MXPA05004486A

MXPA05004486A - Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration.

Info

Publication number: MXPA05004486A
Application number: MXPA05004486A
Authority: MX
Inventors: B Zeldis Jerome
Original assignee: Celgene Corp
Priority date: 2002-10-31
Filing date: 2003-10-31
Publication date: 2005-07-26
Also published as: KR20050062649A; EP1567148A4; BR0315889A; JP2006509743A; EP1567148A2; AU2003285107A1; TW200418455A; WO2004041181A2; AU2003285107B2; CA2504263A1; CN1731997A; ZA200503468B; NZ540185A; WO2004041181A3

Abstract

Methods of treating, preventing and/or managing macular degeneration are disclosed. Specific embodiments encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or surgery. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

METHODS OF ÜSO AND COMPOSITIONS THAT COMPRISE DRUGS CYCLOIN INHIBITORS, SELECTIVE, FOR THE TREATMENT AND MANAGEMENT OF MACULAR DEGENERATION 1. FIELD OF THE INVENTION The invention relates to methods for treating, preventing and managing macular degeneration (MD) and related syndromes, which comprise the administration of selective cytokine inhibitory drugs, individually or in combination with therapeutics known. The invention also relates to pharmaceutical compositions and dosage regimens. In particular, the invention encompasses the use of selective cytosine inhibitory drugs in conjunction with surgical interventions, and / or other standard therapies for degeneration of the macula. 2. BACKGROUND OF THE INVENTION 2.1 PATOBIOLOGY OF MECHANISM DEGENERATION Degeneration of the macula (MD) is an eye disease that destroys central vision by damaging the macula. The macula is part of the retina, a thin layer of nerve cells that covers most of the interior of the eyeball. The nerve cells in the retina detect light and send signals to the brain about what the eye sees. The macula is located near the center of the retina at the back of the eyeball and provides the sharp central vision an animal uses to focus on what is in front of it. The rest of the retina provides lateral (peripheral) vision. There are two forms of MD: atrophic ("dry") and exudative ("wet") - Riordan-Eva, P., Eye in Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). Ninety percent of patients have the dry form, while only ten percent have the wet form. However, patients with the wet form can lose up to ninety percent of their vision. DuBosar, R., J "of Ophthalmic Nursing and Technology, 18: 60-64 (1998) Degeneration of the macula results in the presence of choroidal neovascularization (C VM) and / or geographic atrophy of the pigmented epithelium of the retina. (RPE) in one eye with drusen, Bird, A. C, Surv Ophthamol, 39: 367-74 (1995) .Hyalines are whitish-yellowish spots rounded at the bottom of the eye, located on the outside of the neuroretina. Additional symptoms of MD include detachment of the RPE (PED) and scar tissue in the form of a submacular disc Algvere, PV, Acta Ophthalmologica Scandinavica 80: 136-143 (2002) Choroidal neovascularization is a problem that is related to a A wide variety of diseases of the retina, but is most commonly associated with MD The CNVM is characterized by abnormal blood vessels that arise from the choroid (the layer of tissue rich in blood vessels just behind the retina) that grow through of the layers of the retina. The new vessels are very fragile and break easily, causing blood and fluids to combine within the layers of the retina. When the vessels are spilled, they affect the delicate tissue of the retina, causing vision to deteriorate. The severity of the symptoms depends on the size of the CNVM and its proximity to the macula. The symptoms of the patients can be very moderate, such as a blurred or distorted area of vision, or more severe, such as a central blind spot. Patients who have hyaline and possibly pigmentary abnormalities, but without CNVM or geographic atrophy, are generally diagnosed as suffering from age-related maculopathy (ARM). Id. The distinctive histopathological hallmark of ARM and MD is a continuous layer of fine granular material deposited on the inner part of the Bruch membrane at the base of the RPE cells. Sarks, J. P., et al., Eye 2 (Pt. 5): 552-77 (1988). It is thought that these basal deposits should be accumulated as waste products of the continuous phagocytosis of the RPE or the material of the outer segment of the photoreceptors. The basal deposits lead to a shrinkage and decreased permeability of Bruch's membrane. It has been hypothesized that decreased water permeability impairs nutrient exchange, traps water and accentuates the development of mild drusen and PED and eventually leads to atrophy of RPE cells. Id. However, the current global understanding of the pathogenesis of MRA and MD is incomplete. Cour, M. et al., Drugs Aging 19: 101-133 (2002). Since MD is more prevalent in the elderly, the fastest growing segment of the population, MD is destined to become a significant problem both economically and socially. Degeneration of the macula is the most common cause of visual loss in developed countries in individuals over 60 years of age. The degeneration of the macula has eliminated the central vision of 1.7 million Americans and another 11 million are at risk. DuBosar, R., J ". Of Ophthalmic Nrsing and Technology, 18: 60-64 (1998) .There is currently no cure Rhoodhooft, J., Bull, Soc. Belge Ophthalmol 276: 83-92 (2000). therefore, there is an urgent need for effective treatments for MD. 2. 