat, romidepsin, and pharmaceutically acceptable salts of the foregoing, and the like.

Illustrative anti-VEGF and anti-TNF compounds include, but are not limited to, compounds found in Tripterygium spp., Tripterygium wilfordii, Trypterigium hypoglaucum, Tripterygium regeli, and/or lei gong teng vine, such as but not limited to, triptolide, tripdiolide, triptolidenol, tripchlorolide, 16-hydroxytriplide, T7/19, and the like. In another embodiment, one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof, such as ebselen, are co-administered with one or more HMG-CoA reductase inhibitors or statins. Other combinations of compounds described herein should also be understood to be described herein. In another embodiment, pharmaceutical compositions are described herein that include therapeutically effective amounts of one or more of the foregoing compounds, including the compounds of formulae (I), (II), and (III), and the pharmaceutically acceptable salts of any of the foregoing, adapted for the combination administration or co-therapy as described herein. As used herein, the term "composition" including pharmaceutical compositions generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of or any combination of the various morphological forms and/or solvate or hydrate forms of the compounds described herein. Illustratively, compositions may include one or more carriers, diluents, and/or excipients. The compounds described herein may be formulated in a therapeutically effective amount in conventional dosage forms for the methods described herein, including one or more carriers, diluents, and/or excipients therefor. Such formulation compositions may be administered by a wide variety of conventional routes for the methods described herein in a wide variety of dosage formats, utilizing art-recognized products. See generally, Remington's Pharmaceutical Sciences, (16th ed. 1980).

As used herein, the term "therapeutically effective amount" generally refers to an amount of each component, or the aggregate of multiple components when a co- administration method is used, sufficient to elicit a positive response in a patient in need of relief from an eye disease described herein. That response may include alleviating the symptoms of the disease, stopping the progression of the disease, and in some cases reversing the damage already caused by the disease. It is understood that such reversal of damage may be more easily accomplished when the disease is treated in an earlier stage of disease progression, and accordingly the corresponding therapeutically effective amount might be lower than in the case where the disease is in a later stage. In addition, it is understood herein that when one or more substituted benzisoselenazoles such as ebselen are co-administered with one or more additional component compounds described herein, that the therapeutically effective amount of the benzisoselenazoles, and the therapeutically effective amount of the other components may be lower than would be required in a method where fewer compounds are co-administered, or where a single compound is administered. Alternatively, it is also understood herein that when one or more substituted benzisoselenazoles such as ebselen are co-administered with one or more additional component compounds described herein, that the therapeutically effective amount of the benzisoselenazoles, and the therapeutically effective amount of the other components may be higher than would be tolerated in a method where fewer compounds are coadministered, or where a single compound is administered. For example, embodiments that include co-administration of dipyridamole, the latter may be administered at a lower amount than desirable for optimum efficacy due to the other unwanted NO synthase activity of the dipyridamole. However, when dipyridamole is co-administered with one or more substituted benzisoselenazoles, which as described herein may decrease the amount of NO formed during treatment with dipyridamole, a correspondingly higher amount of dipyridamole may be tolerated, and correspond to the therapeutically effective amount. Similarly, HDAC inhibitors may be administered at a lower amount than desirable for optimum efficacy due to the other unwanted ROS production activity of HDAC inhibitors. However, when one or more HDAC inhibitors is co-administered with one or more substituted benzisoselenazoles, which as described herein may decrease the amount of ROS produced during treatment, a correspondingly higher amount of HDAC inhibitors may be tolerated, and correspond to the therapeutically effective amount.

It is further understood that the therapeutically effective amount of any single component, or aggregate of components, may vary depending upon the manner of administration, and/or the age, body weight, and/or general health of the patient. Ultimately, it is to be understood that the attending physician or veterinarian will decide the appropriate amounts and dosage regimens, and accordingly, such amounts are also referred to as therapeutically effective amounts. As used herein, the term "treating" including with reference to the diseases described herein, such as inflammatory eye disorders and degenerative eye diseases, generally refers to alleviating the symptoms of the disease, stopping the progression of the disease, and in some cases reversing the damage already caused by the disease. It is to be understood that such reversal of damage may be more easily accomplished when the disease is treated in an earlier stage of disease progression. As used herein, the term patient refers to any animal, including warm-blooded vertebrates, humans, and the like.

In another embodiment, inflammatory eye disorders and degenerative eye diseases treatable using the methods and compositions described herein include, but are not limited to dry forms of AMD, such as geographic atrophy, macular dystrophy, and the like. In another embodiment, disorders and diseases treatable using the methods described herein include wet forms of AMD, such as neovascular or exudative AMD. In another embodiment, disorders and diseases treatable using the methods described herein include presumed ocular histoplasmosis syndrome (POHS), diseases caused by abnormal choroidal neovascularisation, such as proliferative vitreoretinopathy, and the like, diseases caused by abnormal vascular endothelial growth factor (VEGF) secretion, such as abnormally high VEGF secretion, angioid streaks, inflammatory eye conditions, such as uveitis, choroiditis, iritis, iridocyclitis, optic neuritis, and the like, and diseases that may include contribution of oxidative stress in their pathology, such as primary open-angle glaucoma, retinitis pigmentosa, Stargardt disease (see for example, Schutt F, Bergmann M, HoIz FG, Kopitz J. Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3663-8), angioproliferative eye- diseases that include an oxidative component, and the like. In another embodiment, disorders and diseases treatable using the methods described herein include diabetic retinopathy.

In another embodiment, methods and pharmaceutical compositions are described herein for treating dry forms of AMD, where the methods include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof. In another embodiment, methods and pharmaceutical compositions are described herein for treating wet forms of AMD, where the methods include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof. In another embodiment, methods and pharmaceutical compositions are described herein for treating diabetic retinopathy, where the methods include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof.

In another embodiment, methods and pharmaceutical compositions are described herein for treating dry forms of AMD, where the methods include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or a pharmaceutically acceptable salt thereof. In another embodiment, methods and pharmaceutical compositions are described herein for treating wet forms of AMD, where the methods include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or a pharmaceutically acceptable salt thereof. In another embodiment, methods and pharmaceutical compositions are described herein for treating diabetic retinopathy, where the methods include the step of administering one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof, in combination with one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or a pharmaceutically acceptable salt thereof. In another embodiment, methods and pharmaceutical compositions are described herein for treating dry forms of AMD, where the methods include the step of administering one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or a pharmaceutically acceptable salt thereof. In another embodiment, methods and pharmaceutical compositions are described herein for treating wet forms of AMD, where the methods include the step of administering one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or a pharmaceutically acceptable salt thereof.

In another embodiment, when a therapeutically effective amount of one or more substituted benzisoselenazoles, such as ebselen, is not included in the method or pharmaceutical composition, the methods and compositions described herein do not include treatments for diabetic retinopathy.

In another embodiment, when a therapeutically effective amount of one or more adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole, is not co-administered in the method with another compound, such as one or more substituted benzisoselenazoles, the methods described herein do not include treatments for diabetic retinopathy.

Without being bound by theory, it is believed herein that one mechanism by which substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof, may be useful in treating the eye diseases described herein includes glutathione- peroxidase (Gpx) mimetic activity. It is believed herein that substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof, may mimic Gpx and exhibit antioxidant properties and lead to overall reduction of hydroperoxides. It is further believed that hydroperoxides may be part of the pathogenesis of one or more of the inflammatory eye disorders and/or degenerative eye diseases, such as AMD, treatable with the methods and compositions described herein. Without being bound by theory, it is also believed herein that another primary mechanism by which substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof, may be useful in treating the eye diseases described herein includes ameliorating mitochondrial dysfunction. It is believed herein that mitochondrial dysfunction may be part of the pathogenesis of one or more of the inflammatory eye disorders and/or degenerative eye diseases, such as AMD, treatable with the methods and compositions described herein.

Without being bound by theory, it is also believed herein that another mechanism by which substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof, may be useful in treating the eye diseases described herein includes interfering with cytokines, such as IL8, and the like. It has been reported that the IL8-251A allele of the IL8 promoter gene polymorphism was more prevalent in AMD patients than controls, and that the pro-inflammatory homozygous IL8-251AA genotype may be an important risk factor for AMD, having implications for future therapy with biological agents that could target this cytokine (Goverdhan et al., Br J Ophthalmol. 2008 Apr;92(4):448-50.) Without being bound by theory, it is also believed herein that anotehr mechanism by which substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof, may be useful in treating the eye diseases described herein is by providing an alternative path for Gpx-like reactions, by accommodating for depressed levels of GSH that may lead to or worsen the eye diseases described herein.