2 TREATMENTS FOR THE DEGENERATION OF THE MACHINE ASSOCIATED WITH AGE Until recently, laser photocoagulation was the only treatment routinely used for MD, and it provides only modest results. Laser photocoagulation is a type of laser surgery that uses an intense beam of light to burn small areas of the retina and abnormal blood vessels behind the macula. The burns form scar tissue and seal the blood vessels, containing them from the spills under the macula. Laser photocoagulation is effective only for patients who have wet MD. In addition, laser photocoagulation is a viable option only for 13% of these patients. Joffe, L. et al., International Ophthalmology Clinics 36 (2): 99-116 (1996). Laser photocoagulation does not cure moist MD, instead it stops or sometimes prevents further loss of central vision. Without treatment, however, loss of vision from the wet MD can progress until the person has no central vision left over. The most serious disadvantage of laser surgery is that the laser damages some of the nerve cells in the macula that react to light, causing some loss of vision. Sometimes, the loss of vision resulting from surgery is as severe or worse than the loss of vision resulting from any treatment. In some patients, however, laser surgery initially worsens vision, but prevents the most severe loss of vision over time. Verteporfin has recently been used to treat MD wet. Cour, M. , et al., Drugs Aging 19: 101-133 (2002). Verteporfin is a photoreactive dye that blocks blood vessels, which is administered by injection. The dye moves to the blood vessels that are responsible for the loss of sight and is then activated by twinkling a non-burning beam of light inside the eye in the presence of oxygen. The verteporfin is transported in the plasma, mainly by means of lipoproteins. Activated verteporfin generates short-lived, reactive oxygen and highly reactive oxygen radicals, resulting in local damage to the neovascular endothelium. This causes the occlusion of the vessels. It is known that the damaged endothelium releases procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction . The verteporfin seems to accumulate to some extent preferably in the neovasculature, including the choroidal neovasculature. However, animal models indicate that verteporfin also accumulates in the retina. Therefore, the administration of verteporfin could collaterally damage retinal structures, including the pigment endothelium of the retina and the outer nuclear layer of the retina. Another strategy that is currently being investigated for the treatment of MD is antiangiogenic pharmacological therapy. Cour, M., et al., Drugs Aging 19: 101-133 (2002). However, a first clinical trial with an antiangiogenic agent, interferon, showed that it was ineffective in treating MD and resulted in a high rate of adverse effects. Arch. Ophthalmol. 115: 855-72 (1997). The intravitreal injection of triamcinolone supposedly inhibits the development of laser-induced CNVM in monkeys, but fails to prevent severe visual loss over a period of one year in patients with MD in a randomized trial. Gillies, M.C., et al., Jnvest. Ophthalmol. Vis. Sci. 42: S522 (2001). A series of anti-angiogenic drugs are in various stages of development for use in patients with MD, including angiostatic steroids (e.g., anecortava acetate, Alcon) and vascular epidermal growth factor (VEGF) antibodies and fragments thereof. Guyer, D.R. , et al., Jnvest. Ophthalmol. Vis. Sci. 42: S522 (2001). One such VEGF antibody is rhuFab. New additional drugs for the treatment of MD include EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and the RETISERT implant (Bausch & amp;; Lomb), which exudes a sterox in the eye for up to three years. Although promising new strategies are being investigated for the treatment of MD and related macular degenerative diseases, there is still no effective treatment available. Accordingly, a need remains in the art for effective treatment for MD. 2.3 SELECTIVE CYTOKINE INHIBITOR DRUGS The compounds known as SelCIDs ™ (Celgene Corporation) or Selective Cytosine Inhibitory Drugs have been synthesized and tested. These compounds potentially inhibit the production of TNF-OI, and exhibit modest inhibitory effects on IL1B and IL12 induced by LPS. L.G. Corral et al., Ann. Rheum. Dis. 58: (Suppl 1) 1107-1113 (1999). Further characterization of selective cytosine inhibitor drugs shows that they are potent inhibitors of PDE4. PDE4 is one of the main isoenzymes of phosphodiesterase found in the myeloids of humans and cells of lymphoid lineages. The enzyme plays a crucial part in the regulation of cellular activity by degrading the second ubiquitous messenger cAMP and maintaining it at low intracellular levels. Id. Inhibition of PDE4 results in increased cAMP levels that lead to the modulation of cytokines induced by LPS including the inhibition of TNF-α production in monocytes as well as in lymphocytes. 3. BRIEF DESCRIPTION OF THE INVENTION This invention encompasses methods for treating and preventing macular degeneration, which comprise administering to a patient in need thereof, a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug. , or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods for managing MD (eg, prolonging the remission time), which comprise administering to a patient in need of such management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof. Another embodiment of the invention encompasses the use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with another therapeutic useful for treating or preventing MD, such as , but not limited to, a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a neovascularization regulator, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an anti-angiogenesis compound, or a combination thereof. Yet another embodiment of the invention encompasses methods of treating, preventing or managing MD, comprising administering to a patient in need thereof, an effective amount of a selective cytokine inhibitory drug or a salt, solvate, hydrate, stereoisomer, pharmacologically acceptable prodrug or clathrate thereof, in combination with a conventional therapy used to treat or prevent MD, such as, but not limited to, surgical intervention (e.g., laser photocoagulation therapy and photodynamic therapy). The invention further encompasses pharmaceutical compositions, individual unit dosage forms, and equipment suitable for use in the