Without being bound by theory, it is also suggested herein that another mechanism by which substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof may be useful in treating the eye diseases described herein is via mitochondrial protection. Mitochondrial protection is believed herein to be involved in for example AMD, and in particular dry AMD. Without being bound by theory, it is also believed herein that another mechanism by which substituted benzisoselenazoles, such as ebselen, and pharmaceutically acceptable salts thereof may be useful in treating the eye diseases described herein is by mimicking selenium-dependent glutathione-peroxidase (Se-GPx) activity and thereby inducing a protection of the membranes against lipid peroxidation. In addition, it is also suggested herein that the substituted benzisoselenazoles may mitigate the induction of an oxidant stress in certain signaling pathways. Such signaling pathways may be evaluated in vitro and in vivo such as by monitoring pericyte apoptosis induced by AGE-methylglyoxal, and like assays. These mechanisms of action are believed herein to be involved in choroidal neovascularization, such as is observed in AMD, and in particular wet AMD. Without being bound by theory, it is also believed herein that increasing extracellular concentrations of adenosine, and/or decreasing levels of adenosine in cells such as platelets, red blood cells and/or endothelial cells is useful in treating inflammatory eye disorders and degenerative eye diseases, including but not limited to age-related macular degeneration. Dipyridamole has been reported to inhibit the enzyme adenosine deaminase which normally breaks down adenosine into inosine. This inhibition leads to further increased levels of extracellular adenosine, inhibits the enzyme phosphodiesterase- 5 (PDE 5) which normally breaks down cGMP, inhibits formation of pro-inflammatory cytokines (MCP-I, MMP-9) in vitro and results in reduction of CRP in patients (see generally, Weyrich et al., Dipyridamole selectively inhibits inflammatory gene expression in platelet- monocyte aggregates. Circulation. 2005 Feb 8; 111 (5):633-42. Epub 2005 Jan 24; Zhao et al., Effect of aspirin, clopidogrel and dipyridamole on soluble markers of vascular function in normal volunteers and patients with prior ischaemic stroke. Platelets. 2006 Mar; 17(2): 100-4) and inhibits proliferation of smooth muscle cells (see generally, Liem et al., Action of dipyridamole and warfarin on growth of human endothelial cells cultured in serum-free media. Clin Biochem. 2001 Mar;34(2): 141-7; Zhuplatov et al., Mechanism of dipyridamole's action in inhibition of venous and arterial smooth muscle cell proliferation.Basic Clin Pharmacol Toxicol. 2006 Dec;99(6):431-9). Adenosine reportedly interacts with the adenosine receptors to cause increased cAMP via adenylate cyclase cAMP, which is believed to impair platelet aggregation and also cause arteriolar smooth muscle relaxation. (Dipyridamole inhibits PDGF-stimulated human peritoneal mesothelial cell proliferation, Kidney Int 60:872-81 (2001); Dipyridamole inhibits human mesangial cell proliferation, Nephron 78:172-8 (1998); mRNA expression of proto- oncogenes and platelet-derived growth factor in proliferative vitreoretinal diseases, Jpn J Ophthalmol 44:308-11 (2000); Role of growth factors and the wound healing response in age- related macular degeneration, Graefes Arch Clin Exp Ophthalmol. 242(l):91-101 (2004); Dipyridamole inhibits PDGF- and bFGF-induced vascular smooth muscle cell proliferation Kidney Int 52:1671-7 (1997); Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates, Circulation 111:633-42 (2005)).

It is further believed herein that these and other mechanisms of adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, including substituted amino pyrimidopyrimidines such as dipyridamole, may inhibit angiogenesis and/or reduce neuroinflammation and therefore are useful in treating the eye diseases described herein.

Without being bound by theory, it is also believed herein that substituted amino pyrimidopyrimidines, such as dipyridamole, may inhibit VEGF expression, and are therefore anti- VEGF compounds (Experimental retinopathy of prematurity: angiostatic inhibition by nimodipine, ginkgo-biloba, and dipyridamole, and response to different growth factors, Eur J Ophthalmol 10:51-9 (Jan-Mar 2000)). Without being bound by theory, it is also believed herein that substituted amino pyrimidopyrimidines, such as dipyridamole, may act as a superoxide scavenger and accordingly has anti- oxidative effects (Dipyridamole, cerebrovascular disease, and the vasculature, Vascul Pharmacol. (Feb 2008)). Those and other mechanisms of action and activity of substituted amino pyrimidopyrimidines, such as dipyridamole, are believed herein to be useful in treating eye diseases. Additional mechanisms of action and activity of dipyridamole that have being reported are believed herein to add to the utility of substituted amino pyrimidopyrimidines in treating patients suffering from eye diseases, such as age-related macular degeneration or diabetic retinopathy, and include inhibition of thromboxane synthase resulting in lowering the levels of TXA2 and slowing or stopping the effects of TXA2 mediated platelet aggregation, bronchioconstriction, vasoconstriction, and angiogenesis (Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents, J Pharmacol Exp Ther. 318(3):1057-67 (2006); Weber et al., Relationship between vessel wall 13-HODE synthesis and vessel wall thrombogenicity following injury: influence of salicylate and dipyridamole treatment, Thromb Res. l;57(3):383-92 (1990)); inhibition of phosphodiesterase enzymes that break down cAMP, increasing cellular cAMP levels and blocking the platelet response to ADP, and/or that break down cGMP. It is appreciated herein that co-administration with NO modulators and/or statins may be advantageous.

Without being bound by theory, it is also believed herein that inhibition of NO synthase by substituted benzisoselenazoles, such as ebselen, or a pharmaceutically acceptable salt thereof, is useful in treating inflammatory eye disorders and degenerative eye diseases, including but not limited to age-related macular degeneration. Without being bound by theory, and in relation to the co-administration of substituted benzisoselenazoles with adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole, it is believed herein that another mechanism by which such a co-therapy may be useful in treating the eye diseases described herein is by inhibition of NO synthase. Dipyridamole is known to increase NO production, which may be an unwanted side effect of the compound when administered for treating the diseases described herein. Accordingly, it is appreciated that the co-administration of one or more substituted benzisoselenazoles, such as ebselen, with dipyridamole may be advantageous compared to treatments including dipyridamole alone.

In another embodiment, methods are described herein for treating inflammatory eye disorders, degenerative eye diseases, and combinations thereof, by co-administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or pharmaceutically acceptable salts of the foregoing in amounts effective to suppress the production of one or more of VEGF, PDGF, bFGF, MCP-I, MCP-9, and/or thromboxane A2 in a patient in need of relief from the disease. In another embodiment, methods are described herein for treating inflammatory eye disorders, degenerative eye diseases, and combinations thereof, by co-administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or pharmaceutically acceptable salts of the foregoing in amounts effective to suppress vascular smooth cell proliferation in a patient in need of relief from the disease. In another embodiment, methods are described herein for treating inflammatory eye disorders, degenerative eye diseases, and combinations thereof, by co-administering one or more substituted benzisoselenazoles, such as ebselen, and adenosine reuptake inhibitors, adenosine deaminase inhibitors, and/or adenosine mimics, such as dipyridamole or pharmaceutically acceptable salts of the foregoing in amounts effective to mimic glutathione peroxidase activity in a patient in need of relief from the disease. Without being bound by theory, and in relation to the co-administration of one or more substituted benzisoselenazoles, such as ebselen, or a pharmaceutically acceptable salt thereof with one or more HDAC inhibitors, it is also believed herein that one mechanism by which substituted benzisoselenazoles may be useful in treating the eye diseases described herein is by decreasing the formation of reactive oxygen species (ROS). HDAC inhibitors act as inhibitors of angiogenesis and/or inhibit clusterin, that is abundantly expressed in drusen.

Accordingly, HDAC inhibitors are expected to be efficacious in both wet-AMD and dry-AMD. Clusterin (apolipoprotein J) is a disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis. Clusterin also regulates the complement system, that participates in the genesis of AMD. HDAC inhibitors mainly affect pathologic and not normal cells, and induce apoptotic cell death on the basis of several mechanisms. One such unfavorable mechanism is by the formation of ROS. Accordingly, co-administration of substituted benzisoselenazoles with HDAC inhibitors may provide a superior method of treatment when compared to administering HDAC inhibitors alone, by having the added benefit of decreasing the formation of ROS caused by administering HDAC inhibitors. In another embodiment, pharmaceutical compositions comprising one or more substituted benzisoselenazoles, such as ebselen, or pharmaceutically acceptable salts thereof are described herein. In one aspect, the pharmaceutical compositions comprise a therapeutically effective amount of one or more substituted benzisoselenazoles for treating an inflammatory eye disorder, a degenerative eye disease, or a combination thereof, in with a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. In another embodiment, pharmaceutical compositions are described comprising a therapeutically effective amount of one or more substituted benzisoselenazoles or a pharmaceutically acceptable salt thereof compounded with one or more other compounds described herein for treating an inflammatory eye disorder, a degenerative eye disease, or a combination thereof. For example, such pharmaceutical compositions may include one or more substituted benzisoselenazoles with a therapeutically effective amount of one or more adenosine mimics or one or more adenosine reuptake inhibitors, such as dipyridamole, or a pharmaceutically acceptable salt thereof, and/or with a therapeutically effective amount of one or more HDAC inhibitors, such as valproic acid, vorinostat, romidepsin, and pharmaceutically acceptable salts of the foregoing, and the like. Alternatively, pharmaceutical compositions described herein may include one or more substituted benzisoselenazoles compounded with a therapeutically effective amount of one or more adenosine mimics or one or more adenosine reuptake inhibitors, such as dipyridamole, or a pharmaceutically acceptable salt thereof, and/or with a therapeutically effective amount of one or more anti-VEGF compounds, such as triptolide, tripdiolide, triptolidenol, tripchlorolide, 16- hydroxytriplide, T7/19, and the like. Other combinations of compounds described herein should also be understood to be included in the pharmaceutical compositions herein.

In embodiments where one or more substituted benzisoselenazoles, such as ebselen, are co-administered with another compound, such as dipyridamole, and/or one or more HDAC inhibitors, and the like, the compounds may be combined at the same dosage that would be administered in the monotherapy in each case. In one variation, each component is administered at a dosage corresponding to a range from about 10% to about 80% of the dose normally administered in a monotherapy. It is understood that upon improvement in the patient's condition, a maintenance dose of the one or more substituted benzisoselenazoles and/or other components may be administered. Similarly, the dose or the frequency of administration can be reduced in relation to the symptoms, and the treatment can be suspended if these symptoms have been limited to the desired level. Similarly, certain patients can require intermittent treatment over the long term until recurrence of one or another symptom of retinopathy.

Combination therapy described herein may be performed alone or in conjunction with another therapy and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the combination therapy depends on the 1) type of disorder being treated, 2) the age and condition of the patient, 3) the stage and type of the patient's disease, and 4) how the patient responds to the treatment. Additionally, a person having a greater risk of developing said disorders (e.g., a person who is genetically predisposed or previously had an inflammatory eye disorder or degenerative eye disease, such as wet age-related macular degeneration, dry age- related macular degeneration or diabetic retinopathy, may receive prophylactic treatment to inhibit or delay their development. The dosage, frequency and mode of administration of each component of the combination can be controlled independently. For example, one compound may be administered orally three times per day, while the second compound may be administered intramuscularly once per day. Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to clear prior doses. The compounds may also be formulated together such that one administration delivers both or greater combinations of compounds.

In each of the foregoing embodiments, the compounds or combination of compounds may be administered by any route. Illustrative routes of administration include, but are not limited to, oral, rectal, vaginal, intravenous, intramuscular, subcutaneous, transdermal, ophthalmic, and like administration routes. It is to be understood that when one or more substituted benzisoselenazoles is co-administered with another component, each component may be administered by a different route. It is also to be understood that each component may be administered separately, contemporaneously, or simultaneously. It is also to be understood, that when components are administered simultaneously, they may yet be separate from each other, or may instead be admixed or compounded. Illustratively, dipyridamole, or a pharmaceutically acceptable salt thereof, may be administered by intravenous injection every second day, and the ebselen may be administered per os twice every day. Other dosing regimens and protocols are contemplated to be included in the invention described herein.

Illustratively, the one or more substituted benzisoselenazoles, such as ebselen and pharmaceutically acceptable salts thereof, and/or any of the combinations thereof with other compounds described herein, may be administered via continuous intravenous infusion. Illustratively, dipyridamole, or a pharmaceutically acceptable salt thereof, may be administered by intravenous injection every second day, and the ebselen may be administered orally twice every day. Illustratively, the one or more substituted benzisoselenazoles, or ebselen combination, may be administered in one or more intra-ocular formulations, or in a single sustained-release intra-ocular formulation. Illustratively, the dipyridamole, or dipyridamole combination, may be administered in one or more modified release formulations. Additional illustrative formulations of ebselen are described in US Patent No. 6,335,036, the disclosure of which is incorporated herein by reference. In another embodiment, one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof, such as ebselen, and/or one or more substituted amino pyrimidopyrimidines, and pharmaceutically acceptable salts thereof, such as dipyridamole, may be present in pharmaceutical compositions that contain a pharmaceutically acceptable carrier, diluent, or excipient, and are administered at dosages and frequencies sufficient exert said biochemical effects enough to produce a therapeutic benefit to the patient. In another embodiment, dosing packs or kits are described herein for those dosing regimens and protocols where the one or more substituted benzisoselenazoles and additional component or components are not admixed or compounded. Such dosing packs or kits may be arranged in a daily or weekly format to facilitate the correct dosing protocol compliance by the patient to be treated or by the care giver providing the patient treatment.

In another embodiment, one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof, such as ebselen, and/or one or more substituted amino pyrimidopyrimidines, and pharmaceutically acceptable salts thereof, such as dipyridamole, can be administered either alone or in combination. When in combination, they can be administered within about 14 days of each other, such as within about 10 days, within about five days, twenty- four hours, or one hour of each other, or even contemporaneously or simultaneously. Administration of each compound can occur for example, 1 to about 5 times each day, or as necessary to alleviate symptoms.

In another embodiment, the one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof, are administered at a daily dose in the range from about 0.01 to about 200 mg/kg, or in the range from about 0.5 to about 75 mg/kg, or in the range from about 1 to about 50 mg/kg, or in the range from about 1 and about 25 mg/kg, or in the range from about 1 to about 10 mg/kg, or in the range from about 0.1 to about 25 mg/kg, or in the range from about 0.1 to about 10 mg/kg, or in the range from about 0.1 to about 5 mg/kg of body weight. In another embodiment, the one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof, are administered at a daily dose in the range from about 0.5 to about 5 mg/kg, 1 to about 5 mg/kg, 0.5 to about 2 mg/kg, or about 1 to about 2 mg/kg of body weight.

In another embodiment, the one or more substituted benzisoselenazoles, or pharmaceutically acceptable salts thereof, are administered at a daily dose in the range from about 1 mg to about 3000 mg, or at a daily dose in the range from about 5 mg to about 3000 mg, or a daily dose from about 50 mg to about 500 mg, or a daily dose from about 100 mg to about 500 mg, or a daily dose from about 200 mg to about 400 mg. In another embodiment ebselen or an analog or derivative thereof, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 300 mg/kg.

It is also to be understood that such a daily doses may be administered as a single or as a plurality of divided doses. In addition, it is to be understood that such a daily doses may be administered once a day, whether single or divided, or multiple times a day, such as bid, tid, and the like. It is also to be understood that such daily doses need not be administered every day. Illustratively, the doses described herein may be administered on alternate days, on weekdays, on alternate weekdays, or even once a week, once every other week, and the like.

In another embodiment, dipyridamole, or an analog or derivative thereof, or a pharmaceutically acceptable salt of the foregoing, such as mopidamol, is administered at a daily dose in the range from about 0.5 mg to about 800 mg, from about 18 mg to about 600 mg, or from about 50 mg to about 400 mg. In another embodiment, dipyridamole, or a pharmaceutically acceptable salt thereof, is administered at a daily dose in the range from about 20 mg to about 80 mg. It is to be understood that such a daily doses may be administered in as a single or as a plurality of divided doses. It is to be understood that such a daily doses may be administered once a day, whether single or divided, or multiple times a day, such as bid, tid, and the like. It is also to be understood that such a daily doses need not be administered every day. Illustratively, the doses described herein may be administered on alternate days, on weekdays, on alternate weekdays, or even once a week, once every other week, and the like.