treatment, prevention and / or management of MD, which comprise a selective cytokine inhibitory drug, or a salt, solvate , hydrate stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof. 4. DETAILED DESCRIPTION OF THE INVENTION A first embodiment of the invention encompasses methods for treating and preventing MD, which comprise administering to a patient (e.g., a mammal, such as a human) in need thereof, an amount therapeutically or prophylactically effective of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The invention also relates to the treatment or prevention of specific types of MD and related syndromes including, but not limited to, atrophic MD (dry), exudative (wet) MD, age-associated maculopathy (ARM), choroidal neovascularization ( CNVM), detachment of the pigmented epithelium of the retina (PED), and atrophy of the pigmented epithelium of the retina (RPE). As used herein, the term degeneration of the macula (MD) encompasses all forms of degenerative diseases of the macula, regardless of the age of the patient, although some degenerative diseases of the macula are more common in certain age groups. These include, but are not limited to, Best or vitelliform disease (most common in patients younger than approximately 7 years of age); Stargardt's disease, juvenile macula dystrophy or fundus flavimaculatus (more common in patients between approximately 5 and 20 years of age) Behr's disease, Sorsby's disease, Doyne's disease or honeycomb dystrophy (more common in patients between approximately 30 and 50 years old); and degeneration of the macula associated with age (more common in patients approximately 60 years of age or older). The causes of MD include, but are not limited to, genetics, physical trauma, diseases such as diabetes, and infections, such as bacterial infections (eg, leprosy and ENL in particular). Another embodiment of the invention encompasses methods for managing MD, which comprise administering to a patient in need of such management, a prophylactically effective amount of a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate , or pharmaceutically acceptable prodrug thereof. Another embodiment of the invention encompasses a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier. Also encompassed by the invention are individual unit dosage forms comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

Another embodiment of the invention encompasses a kit comprising: a pharmaceutical composition comprising a selective inhibitory drug of the cytokine, or a salt, solvate, hydrate, stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof. The invention also encompasses the equipment comprising the individual unit dosage forms. The equipment encompassed by this invention may further comprise additional active agents. A specific team comprises an Amsler grid to detect or diagnose MD. Without being bound by theory, it is believed that certain selective cytokine inhibitory drugs and other medications that can be used to treat MD symptoms may act in complementary or synergistic ways in the treatment or management of MD. Therefore, one embodiment of the invention encompasses a method for treating, preventing and / or managing MD, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent. Examples of the second active agents include, but are not limited to, the conventional therapeutics used to treat or prevent MD, such as steroids, light sensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neutrotrophic factors. , regulators of neovascularization, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds and antiangiogenesis compounds, and other therapeutics found, for example, in the Physician's Desk Reference 2003. Specific examples of second active agents include, but are not they limit to, verteporfin, purlitin, an angiostatic steroid, rhuFab, interferon-2a, an integrin, an antioxidant, and pentoxifylline. The invention also encompasses pharmaceutical compositions, forms. of individual unit dosages, and the kits comprising a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof, and a second active agent. For example, a kit can contain a compound of the invention and a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound, or a combination thereof, or another drug capable of alleviating or alleviating a MD symptom. It is believed that particular selective cytokine inhibitory drugs can reduce or eliminate the adverse effects associated with the administration of the therapeutic agents used to treat MD, thereby allowing the administration of larger amounts of agents to patients and / or increasing patient compliance. Accordingly, another embodiment of the invention encompasses a method for reversing, reducing or avoiding an adverse effect associated with the administration of a second active agent, in a patient suffering from MD, which comprises administering to a patient in need thereof, a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. As discussed elsewhere herein, the symptoms of MD can be treated with surgical interventions, such as, but not limited to, light or laser therapy, radiation therapy, transplantation of the pigmented epithelium of the retina, and translocation of the fovea Without being limited by theory, it is believed that the combined use of such conventional therapies and a selective cytokine inhibitory drug can be highly effective. Therefore, this invention encompasses a method for treating, preventing and / or managing MD, which comprises administering to a patient a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug. acceptable, before, during, or after surgery, or other therapies not based on drugs. 4.1 SELECTIVE INHIBITOR DRUGS OF CYTOKINE Compounds used in the invention include selective, racemic, stereomerically pure and stereomerically racemic inhibitory cytosine drugs, stereomerically and enantiomerically pure compounds having selective cytokine inhibitory activities, and salts, solvates , hydrates, stereoisomers, clathrates, and pharmaceutically acceptable prodrugs thereof. Preferred compounds used in the invention are the known Cytokine Selective Inhibiting Drugs (SelCIDs ™), from Celgene Corporation, NJ. As used here unless otherwise indicated, the terms "selective cytokine inhibitory drugs" and "SelCIDs ™" encompass drugs of small molecules, for example, small organic molecules which are not peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Preferred compounds inhibit the production of TNF-OI. The compounds may also have a modest inhibitory effect of ILi and IL12 induced by LPS. More preferably, the compounds of the invention are potent inhibitors of PDE4. Specific examples of selective cytokine inhibitor drugs include, but are not limited to, the cyclic imides described in U.S. Patent Nos. 5,605,914 and 5,463,063; the cycloalkyl amides and cycloalkyl nitriles of U.S. Patent Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281; aryl amides (for example, one embodiment is N-benzoyl-3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide) of US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780; the imide / amide ethers and alcohols (for example, 3-phthalimido-3- (3'-dimethoxyphenyl) propan-1-ol) described in US Pat. No. 5,703,098; succinimides and maleimides (for example, 3- (3 ',', 5 ', 6' -petrahydroftalmyl) -3 - (3", 4" -dimethoxyphenyl) propionate) described in US Pat. No. 5,658,940; 'the imido and amido substituted alkanohydroxamic acids described in US Pat. No. 6,214,857 and WO 99/06041; the substituted phenethylsulfones described in US Pat. Nos. 6,011,050 and 6,020,358; the substituted imides (for example, 2-phthalimido-3 - (3 ', 4' -dimethoxyphenyl) -panoid) described in US Pat. No. 6,429,221; the substituted 1, 3, 4-oxadiazoles (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,3,4-oxadiazol-2-yl) ethyl] -5-methylisoindoline- 1, 3-dione) described in U.S. Patent No. 6,326,388; the cyano and carboxy derivatives of substituted styrenes (for example, 3,3-bis- (3,4-dimethoxyphenyl) acrylonitrile) described in US Patents Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554; isoindolin-l-one and isoindoline-1,3-dione substituted at the 2-position with an a- (3,4-disubstituted phenyl) alkyl group and at the 4-position and / or 5 with a nitrogen-containing group described in WO 01/34606; and the imido- and amido-substituted acylhydroxamic acids (for example, 3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propamoylamino) propanoate described in WO 01/45702. The totalities of each of the patents and patent applications identified herein are incorporated herein by reference.The additional selective cytokine inhibitory drugs belong to a family of synthesized chemical compounds of which typical embodiments include 3- (1, 3 -dioxobenzo- [f] isoindol-2-yl) -3- (3-cyclopentyloxy-4-methoxyphenyl) propionamide and 3- (1, 3-dioxo-4-azaisoindol-2-yl) -3- (3, 4 -dimethoxyphenyl) -propionamide Other specific selective cytokine inhibitory drugs belong to a class of non-polypeptide cyclic amides described in U.S. Patent Nos. 5,698,579 and 5,877,200, both of which are incorporated herein. Representative cyclic amides include the compounds of the formula: where n has a value of 1, 2, or 3; R5 is o-phenylene unsubstituted or substituted by 1 to 4 substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, and halo; R7 is (i) phenyl or phenyl substituted with one or more substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy , amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl , carbotoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (iv) benzyloxy; R12 is -OH, alkoxy of 1 to 12 carbon atoms, or R8 is hydrogen or alkyl of 1 to 10 carbon atoms; and R9 is hydrogen, alkyl of 1 to 10 carbon atoms, -COR10, or -S02R10, wherein R10 is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl. Specific compounds of this class include, but are not limited to: 3-phenyl-2- (1-oxoisoindolin-2-yl) propionic acid; 3-phenyl-2- (l-oxoisoindolin-2-yl) ropionamide; 3-phenyl-3- (l-oxoisoindolin-2-yl) propionic acid; 3-phenyl-3- (l-oxoisoindolin-2-yl) propionamide; 3- (4-methoxyphenyl) -3- (1-oxisoindolin-yl) propionic acid; 3- (4-methoxyphenyl) -3- (1-oxisoindolin-yl) propionamide; 3- (3, 4-dimethoxyphenyl) -3- (1-oxisoindolin-2-yl) propionic acid; 3- (3, -dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydroisoindol-2-yl) ropionamide; 3- (3, -dimethoxyphenyl) -3- (l-oxisoindolin-2-yl) pro-ionamide; 3- (3,4-diethoxyphenyl) -3- (1-oxoisoindolin-yl) propionic acid; 3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionate methyl; 3- (l-Oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionamide; 3- (l-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionamide; 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionate methyl; and methyl 3- (l-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionate. Other selective inhibitory drugs of the cytokine include the imido and amido-substituted alkanehydroxamic acids described in O 99/06041, which are incorporated herein by reference. Examples of such compounds include, but are not limited to: wherein each of R1 and R2, when taken independently of one another, is hydrogen, lower alkyl, or R1 and R2, when taken together with the carbon atoms represented to which they are linked each, is or phenylene, o-naphthylene, or cyclohexen-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; R3 is phenyl substituted with one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy from 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, cycloalkylidenemethyl of C4-C6, alkylidenemethyl of C3-Ci0, indanyloxy, and halo; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; R4 'is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is -C¾-, -CH2-C0-, -S02-, -S-, or -NHCO-; n has a value of 0, 1, or 2; and the acid addition salts of said compounds, which contain a nitrogen atom capable of being protonated.