In another embodiment, dipyridamole, or an analog or derivative thereof, or a pharmaceutically acceptable salt of the foregoing, such as mopidamol, is administered orally in a daily dosage in the range from about 25 mg to about 450 mg, in the range from about 50 mg to about 240 mg, or in the range from about 75 mg to about 200 mg. In the another embodiment, the dipyridamole is administered in repeated doses of about 25 mg, in a sustained release or immediate release formulation, three times a day or four times a day. In the another embodiment, the dipyridamole is administered parenterally in the range from about 0.5 mg/kg to about 5 mg/kg body weight, or in the range from about 1 mg/kg to about 3.5 mg/kg body weight, during 24 hours as slow i.v. infusion, such as not faster than 0.2 mg/min.

When co-administered with one or more substituted benzisoselenazoles, including ebselen, the above dosage ranges may be followed, or alternatively, the dipyridamole may be administered orally in a daily dosage in the range from about 50 mg to about 300 mg, or in the range from about 80 mg to about 240 mg.

In another embodiment, valproic acid, or a pharmaceutically acceptable salt thereof, is administered at a daily dose from about 1 mg/kg to about 100 mg/kg. In one variation, the valproic acid, or a pharmaceutically acceptable salt thereof, is initially administered at a lower daily dose that is gradually increased to a higher daily dose. In one embodiment thereof, the initial lower daily dose is from about 10 mg/kg to about 15 mg/kg, and the higher daily dose is from about 30 mg/kg to about 45 mg/kg. A typical daily adult dose is in the range from about 500 mg to about 2500 mg, or about 1500 mg. It is to be understood that such a daily doses may be administered in as a single or as a plurality of divided doses. It is to be understood that such a daily doses may be administered once a day, whether single or divided, or multiple times a day, such as bid, tid, and the like. It is also to be understood that such a daily doses need not be administered every day. Illustratively, the doses described herein may be administered on alternate days, on weekdays, on alternate weekdays, or even once a week, once every other week, and the like. In another embodiment, vorinostat, or a pharmaceutically acceptable salt thereof, is administered at a daily dose from about 100 mg to about 800 mg. In one variation, vorinostat, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 400 mg. It is to be understood that such a daily doses may be administered in as a single or as a plurality of divided doses. It is to be understood that such a daily doses may be administered once a day, whether single or divided, or multiple times a day, such as bid, tid, and the like. It is also to be understood that such a daily doses need not be administered every day. Illustratively, the doses described herein may be administered on alternate days, on weekdays, on alternate weekdays, or even once a week, once every other week, and the like.

In another embodiment, romidepsin, or a pharmaceutically acceptable salt thereof, is administered at a daily dose from about 1 mg/m² to about 100 mg/m². In one variation, romidepsin, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 7, 10, 12.5, or 14 mg/m². It is to be understood that such a daily doses may be administered in as a single or as a plurality of divided doses. It is to be understood that such a daily doses may be administered once a day, whether single or divided, or multiple times a day, such as bid, tid, and the like. It is also to be understood that such a daily doses need not be administered every day. In another variation, romidepsin, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 28-day cycle. In another variation, the daily dose of romidepsin, or a pharmaceutically acceptable salt thereof, is administered by infusion parenterally, such as intravenously, over several hours, such as about 4 hours. In another embodiment, triptolide is administered at a daily dose from about 10 mg to about 100 mg. In another embodiment, triptolide is administered at a daily dose of about 30 mg or about 40 mg. It is to be understood that such a daily doses may be administered in as a single or as a plurality of divided doses. It is to be understood that such a daily doses may be administered once a day, whether single or divided, or multiple times a day, such as bid, tid, and the like. It is also to be understood that such a daily doses need not be administered every day. Illustratively, triptolide is administered at a daily dose of 10 mg tid (i.e. 30 mg/day).

The carrier is desirably pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Supplementary active compounds also can be incorporated into the formulations. The formulations may conveniently be presented in dosage unit form and may be prepared by any conventional methods. In general, some formulations are prepared by bringing the active molecule into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

A pharmaceutical composition described herein is desirably formulated to be compatible with its intended route of administration. Examples of routes of administration include local or systemic routes. Local routes include, for example, topical application to the eye, or intraorbital, periorbital, sub-tenons, intravitreal and transscleral delivery. Systemic routes include, for example, oral or parenteral routes, or alternatively via intramuscular, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal routes.

Formulations suitable for oral or parenteral administration may be in the form of discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the active agent; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion. Formulations suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR EL castor oil (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Formulations may also be in the form of a sterile aqueous preparation of the drug which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the drug, such as for ophthalmic administration. Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations.

The administration of each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other component, is effective upon reaching the target region. The compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), ocular, or intra-ocular administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Pharmaceutical compositions described herein may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (sawtooth kinetic pattern); (iv) formulations that localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.

It is appreciated herein that administration of compounds in the form of a controlled release formulation is illustratively performed in cases in which the compound, either alone or in combination, has (i) a narrow therapeutic index; (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a very short biological half-life so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.

Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including for example, various types of controlled release compositions and coatings. The drug is also formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.

Formulations for oral use include solid dosage forms including tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

The tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the active drug substance in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active drug substance until after passage of the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose). Furthermore, a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.

The solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, such as chemical degradation prior to the release of the active drug substance. The coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology. The one or more substituted benzisoselenazoles and one or more other components may be mixed together in the tablet, or may be partitioned. In one example, the first drug is contained on the inside of the tablet, and the second drug is on the outside, such that a substantial portion of the second drug is released prior to the release of the first drug.

Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, for example, a mixer, a fluid bed apparatus, or a spray drying equipment.

Controlled release compositions for oral use may, for example, be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance. Illustrative sustained release formulations are described in US Patent Nos. 3,847,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,610; 4,769,027; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,566; and 5,733,566, the disclosures of which are incorporated herein by reference.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon. A controlled release composition containing one or more of the compounds described herein may also be in the form of a buoyant tablet or capsule, such as a tablet or capsule that, upon oral administration, floats on top of the gastric content for a certain period of time. A buoyant tablet formulation of the compound(s) can be prepared by granulating a mixture of the drug(s) with excipients and 20-75% w/w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. The obtained granules can then be compressed into tablets. On contact with the gastric juice, the tablet forms a substantially water-impermeable gel barrier around its surface. This gel barrier takes part in maintaining a density of less than one, thereby allowing the tablet to remain buoyant in the gastric juice. Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration. Formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents are, for example, naturally-occurring phosphatides, such as lecithin or condensation products of ethylene oxide with a fatty acid, a long chain aliphatic alcohol, or a partial ester derived from fatty acids, and a hexitol or a hexitol anhydride, such as polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, and the like. Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and the like. The pharmaceutical compositions may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. Illustrative formulations can be found in Remington: The Science and Practice of Pharmacy, supra.

Compositions for parenteral use may be provided in unit dosage forms, for example in single-dose ampoules, or in vials containing several doses and in which a suitable preservative may be added. The composition may be in form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from the active drug(s), the composition may include suitable parenterally acceptable carriers and/or excipients. The active drug(s) may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release. Furthermore, the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents. As indicated above, the pharmaceutical compositions described herein may be in the form suitable for sterile injection. To prepare such a composition, the suitable active drug(s) are dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p- hydroxybenzoate). In cases where one of the compounds is only sparingly or slightly soluble in water, a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like. Controlled release parenteral compositions may be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, or emulsions. Alternatively, the active drug(s) may be incorporated in biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices. Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactia poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L- glutamnine) and, poly(lactic acid). Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters)). The pharmaceutical composition can also be included in any suitable pharmaceutical preparation or system for administration via intraocular or periocular routes of administration, together with pharmaceutically acceptable carriers, adjuvants or vehicles. Targeting of ocular tissues may be accomplished in any one of a variety of ways. The pharmaceutical preparation for intraocular or periocular administration may also include one or more excipient components, such as effective amounts of buffering agents, preservatives, emulsifiers, salts, lubricants, polymers, solvents, and other known excipients for ocular pharmaceutical formulations, and the like. In one embodiment, the pharmaceutical composition includes an emulsifier and a buffered carrier such as Polysorbate 80 in HBSS (Hank's Balanced Salt Solution). Suitable water soluble buffering agents include, without limitation, alkali and alkaline earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate and the like. These agents are advantageously present in amounts sufficient to maintain a pH of the system of between about 2 to about 9, and more preferably about 4 to about 8. As such the buffering agent may be as much as about 5% by weight of the total system. Suitable water soluble preservatives include sodium bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and the like and mixtures thereof. Such agents may be present in amounts as needed, such as from about 0.001 to about 5% by weight, or from about 0.01 to about 2% by weight. The pharmaceutical preparation can be administered by any route of ocular administration known in the art including, but not limited to, topical ocular, subtenons, subconjunctival, intracameral, or intravitreal routes. In one embodiment, the pharmaceutical preparation can be delivered topically, e.g., via an eye drop, gel, ointment, or salve. In other embodiments, the pharmaceutical preparation can be delivered via an acute delivery system, e.g., using nanotubes, local injection, micro-injection, syringe or scleral deposition, or ultrasound.