Specific, additional, selective cytosine inhibitor drugs used in the invention include, but are not limited to: 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) ropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-methoxy-3- (1-oxoisoindolinyl) propionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3-phthalimidopropionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (1-oxoisoindolinyl) -propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide; N-hydroxy-3- (3,4-dimethoxyphenyl) -3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-nitrophthalimido) propionamide; N-hydroxy-3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) -propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-methyl-phthalimido) propionamide; 3- (3-Cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-lH-benzo [f] isoindol-2-yl) propionamide; N-hydroxy-3-. { 3- (2-propoxy) -4-methoxyphenyl} -3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -3- (3,6-difluorophthalimido) -N-hydroxypropionamide; 3- (4-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide; 3- (3-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide; N-hydroxy-3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) -propionamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide; and N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide. Additional selective cytokine inhibitory drugs used in the invention include substituted phenethylsulfones, substituted in the phenyl group with an oxoisoindino group. Examples of such compounds include, but are not limited to, those described in U.S. Patent No. 6,020,358, which is incorporated herein, which include the following: wherein the designated carbon atom * constitutes a center of chirality; Y is C = 0, CH2, S02, or C¾C = 0; each of S1, R2, R3, and R4, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR8R9; or any two of R1, R2, R3, and R4, in adjacent carbon atoms, together with the represented phenylene ring are naphthylidene; each of R5 and R6, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms; R7 is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR8 < R9 '; each of R8 and R9, taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R8 and R9 is hydrogen and the other is -COR10 or -S02R10, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene, or -CH2CH2X1CH2CH2- wherein X1 is -O-, -S- or -NH-; and each of R8 'and R9' taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R8 'and R9' is hydrogen and the other is -COR10 'or - S02R10, or R8 'and R9' taken together are tetramethylene, pentamethylene, hexamethylene, or -CH2CH2X2CH2CH2- wherein X2 is -0-, -S-, or -NH-. It will be appreciated that while for convenience the above compounds are identified as phenethylsulfones, these include the sulfonamides wherein R7 is NR8'R9 '. Specific groups of such compounds are those in which Y is C = 0 or CH2. A further specific group of such compounds are those in which each of R1, R2, R3, and R4, independently of the others, is hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or - NR8R9 in which each of R8 and R9 taken independently of the other is hydrogen or methyl or one of R8 and R9 is hydrogen and the other is -COCH3. The particular compounds are those in which one of R1, R2, R3, and R4 is - H2 and the rest of R1, R2, R3, and R4 are hydrogen. Particular compounds are those in which one of R1, R2, R3, and R4 is -NHCOCH3 and the remainder of R1, R2, R3, and R, are hydrogen. Particular compounds are those in which one of R1, R2, R3, and R4 is -N (CH3) 2 and the remainder of R1, R2, R3, and R4, are hydrogen. A further preferred group of such compounds are those in which one of R1, R2, R3, and R4 is methyl and the remainder of R1, R2, R3, and R4 are hydrogen. Particular compounds are those in which one of R1, R2, R3, and R4 is fluorine and the remainder of R1, R2, R3, and R4, are hydrogen. Particular compounds are those in which one of R5 and RS, independently of the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy, or cyclohexoxi. Particular compounds are those in which R5 is methoxy and R6 is monocycloalkoxy, polycycloalkoxy, and benzocycloalkoxy. Particular compounds are those in which R5 is methoxy and R6 is ethoxy. Particular compounds are those in which R7 is hydroxy, methyl, ethyl, phenyl, benzyl, or R8'R9 'in which each of R8' and R9 'taken independently of the other is hydrogen or methyl. Particular compounds are those in which R7 is methyl, ethyl, phenyl, benzyl, or NR8'R9 'in which each of R8' and R9 'taken independently of the other is hydrogen or methyl. Particular compounds are those in which R7 is methyl. Particular compounds are those in which R7 is NR8'R9 'in which each of R8' and R9 'taken independently of the other is hydrogen or methyl. Other selective cytokine inhibitory drugs include the fluoroalkoxy-substituted 1,3-dihydroisoindolyl compounds found in U.S. Provisional Application No. 60 / 436,975 by G. Muller et al., Filed December 30, 2002 , which is incorporated here as a reference in its entirety. Representative 1,3-dihydroisoindolyl substituted with fluoroalkoxy compounds include the compounds of the formula: wherein: Y is -C (O) -, -CH2, -C¾C (0) -, -C (0) CH2-, or S02; Z is -H, -C (0) R3, - (C0-a) alkyl -S02- (Ci-4 alkyl), -Ci-a- alkyl, -CH 2 OH, CH 2 (O) (-8 alkyl) or -CN; Ri and R2 are each independently -CHF2-, -Ca_8 alkyl-, -C3_iB- cycloalkyl-, or - (Ci_io alkyl) (C3_18 cycloalkyl), and at least one of Rx and R2 is CHF2; R3 is -R4RS, -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl, or substituted benzyl; R4 and R5 are each independently -H, alkyl of Ca_ a, -OH, -OC (0) R6; R6 is -alkyl of Cx-s, -amino (Ci-8 alkyl), -phenyl, -benzyl, or -aryl; Xi, X2, X3, and are each independently -H, halogen, -nitro, -NH2, -FC3, -C1_6 alkyl / - (C0-4 alkyl) - (C3-e cycloalkyl), C0-4) -NR7R8, (C0-4 alkyl) -N (H) C (0) - (R8), (C0-4 alkyl) -N (H) C (O) N (R7R8), ( C0-4 alkyl) -N (H) C (0) 0 (R7R8), (C0-4 alkyl) -N (H) C (O) O (R7R8), (C0-4 alkyl) -OR3 , (C0-4 alkyl) -imidazolyl, (C0-4 alkyl) -pyrrolyl, (C0-4 alkyl) -oxadiazolyl, or (C0-4 alkyl) -triazolyl or two of Xi, X2, X3, and X4 may be joined together to form a cycloalkyl or heterocycloalkyl ring (for example, Xi and X2l X2 Y X3 / X3 and X4, X: and X3 / X2 X4 / o Xa and X4 may form a ring of 3, 4, 5, 6, or 7 members which may be aromatic, thereby forming a bicyclic system with the isoindolyl ring); and R7 and R8 are each independently H, C1-9 alkyl, C3-S cycloalkyl, (d6 alkyl) - (C3_s cycloalkyl), (C1_6 alkyl) -N (R7R8), (alkyl of Ca_s) -OR8, phenyl, benzyl, or aryl, or a pharmaceutically acceptable salt, sol ato, hydrate, stereoisomer, clathrate, or prodrug thereof. Preferred compounds of the invention include, but are not limited to: 3- (4-Acetylamino-l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-) difluoromethoxy-phenyl) propionic; 3- (4-acetylamino-l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3 (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -N, -dimethyl-propionamide; 3- (4-acetylamino-l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -propionamide; 3- (3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -propionic acid; 3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-propionamide; 3 - (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (7-nitro-1-oxo-l, 3-dihydro-isoindol-2-yl) -propionic acid methyl ester; 3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid; 3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl-3- (7-nitro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N, N-dimethyl-propionamide; amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -N, -dimethyl-propionamide; methyl ester of 3 - (4-difluoromethoxy) -3-ethoxy-phenyl) 3- (7-nitro-l-oxo-l, 3-dihydro-isoindol-2-yl) -propionic acid; 3- (7-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester; 3- [7- (Cyclopropanecarbonyl-amino) -1-oxo-1,3-dihydro-isoindol-2-yl] -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester; methyl 3- (7-acetylamino-l-oxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy--ethoxy-phenyl) -propionic acid methyl ester; 3- (7-Acetylamino-l-oxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid; 3- [7- (Cyclopropanecarbonyl-amino) -l-oxo-1,3-dihydro-isoindol-2-yl] -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid; . { 2- [2-carbamoyl-1- (4-difluoromethoxy-3-ethoxy-phenyl) -ethyl] -3-0x0-2, 3-dihydro-lH-isoindol-4-yl} cyclopropanecarboxylic acid amide; . { 2- [1- (4-difluoromethoxy-3-ethoxy-enyl) -2-dimethyl-carbamoyl-ethyl] -3-yl-2,3-dihydro-lH-isoindol-4-yl} - of cyclopropanecarboxylic acid; . { 2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-hydroxycarbamoyl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4-yl} cyclopropanecarboxylic acid amide; 3- (7-acetylamino-l-oxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionamide; 3- (7-acetylamino-l-oxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -?,? - dimethyl-propionamide; 3- (7-acetylamino-l-oxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N-hydroxy-propionamide; 3- (4-acetylamino-l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid; 3- (4-acetylamino-l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3 - (4-difluoromethoxy-3-ethoxy-phenyl) -propionamide; 3- (4-acetylamino-l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N, N-dimethyl-propionamide, -3 - (4-acetylamino-l, 3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N-hydroxy-propionamide; . { 2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl-ethyl] -3-OXO-2,3-dihydro-lH-isoindol-4-yl} aminocarboxylic acid cyclopropyl amide; N-. { 2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl-ethyl] -1,3-dioxo-2,3-dihydro-lH-isoindol-4-yl} -acetamide; Y . { 2- [2-carbamoyl-1- (4-difluoromethoxy-3-ethoxy-phenyl) -ethyl] -7-chloro-3-oxo-2,3-dihydro-lH-isoindol-4-yl} -cyclopropanecarboxylic acid amide. Other selective cytokine inhibitory drugs include the 7-amido-substituted isoindolyl compounds found in U.S. Provisional Application No. 60 / 454,155 by G. Muller et al., Filed March 12, 2003, which is incorporated herein by reference. It is incorporated here in its entirety as a reference. The isoindolyl compounds substituted with 7-amido include the compounds of the formula: where: Y is -C (0) -, -C¾, -C¾C (0) -, or S02: X is H; Z is (C0-4 alkyl) -C (0) R3, Ci_4 alkyl, (C0-4 alkyl) -OH, (Ci_4 alkyl) -O ((-¼.4_4) alkyl, < ¼._4) -S02 (C1-4 alkyl), (C0-4 alkyl) -SO (4-alkyl), (C0-4 alkyl) -NH2, (C0-4 alkyl) (alkyl of ¾_8), (C0-4 alkyl) -N (H) (OH), CH2NS02 (alkyl of ¾_), Ri and R2 are independently 0-8 alkyl, cycloalkyl, or (Ci_4 alkyl) cycloalkyl; R3 is , R R5, OH, or 0- (alkyl of Ca_8); R4 is H; R5 is -OH, or -0C (0) R6; Rs is Ci_8 alkyl, amino- (Ci_8 alkyl), (Ca_8 alkyl) ) - (C3-6 cycloalkyl), C3-6 cycloalkyl, phenyl, benzyl, or aryl, or a salt, solvate, hydrate, stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof, or the formula: wherein: Y is -C (0) -, -CH2 / -CH2C (0) -, or S02; X is halogen, -CN, -NR7R8, -N02, or -CF3, W is Z is (C0-4 