Intraocular Compositions for injection are described herein and include injection into the aqueous or vitreous humor of the eye. In one embodiment, the compounds and/or compositions described herein are administered via intra-ocular sustained delivery (such using VITRASERT or ENVISION, or related technologies). In another embodiment, the compounds and/or compositions are delivered by posterior suborbital injection.

For administration by inhalation, typical dosage forms include nasal sprays and aerosols. In a typically nasal formulation, the active ingredient(s) are dissolved or dispersed in a suitable vehicle. The pharmaceutically acceptable vehicles and excipients (as well as other pharmaceutically acceptable materials present in the composition such as diluents, enhancers, flavoring agents, and preservatives) are selected in accordance with conventional pharmaceutical practice in a manner understood by the persons skilled in the art of formulating pharmaceuticals. The pharmaceutical compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally nontoxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes. The formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters, and other kinds of transdermal drug delivery systems. The pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, and skin protective agents. Examples of emulsifying agents are naturally occurring gums, such as gum acacia or gum tragacanth, and naturally occurring phosphatides, such as soybean lecithin and sorbitan monooleate derivatives. Examples of antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole, and cysteine. Examples of preservatives are parabens, such as methyl or propyl p-hydroxybenzoate, and benzalkonium chloride. Examples of humectants are glycerin, propylene glycol, sorbitol, and urea. Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, and AZONE. Examples of chelating agents are sodium EDTA, citric acid, and phosphoric acid. Examples of gel forming agents are CARBOPOL, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone. Examples of ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide, such as polyoxyethylene sorbitan monooleate (TWEEN).

Controlled Release Percutaneous and Topical Compositions are described herein. There are several approaches for providing rate control over the release and transdermal permeation of a drug, including: membrane-moderated systems, adhesive diffusion-controlled systems, matrix dispersion-type systems, and microreservoir systems. A controlled release percutaneous and/or topical composition may be obtained by using a suitable mixture of the above-mentioned approaches.

In a membrane-moderated system, the active drug is present in a reservoir which is totally encapsulated in a shallow compartment molded from a drug-impermeable laminate, such as a metallic plastic laminate, and a rate-controlling polymeric membrane such as a microporous or a non-porous polymeric membrane, such as ethylene-vinyl acetate copolymer. The active compound is only released through the rate-controlling polymeric membrane. In the drug reservoir, the active drug substance may either be dispersed in a solid polymer matrix or suspended in a viscous liquid medium such as silicone fluid. On the external surface of the polymeric membrane, a thin layer of an adhesive polymer is applied to achieve an intimate contact of the transdermal system with the skin surface. The adhesive polymer is preferably a hypoallergenic polymer that is compatible with the active drug.

In an adhesive diffusion-controlled system, a reservoir of the active drug is formed by directly dispersing the active drug in an adhesive polymer and then spreading the adhesive containing the active drug onto a flat sheet of substantially drug-impermeable metallic plastic backing to form a thin drug reservoir layer. A matrix dispersion-type system is characterized in that a reservoir of the active drug substance is formed by substantially homogeneously dispersing the active drug substance in a hydrophilic or lipophilic polymer matrix and then molding the drug-containing polymer into a disc with a substantially well- defined surface area and thickness. The adhesive polymer is spread along the circumference to form a strip of adhesive around the disc.

In a microreservoir system, the reservoir of the active substance is formed by first suspending the drug solids in an aqueous solution of water-soluble polymer, and then dispersing the drug suspension in a lipophilic polymer to form a plurality of microscopic spheres of drug reservoirs.

The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage used.

As described above, the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied.

The following examples further illustrate the invention described herein; however, such examples are illustrative only and should not be interpreted to limit the invention described herein in any way. The effective use of the methods and compositions described herein for treating or ameliorating one or more effects of eye diseases using one or more compounds described herein may be based upon animal models, such as murine, canine, porcine, and non-human primate animal models of disease. For example, it is understood that the inflammatory eye disorders and degenerative eye diseases described herein in humans, including AMD, Stargardt disease, and diabetic retinopathy may be characterized by a loss of function, and/or the development of symptoms, each of which may be elicited in mice, and other surrogate test animals. In particular the Retinal Photoreceptor Damage Recovery in Pigmented Rats model may be used to evaluate the methods of treatment and the pharmaceutical compositions described herein to determine the therapeutically effective amounts described herein.

EXAMPLES

EXAMPLE. A stock solution of 10 mM of ebselen is prepared from 2.74 g of the product added to 1 ml of ethanol. The solution is then divided into aliquot parts and stored at -2O⁰C. This solution is used in the in vivo and in vitro methods described herein. EXAMPLE. Ebselen fine granules are prepared according to the processes described by US Patent No. 5,008,394. Those fine granules are used in the in vivo and in vitro methods described herein.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from wet age- related macular degeneration or dry age-related macular degeneration. The duration of this treatment regimen is determined according to the progression of wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from wet age- related macular degeneration or dry age-related macular degeneration. The duration of this treatment regimen is determined according to the progression of wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Dipyridamole tablets 2 X 25 mg (Boehringer Ingelheim

International GmbH) are administered four times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Dipyridamole tablets 3 X 25 mg (Boehringer Ingelheim

International GmbH) are administered four times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Dipyridamole tablets 2 X 50 mg (Boehringer Ingelheim International GmbH) are administered four times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Dipyridamole tablets 75 mg (Boehringer Ingelheim International

GmbH) are administered four times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, two 25 mg dipyridamole tablets (Boehringer Ingelheim International GmbH) are administered four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, two 50 mg dipyridamole tablets (Boehringer Ingelheim International GmbH) are administered four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, two 50 mg dipyridamole tablets (Boehringer Ingelheim International GmbH) are administered four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, one 75 mg dipyridamole tablets (Boehringer Ingelheim International GmbH) is administered four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 250 mg valproic acid (valproic acid syrup oral solution, Pharmaceutical Associates, per 5 mL) is administered one to four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 250 mg valproic acid (valproic acid syrup oral solution, Pharmaceutical Associates, per 5 mL) is administered one to four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 250 mg valproic acid capsules (Watson Pharmaceuticals) is administered one to four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 250 mg valproic acid capsules (Watson Pharmaceuticals) is administered one to four times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 2 X 250 mg valproic acid capsules (Watson Pharmaceuticals) is administered one to three times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 2 X 250 mg valproic acid capsules (Watson Pharmaceuticals) is administered one to three times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 2 X 250 mg valproic acid capsules (Watson Pharmaceuticals) is administered three times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 2 X 250 mg valproic acid capsules (Watson Pharmaceuticals) is administered three times daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 3 X 100 mg vorinostat capsules (Merck) is administered once daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. For maintenance dosing or for tolerance issues of the patient being treated, this dosing may be modified such that the 3 X 100 mg vorinostat capsules (Merck) is administered once daily on weekdays only, with an off period on the weekends.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 3 X 100 mg vorinostat capsules (Merck) is administered once daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. For maintenance dosing or for tolerance issues of the patient being treated, this dosing may be modified such that the 3 X 100 mg vorinostat capsules (Merck) is administered once daily on weekdays only, with an off period on the weekends.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered two times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 4 X 100 mg vorinostat capsules (Merck) is administered once daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. For maintenance dosing or for tolerance issues of the patient being treated, this dosing may be modified such that the 4 X 100 mg vorinostat capsules (Merck) is administered once daily on weekdays only, with an off period on the weekends.

EXAMPLE. Ebselen fine granules are dispersed in water and 150 mg are administered three times daily to a patient suffering from or in need of relief from diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration. In addition, 4 X 100 mg vorinostat capsules (Merck) is administered once daily. The duration of this treatment regimen is determined according to the progression of diabetic retinopathy, wet age-related macular degeneration or dry age-related macular degeneration in each individual patient and dose adjustments are made accordingly. For maintenance dosing or for tolerance issues of the patient being treated, this dosing may be modified such that the 4 X 100 mg vorinostat capsules (Merck) is administered once daily on weekdays only, with an off period on the weekends.