alkyl) -S02 (0-4 alkyl), - (C04 alkyl) -CN, - (C0-4 alkyl) -C (0) R3, Ci_4 alkyl, C0-4) OH, (C0-4 alkyl) O (Ci_4 alkyl), (C0-4 alkyl) 0 (Ca_4 alkyl), (C0_4 alkyl) SO (< 4 alkyl), (alkyl) of C0-4) NH2, (C0_4 alkyl) N (C1.a) alkyl 2 / C0-4 alkyl) N (H) (OH), or (C0-4 alkyl) NS02 (C1-6 alkyl) 4); W is-C3-Scycloalkyl, - (Ci_8 alkyl) - (C3_s cycloalkyl), - (C0-e alkyl) - (C3_S cycloalkyl) -NR7R3, (C0-8 alkyl) -NR7R8, (C0-4 alkyl) -CHRg- (Co-4 alkyl) -NR7R8; i and R2 are independently Ci-8 alkyl, cycloalkyl, or (Ci_4 alkyl) cycloalkyl, - R3 is Cx-8 alkyl, NRR5, OH, 0- (alkyl of ¾_8), · R4 and R5 are independently H, alkyl of Ci-8, (Co-8 alkyl) - (C3_6 cycloalkyl), OH or -0C (0) Re; R6 is Ci_8 alkyl, (Co-s alkyl) - (cycloalkyl) C3_s), amino (Ci_8 alkyl), phenyl, benzyl, or aryl; R7 and R8 are each independently H, alkyl of QL-8, (C0-8 alkyl) - (C3_6 cycloalkyl), phenyl, benzyl, aryl, or can be taken together with the atom connecting them to form a ring Heterocyclic or heteroaryl of 3 to 7 members; R9 is C1_alkyl, (C0-4alkyl) aryl, (C0-4alkyl) - (C3_6 cycloalkyl), C0_4alkyl) -heterocycle; or a salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Still other selective cytokine inhibitory drugs include the N-alkyl-hydroxamic-isoindolyl acid compounds found in U.S. Provisional Application No. 60 / 454,149 by G. Muller et al., Filed March 12, 2003, which is incorporated herein in its entirety as a reference. Representative N-alkyl-hydroxamic-isoindolyl acid compounds include the compounds of the formula: wherein Y is -C (O) -, -C¾, -CH2C (0) - or S02; Ri and R are independently alkyl of ¾-8, CF2H, CF3, CH2CHF2, cycloalkyl, or (Ci-8 alkyl) cycloalkyl; Zi is H, Ci_6l alkyl -NH2-NR3R4 or OR5; Z2 is H or C (0) R5; Xi, X2, 3 and X4 are each independently H, halogen, N02, OR3, CF3, alkyl of ¾_6, (C0-4 alkyl) - (C3_6 cycloalkyl), (C0-4 alkyl) -N- ( R8R9), (C4-4 alkyl) - (R8), (C0-4 alkyl) -NHC (0) CH (R8) (R9), (C0-4 alkyl) -NHC (0) N (R8R9 ), (C0-4 alkyl) -NHC (0) 0 (R8), (C0_4 alkyl) -0-R8, (C0.4 alkyl) -imidazolyl, (C0-4 alkyl) -pyrrolyl, ( C0-4 alkyl) -oxadiazolyl, (C0.4 alkyl) -triazolyl, or (C0_4 alkyl) -heterocycle; 3 R4 and 5 are each independently H, alkyl of QL-6; O-alkyl of < - E, phenyl, benzyl, or aryl; R6 and R7 are independently alkyl of C% sR8 and R9 are each independently H, Ci_9 alkyl / C3_s cycloalkyl, (Ci_6 alkyl) - (C3_6 cycloalkyl), (C0-s alkyl) -n (R4R5), (Ci_6 alkyl) -0R5, phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrolidinyl, morpholino, or C3_7 heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Selective cytokine inhibitory drugs include, but are not limited to: 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -isoindolin-1 -one; 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (N, N-dimethylaminosulfonyl) -ethyl] -isoindolin-l-one; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl) -isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -5-nitro-isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -4-nitroisoindolino-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolino-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -5-methylisoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -5-acetamidoisoindolino-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-dimethylaminoisoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -5-dimethylaminoisoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -benzo [e] -isoindolino-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-methoxyisoindolino-1,3-dione; 1- (3-cyclopentyloxy-4-methoxyphenyl) -2-methyl-sulfonylethylamine; 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -isoindoline-1,3-dione; and 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-dimethylaminoisoindoline-1,3-dione. Additional selective cytokine inhibitory drugs include the enantiomerically pure compounds described in U.S. Patent Application No. 10 / 392,195, filed March 10, 2003; the international patent application no. PCT / US03 / 0873, filed on March 20, 2003; US provisional patent applications nos. 60 / 438,459 and 60 / 438,448, by G. Muller et al., Both of which were filed on January 7, 2003; and the North American provisional patent application no. 60 / 452,460 by G. Muller et al., Filed March 5, 2003, all of which are incorporated herein by reference. Preferred compounds include an enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -4-acetylamino-isoindoline-1,3-dione and an enantiomer of 3- (3,4-dimethoxy) -phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide. The selective cytokine inhibitory drugs used in the invention are 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide and. { 2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4-yl} -cyclopropanecarboxylic acid amide, which are available from Celgene Corp., Warren, NJ. 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide has the following chemical structure: The . { 2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-OXO-2,3-dihydro-lH-isoindol-4-yl} -cyclopropanecarboxylic acid amide has the following chemical structure: The compounds of the invention are commercially available or prepared according to the methods described in the patents or patent publications described herein. In addition, the optically pure compositions can be synthesized or resolved asymmetrically using the known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" embraces the non-toxic acid and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid , succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.