EXAMPLE. In Vitro Matrigel Assay. Human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMVEC; up to 5^th passage; BioWhittaker, Walkersville, Md.) are grown in EGM-MV supplemented with 5% FBS, 0.5 ml hEGF, 0.2 ml hydrocortisone, 2.0 ml BBE, and 0.5 ml GA-1000 (Biowhittaker). Four-well chamber slides are coated with growth factor enhanced Matrigel (Becton Dickinson, Bedford, Mass.) and equilibrated with basal medium (Kureishi et al. (2000) Nat Med 6:1004-1010). Cells are seeded on top of the gel at a density of 10³ cells/well in fresh basal medium containing 5% FBS. After two hours, increasing concentrations of ebselen or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide (10^~12 to 10^"4 M; Sigma, St. Louis, Mont.) are added to the medium, and compared to the control addition of vehicle alone. Development of tube formation in the center of each well is investigated at 24, 48, and 72 hours. EXAMPLE. Disc Angiogenesis System. A disc of polyvinyl alcohol sponge

(Rippey, El Dorado Hills, Calif.), covered with nitrocellulose cell-impermeable filters (Millipore, Burlington, Mass.), allows capillaries to grow only through the rim of the disc. The randomized treatment for the 2-week study period is delivered via osmotic minipumps (0.25 μL/hr; Durect, Cupertino, Calif.). Those discs are subcutaneously implanted in the back of 10- week old C57BL/6J mice or in some experiments in the back of α7-nAChR-deficient

(B6.129S7-Chrna7^tmlBay) mice (n=6 per group; Jackson, Bar Harbor, Me.). Two weeks later, mice are anaesthetized and infused with space-filling fluorescent microspheres (0.2 μm, Molecular Probes, Eugene, Oreg.) through the left ventricle of the heart. Both the area of the disc covered with perfused vessels and the vessel density are quantified (Heeschen et al. (2001) Nat Med 7:833-837; and Jang et al. (2000) Circulation 102:1414-1419 (3, 10)). The α7-nAChR in growing vessels are identified by immunohistochemistry (Santa Cruz Biotechnology, Santa Cruz, Calif.). To verify the specificity of the staining, discs explanted from homozygous α7- nAChR^"7" mice are used as a negative control. The efficacy of administering ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide to mice is evaluated compared to controls. EXAMPLE. Uveitis Assay. Prevention of the development of uveitis by administering ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide to a mammal at risk of developing uveitis is evaluated. Endotoxin induced uveitis is created in a Lewis rat by injecting lipopolysaccharide (LPS) into the footpad of the rat (Rosenbaum et al. (1980) NATURE 7: 611-3). Immediately after the LPS administration, the animals are randomized in two groups, which receive either a single intraperitoneal injection of increasing concentrations of ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide (n=ll), or an isotype- matched IgG (anti-rat IgGl, n=13) (Southern Biotech, Inc, Alabama, US). Twenty- four hours after the induction of uveitis, the severity of uveitis is evaluated in vivo using slit-lamp biomicroscopy and by cell and protein measurement following aspiration of the aqueous fluid. Retinal leukocyte adhesion is quantified with FITC-lectin labeling (Joussen et al. (2003) Invest. Ophthal. Vis. Sci. 44(5): 2184-91) and by counting of vitreous leukocytes in H&E-stained sections of paraffin-embedded eyes. Retinal vascular cell adhesion molecule- 1 (VCAM-I) levels are evaluated by Western Blotting (Chen et al. (2002) Kidney Int. 61(2):414-24)). Leukocytes from LPS-injected and control rats are isolated with a density gradient, and leukocyte adhesion to rat endothelial cells is quantified using a static in vitro adhesion assay. Analysis of the prevention of the development of intraocular inflammation in the animal model of uveitis is indicative of efficacy. EXAMPLE. Diabetic Retinopathy Assay. Blocking leukostasis during early diabetic retinopathy. Streptozotocin is administered to Long Evans rats to induce diabetes (Joussen et al. (2001) Am J. Pathol. 158(1):147-152). Ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide is administered intraperitoneally at a increasing concentrations for 11 or 13 days after the induction of diabetes. The effect on retinal leukocyte adhesion is quantified 14 days after the induction of diabetes in a retinal flatmount via FITC-ConA lectin staining (Joussen et al. (2001)). The presence of VCAM-I in diabetic retina is investigated by Western Blotting (Chen et al. (2002) Kidney Int. 61(2): 414-24).

EXAMPLE. Treatment of Choroidal Neovascularization Via Combination Therapy Using Photodynamic Therapy and Ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide. Cynomolgus monkeys weighing 3-4 kg are anesthetized with an intramuscular injection of ketamine hydrochloride (20 mg/kg), diazepam (1 mg/kg), and atropine (0.125 mg/kg), with a supplement of 5-6 mg/kg of ketamine hydrochloride as needed. For topical anesthesia, proparacaine (0.5%) is used. The pupils are dilated with 2.5% phenylephrine and 0.8% tropicamide. Choroidal neovascularization is induced in the eyes of the monkeys using a modification of the Ryan model, in which burns are placed in the macula, causing breaks in Bruch's membrane, with a laser, such as a COHERENT ARGON DYE LASER 920 laser (Coherent Medical Laser, Palo Alto, CA; Ohkuma, H. et al. Arch. Ophthalmol. (1983) 101: 1102-1110; Ryan, S. J. Arch. Ophthalmol. (1982) 100: 1804-1809)). Initially, a power of 300- 700 mW for 0.1 seconds is used to form spots of about 100 μm, but improved rates of neovascularization can be obtained with 50 micron spots using a power of about 300-450 mW for 0.1 second.

The resulting choroidal neovascularizations are observed by one or more of (1) fundus photography (such as by using a CANON FUNDUS CF-60Z camera, Lake Success, Long Island, N.Y.); (2) by fluorescein angiography (such as by using about 0.1 mL/kg body weight of 10% sodium fluorescein via saphenous vein injection); and (3) histologic examination by light and electron microscopy.

Immediately before use, benzoporphyrin derivative-monoacid is dissolved in dimethyl sulfoxide (Aldrich Chemical Co., Inc., Milwaukee, Wis.) at a concentration of about 4 mg/mL. Dulbeccos phosphate buffered salt solution is then added to the stock to achieve a final BPD concentration of 0.8 mg/mL. Human low-density- lipoprotein (LDL) prepared from fresh frozen plasma is added at a ratio of 1:2.5 mg BPD-MA:LDL. The green porphyrin dye and dye solutions are protected from light at all times. After mixing, the dye preparation is incubated at 37⁰C. for 30 minutes prior to intravenous injection. The monkeys then are injected intravenously via a leg vein with 1-2 mg/kg of the BPD-MA complexed with LDL over a five- minute period, followed by a flush of 3-5 mL of normal saline. Ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide is also concurrently injected intravenously via a leg vein. Following intravenous injection, the eyes of the monkeys are irradiated with 692 nm light from an argon/dye laser (such as a COHERENT 920, Coherent Medical Laser, Palo Alto, CA), using a slit lamp, such as a COHERENT LDS-20 slit lamp (Coherent Medical Laser, Palo Alto, CA). The standard fiber is coupled to larger 400 μm silica optical fiber (Coherent Medical Laser, Palo Alto, CA) to allow larger treatment spots as desired. The photodynamic irradiation treatments are carried out with a piano fundus contact lens (such as OGFA, Ocular Instruments, Inc., Bellvue, Mass.). The fluence at each treatment spot is 50, 75, 100 or 150 Joules/cm². Initially, the irradiance is set at 150 mW/cm² to avoid any thermal effect but, as the experiment proceeds, the irradiance can be increased to 300 mW/cm² or 600 mW/cm² to reduce the treatment duration time. The time interval between injection of the green porphyrin dye and the treatment irradiating step can range from about 1 to about 81 minutes.

"Dye only" controls, which are exposed to dye but not to laser light, are examined in the areas of normal retina/choroid. Areas of choroidal neovascularization are examined angiographically and histologically. Following photodynamic therapy, the monkeys are returned to an animal care facility. No attempt is made to occlude the animals' eyes, but the room in which they are housed is darkened overnight.

The condition of the choroidal neovasculature is followed by one or more of fundus photography, fluorescein angiography, and histologic examination. In particular, the eyes of the monkeys are examined by fluorescein angiography acutely and at 24 hours after the photodynamic therapy. In some cases, follow-up by fluorescein angiography is performed at 48 hours and at one week, until the eyes are harvested and the animals killed at specific time points, acutely, at 24 hours, 48 hours, and 8 days following photodynamic therapy. Animals are sacrificed with an intravenous injection of 25 mg/mg Nembutal. Efficacy is supported by observing that more choroidal neovascularization are closed by photodynamic therapy in combination with ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide relative to photodynamic therapy alone.

EXAMPLE. Mice with a null mutation in Ccl-2 or Ccr-2 genes is an animal model of age-related macular degeneration (AMD). These mice develop cardinal features of AMD, including accumulation of lipofuscin in and drusen beneath the retinal pigmented epithelium (RPE), photoreceptor atrophy and choroidal neovascularization (CNV). These features develop beyond 6 months of age. Ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide are tested for the formation of drusen, photoreceptor atrophy and choroidal neovascularization compared to controls.

EXAMPLE. SODl or SOD2 deficient mice is are animal models of age-related macular degeneration (AMD). Such mice are commercially available (Jackson Laboratories) and are known to develop macular degeneration. Ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide are tested for the onset and severity of macular degeneration compared to controls.

EXAMPLE. Procedure to Determine Efficacy of a Fusion Protein to Prevent Neovascularization of the Retina. Uncontrolled retinal angiogenesis can contribute to the pathology of a number of diseases of the retina such as wet macular degeneration, retinitis pigmentosa, Stargardt's Disease, diabetic retinopathy, hypertensive retinopathy, and occlusive retinopathy. Vascular endothelial growth factor (VEGF) production is increased by hypoxia in the retina, and neovascularization of the retina is thereby induced.

A mouse model of ischemia- induced retinal neovascularization employs newborn C57BL/6J mice which are exposed to 75% 02 from postnatal day (P) 7 to P12, along with their nursing mothers, followed by a return to room air. To accomplish this, the mice are weighed and placed at day P7 in a plexiglass box which serves as an oxygen chamber together with enough food and water for 5 days to P12. An oxygen flow rate of 1.5 L/min is maintained through the box for 5 days. The flow rate is checked twice daily with a Beckman oxygen analyzer (model D2, Irvine CA). The chamber is not opened during the 5 days of hyperoxia. An intraocular application or injection of Ebselen, or combinations of ebselen and other components, such as dipyridamole, HDAC inhibitors, or triptolide is performed at day P12 and the mice are removed to ambient air thereby inducing hypoxia. At day P 17 the mice are sacrificed by cardiac perfusion with saline followed by 4% paraformaldehyde (PF), and their eyes are removed and fixed in PF overnight. The eyes are then rinsed, brought through a graded alcohol series, and then radial sections 6 um thick are cut. Sections through the optic nerve head are stained with periodic acid/Schiff reagent and hematoxylin. Sections 30 μm apart are evaluated for a span of 300 μm through the retina. All retinal vascular nuclei anterior to the internal limiting membrane are counted in each section. The mean of 10 counted sections is determined to give the average number of neovascular nuclei per section per eye. No vascular cell nuclei anterior to the limiting membrane are observed in normal, unmanipulated animals. Efficacy is supported by a reduction in the number of retinal vascular nuclei relative to the number observed in the control group.

EXAMPLE. Retinal Photoreceptor Damage Recovery in Pigmented Rats. Recovery of retinal electric activity and retinal tissue integrity after a transient retinal ischemia through ligatures of the optic nerve vasculature is evaluated. The relation of retinal ganglion cell (RGC) count to age-related macular degeneration (AMD) is generally described in Eichler et al., "Growth-related effects of oxidant- induced stress on cultured RPE and choroidal endothelial cells" Experimental Eye Research 87:342-348 (2008) (oxidative stress in AMD; loss of retinal pigment epithelium cells a crucial event in the development of AMD), Feigl, "Age-related maculopathy in the light of ischaemia" Clin Exp Optom 90(4):263-271 (2007)

(RGCs are the first to degenerate when the retinal pigment cells are affected; RGCs can be used as a marker of AMD), and Nishijima et al., "Vascular Endothelial Growth Factor-A Is a Survival Factor for Retinal Neurons and a Critical Neuroprotectant during the Adaptive Response to Ischemic Injury" American Journal of Pathology 171(l):53-67 (July 2007) (histology study on AMD relying on RGC counts rather than ERGs). Test compounds are dissolved in 0.5% carboxymethyl cellulose (CMC). Test solutions are generally made fresh before each administration, but may be made in advance, and stored on ice after preparation and prior to use. The test solutions may be maintained in an oxygen free or oxygen depleted atmosphere after preparation and prior to use. The positive control is nicardipine (50 mg/mL in 100% EtOH).

Male pigmented (Long Evans) rats approximately 8 weeks old, 200-250 mg (obtainable from Elevage Janvier, Genest-Saint-Isle, France) are used in this Example. Test animals are housed by 3 in standard cages (420x270x190 mm³) at 22 +/- 2 C and 55 +/- 10% relative humidity, maintained on a 12/12 light dark cycle, and acclimatized for approximately 2 weeks before use. Animals are routinely exposed (in-cage) to 200-500 lux light; food and water ad lib, standard diet distributed daily. Test animals are evaluated for visual signs of optical defects. Allocation into treatment groups is decided according to the amplitude of the b-wave by a random function, such as using EXCEL software.

Test compound ebselen (BVA-301: 10, 30, and 100 mg/kg po) is administered to three groups of eight animals each, and compared to nicardipine positive control (20 mg/kg ip) administered to one group of eight, vehicle treated control (0.05% aqueous CMC, po) administered to one group of eight, and untreated/uninduced control (one group of three).

Animals are anesthetized with xlazine/ketamine IM. Within 1 hour after the above dosing schedule, retinal ischemia is induced by vascular ligation of the optic nerve vasculature of the right eye and maintained for 45 minutes. The reperfusion period is initiated by release of the ligation and is evaluated by electroretinography (ERG) measurement after reperfusion.

Animal body weights are measured before dosing and at the end of the evaluation period. ERG measurement is performed under a dim red light with overnight-dark or minimum 3 h adapted animals. Animals are anesthetized with xlazine/ketamine EVI. Mydriaticum® (0.5% tropicamide, lOuL) is instilled for pupillary dilatation. ERG is recorded at baseline and after reperfusion (6 h and 24 h time points). Implicit times and amplitudes are measured for both the a- wave and b-wave for each ERG. The implicit times are expressed in milliseconds and the a- wave and b-wave as a percentage of the baseline value. The ERG parameters are as follows: Color - white maximum; Maximum intensity - 2.6 cd.s/m2 (0 dB); Duration - 0.4 msec; Number of flashes - 8; Period - 10 sec; Filter - 50 Hz; Impedence Threshold - 90 k-ohm. Group mean values and standard deviation are calculated for each measurement. Additional details of this AMD animal model are described in Gehlbach et al., "A paired comparison of two models of experimental retinal ischemia" Curr Eye Res 13:597- 602 (1994); Block et al., "Retinal ischemia induced by the intraluminal suture method in rats" Neurosci Lett 232:45-48 (1997); Hayashi et al., "A protein tyrosine kinase inhibitor, ameliorates retinal degeneration after ischemia-reperfusion injury in rat" Invest. Opthalmol. Vis Sci

38:1193-1202 (1997); Chiou et al., "Facilitation of retinal function recovery by natural products after temporary ischemic occlusion of central retinal artery" J Ocul Pharmacol 10:493-498 (1994); Hosebe. Y., "The effect of nicardipine on ischemic injury of rabbit retina" Nippon Ganka Gakkai Zasshi 100:665-671 [in Japanese] (1996); Mori et al., "The effect of calcium channel antagonist on ischemia-reperfusion of the rabbit retina" Nippon Ganka Gakkai Zasshi 100:773-776 [in Japanese] (1996); Block et al., "Flupirtine protects against ischaemic retinal dysfunction in rats" Neuroreport 5:2630-2632 (1994); Morel-Mandrino et al., "Protection induced by isopropyl unoprostone treatment after retinal ischemic injury in the rat" Invest Opthalmol Vis Sci 38:S103 (1997); Roth et al., "Concentrations of adenosine and its metabolites in the rat retina/choroids during reperfusion after ischemia" Curr Eye Res 16:875- 885 (1997). The results of the ERG are shown in the following tables.

Table 1. Electroretinography (ERG) measurement in right eyes of pigmented rats (single administration 1 hour before ischemia).

OdB wave A implicit time (ms) % of baseline normalized to 100% as reference

OdB wave A amplitude (μv) % of baseline normalized to 100% as reference

Table 2. Electroretinography (ERG) measurement in right eyes of pigmented rats (single administration 1 hour before ischemia).

OdB wave B implicit time (ms) % of baseline normalized to 100% as reference

OdB wave B amplitude (μv) % of baseline normalized to 100% as reference

Based on the Electroretinogram (ERG), the test compounds are efficacious in B wave amplitude recovery after 24 hours. The amplitude of the B wave recovered at 24 hours by 38% in the non-treated control, and by 52% in the group treated with the 30mg/kg dose (p=0.098). The 30mg/kg dose of test compound shows the best numerical result, though the 30mg/kg dose result is not statistically significant from the 10 or 100 mg/kg doses. In addition, the test compound performed numerically better than the positive control (mean recovery was 47.9%), though the difference is not statistically significant.

Tissue histology also indicates that the compounds described herein are efficacious for treating age related macular degeneration and other eye diseases.

EXAMPLE. RGC Examination with alpha-BrN3A. During the week after ischemia-reperfusion as described in the preceding Example, retinal ganglion cells (RGCs) are labeled with BrN3A antibody. On day 8 after ischemia, and after euthanasia (via overdosed phenolbarbital IP), the retinae of induced eyes are flatmounted. Fluorescent retina are assessed with a suitable microscope (e.g. Apotome microscope, Zeiss, Gottinger, Germany). The number of RGCs are counted with suitable software (e.g. Axio Vision 4.2). Group mean values and standard deviation are calculated for each measurement. The results are shown in the following table.

Table 3. RGC Examination of pigmented rats 8 days after ischemia (single administration 1 hour before ischemia)

* Statistically significant (p<0.05) over untreated (0.5% aqueous CMC vehicle only) control.

The test compound showed protection of the Retinal Ganglion Cell (RGC) counts in the 30 mg and 10mg/kg doses (p < 0.05 and close to 0.01). The mean number of RGCs in the group where no ischemia was induced was 2552, in the non-treated controls (0.5% aqueous CMC vehicle) it was 56, and in the 30mg/kg BVA-301 group it was 251.

It was observed that the ischemia induced in the test animals was quite severe, as evidenced by the untreated controls showing RGC counts of only 56 (well-below about 200- 300), and compared to the no induction/no treatment group showing RGC counts greater than 2500. Even so, the treated groups showed efficacy in this severely induced group with an RGC count of 251. Though below that expected for more mild ischemia (about 700), the efficacy was significant over control, and numerically superior to, though not statistically different from, the positive control (mean of 144 RGCs).

Claims

WHAT IS CLAIMED IS:

1. A method for treating a patient in need of relief from one or more inflammatory eye disorders, degenerative eye diseases, or a combination thereof, the method comprising the step of administering to the patient a therapeutically effective amount of one or more substituted benzisoselenazoles, and pharmaceutically acceptable salts thereof.

2. The method of claim 1 wherein at least one benzisoselenazole is a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R^A is independently selected in each instance, and represents hydrogen or one or more aryl substituents; and Q is oxygen or sulfur.

3. The method of claim 1 wherein at least one benzisoselenazole is ebselen or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 further comprising the step of administering a therapeutically effective amount of one or more adenosine reuptake inhibitors, one or more adenosine deaminase inhibitors, or a combination thereof.

5. The method of the preceding claim wherein at least one adenosine reuptake inhibitor is a substituted amino pyrimidopyrimidine, or a pharmaceutically acceptable salt thereof.

6. The method of the preceding claim wherein the substituted amino pyrimidopyrimidine is dipyridamole, or a pharmaceutically acceptable salt thereof.

7. The method of the preceding claim wherein dipyridamole or a pharmaceutically acceptable salt thereof is administered in an amount in the range from about 5 mg/day to about 600 mg/day, and ebselen or a pharmaceutically acceptable salt thereof is administered in an amount in the range from about 50 mg/day to about 3000 mg/day.

8. The method of the preceding claim wherein dipyridamole or a pharmaceutically acceptable salt thereof is administered in an amount in the range from about 50 mg/day to about 400 mg/day, and the ebselen or a pharmaceutically acceptable salt thereof is administered in an amount in the range from about 50 mg/day to about 3000 mg/day.

9. The method of any one of claims 1 to 8 wherein at least one benzisoselenazole or a pharmaceutically acceptable salt thereof, and at least one substituted amino pyrimidopyrimidine or a pharmaceutically acceptable salt thereof are administered contemporaneously.

10. The method of any one of claims 1 to 8 wherein at least one substituted benzisoselenazoles or a pharmaceutically acceptable salt thereof, and at least one substituted amino pyrimidopyrimidine or a pharmaceutically acceptable salt thereof are administered sequentially.

11. The method of any one of claims 1 to 8 wherein at least one benzisoselenazole or a pharmaceutically acceptable salt thereof, and at least one substituted amino pyrimidopyrimidine or a pharmaceutically acceptable salt thereof are administered simultaneously.

12. The method of any one of claims 1 to 8 wherein at least one benzisoselenazole or a pharmaceutically acceptable salt thereof, and at least one substituted amino pyrimidopyrimidine or a pharmaceutically acceptable salt thereof are compounded for administration.

13. The method of any one of claims 1 to 8 wherein the disease is wet age- related macular degeneration.

14. The method of any one of claims 1 to 8 wherein the disease is dry age- related macular degeneration.

15. The method of any one of claims 1 to 8 wherein the disease is diabetic retinopathy.

16. The method of any one of claims 1 to 8 wherein the disease is Stargardt disease.

17. The method of any one of claims 1 to 8 further comprising the step of administering a therapeutically effective amount of one or more HDAC inhibitors.

18. The method of the preceding claim wherein at least one HDAC inhibitor is selected from the group consisting of vorinostat, romidepsin, valproic acid, and pharmaceutically acceptable salts of the foregoing, and combinations thereof.

19. The method of any one of claims 1 to 8 further comprising the step of administering a therapeutically effective amount of one or more anti-VEGF compounds.

20. The method of any one of claims 1 to 8 further comprising the step of administering a therapeutically effective amount of one or more anti-TNF compounds.

21. The method of any one of claims 1 to 8 further comprising the step of administering a therapeutically effective amount of one or more compounds selected from the group consisting of triptolide, tripdiolide, triptolidenol, tripchlorolide, 16-hydroxytriplide, and T7/19, and pharmaceutically acceptable salts thereof.

22. The method of any one of claims 1 to 8 further comprising the step of administering a therapeutically effective amount of triptolide or a pharmaceutically acceptable salt thereof.

23. A method for treating a patient in need of relief from one or more inflammatory eye disorders, degenerative eye diseases, or a combination thereof, the method comprising the step of administering to the patient a therapeutically effective amount of one or more substituted amino pyrimidopyrimidines, or pharmaceutically acceptable salts thereof.

24. The method of the preceding claim wherein at least one substituted amino pyrimidopyrimidine is a compound of the formula

or a pharmaceutically acceptable salt thereof; wherein Z¹ and Z² are independently selected in each instance from NR₂, OR, (CH₂)_n-SO₂R, and (CH₂)_n-Pθ3R₂; where R is independently selected in each instance from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted arylalkyl; or, when any of Z¹ and Z² is NR₂, then R and R are independently taken together with the attached nitrogen to form an optionally substituted independently selected heterocycle; and n is an integer between 0 and 4; providing that at least one Z¹ or Z² is NR₂.

25. The method of the preceding claim wherein each Z is a nitrogen containing heterocyclyl attached at nitrogen.

26. The method of the preceding claim wherein each Z² is an optionally substituted piperidin-1-yl.

27. The method of claim 24 wherein each Z² is an optionally substituted benzylamino.

28. The method of any one of claims 24 to 27 wherein each Z¹ is a bis(optionally substituted alkyl)amino.

29. The method of the preceding claim wherein each Z¹ is a bis (hydroxyalkyl) amino .

30. The method of any one of claims 24 to 27 wherein each Z¹ is a bis(alkoxyalkyl)amino.

31. The method of any one of claims 24 to 27 wherein each Z¹ is a alkoxyalkyloxy.

32. The method of any one of claims 24 to 27 wherein each Z¹ is a heterocyclylalkyloxy.

33. The method of claim 23 wherein at least one substituted amino pyrimidopyrimidine is a compound of the formula

or a pharmaceutically acceptable salt thereof.

34. The method of any one of claims 23 to 27 wherein the disease is wet age- related macular degeneration.

35. The method of any one of claims 23 to 27 wherein the disease is dry age- related macular degeneration.

36. The method of any one of claims 23 to 27 wherein the disease is Stargardt disease.