The compounds that are acidic in nature are capable of forming salts with several pharmaceutically acceptable bases. The bases that can be used to prepare the pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts, ie, the salts containing pharmacologically acceptable cations, such as, but not limited to, , salts of alkali metals or alkaline earth metals and the salts of calcium, magnesium, sodium or potassium in particular. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine. As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound Examples of prodrugs include, but are not limited to, derivatives of selective cytokine inhibitory drugs comprising biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of selective cytokine inhibitory drugs comprising portions of -NO, -N02, -0N0, or -0N02 - prodrugs can typically be prepared using well-known methods, such as those described in 1 Burger's Medical Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E, olf ed., 5th Edition, 1995), and Design of Prodrugs (H. Bundgaard ed., Elsevier, New York 1985). As used herein and unless otherwise indicated, "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", and "biohydrolyzable phosphate" mean an amide, ester, carbamate , of ureide carbonate, or phosphate, respectively, of a compound which: 1) does not interfere with the biological activity of the compound but which gives that compound advantageous in vivo properties, such as absorption, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo into the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters) lactonyl esters (such as phthaloyl and thiophtalidyl esters), esters of lower alkoxyacyloxyalkyl (such as methoxycarbonyloxymethyl), ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl esters, alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxy acid amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines. Several selective inhibitory drugs of the cytokine contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of pure stereomeric forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of selective cytokine inhibitory drugs can be used in the methods and compositions of the invention, the purified (R) or (S) enantiomers of the specific compounds described herein. , they can be used substantially free of their other enantiomer. As used herein, unless otherwise indicated, the term "stereomerically pure" means a composition that comprises a stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having a chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound. More preferably more than about 90% by weight of a stereoisomer of the compound and less than about 105 by weight of the other stereoisomers of the compound, even more preferably more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and more preferably more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition comprising more than about 60% by weight of a stereoisomer of a compound, preferably more than about 70% by weight, more preferably, more than about 80% by weight of a stereoisomer of a compound. As used herein and unless otherwise indicated, the term "pure enantiomerically" means a stereomerically pure composition of a compound having a chiral center. Similarly, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having a chiral center. It should be noted that if there is a discrepancy between a structure represented and a name given to that structure, the structure represented should be given more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated, for example, with bold or dashed lines, the structure or portion of the structure should be interpreted as encompassing all stereoisomers thereof. 4.2 SECOND ACTIVE AGENTS a second active agent can be used in the methods and compositions of the invention together with a selective cytokine inhibitory drug. In a preferred embodiment, the second active agent is capable of inhibiting or alleviating the conditions that cause damage to the macula., providing anti-angiogenesis or anti-inflammatory effects, to ensure patient comfort. Examples of second active agents include, but are not limited to, steroids, light sensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neutrotrophic factors, neovascularization regulators, anti-VEGF antibodies, prostaglandins, antibiotics. , phytoestrogens, anti-inflammatory compounds, antiangiogenesis compounds, other therapeutics known to inhibit or alleviate a symptom of MD, and the pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate, prodrug and pharmacologically active metabolite salts thereof. In certain embodiments, the second active agent is verteporfin, purlitin, an angiostatic spheroid, rhuFabm interferon-2a, or pentoxifylline. Examples of light sensitizers include, but are not limited to, verteporfin, tin etiopurpurine and motexafin lutetium. Verteporfin can be used to treat wet MD. Cour, M. et al., Drugs Aging 19: 101-133 (2002). Verteporfin is a photoreactive dye that blocks blood vessels, which can be administered by injection.

Examples of xanthine derivatives include, but are not limited to, pentoxifylline. Examples of anti-VEGF antibodies include, but are not limited to rhuFab. Examples of steroids include, but are not limited to 9-fluoro-11, 12-dihydroxy-16,17,1-methylethylidenebis (oxy) -pregna-1,4-diene-3,4-dione. Examples of prostaglandin F2a derivatives include, but are not limited to latanoprost (see U.S. Patent No. 6,225,348, which is incorporated herein by reference in its entirety). Examples of antibiotics include, but are not limited to tetracycline and its derivatives, rifamycin and its derivatives, macrolides, and metronidazole (see US Pat. Nos. 6,218,369 and 6,015,803, the totalities of which are incorporated by reference). Examples of phytoestrogens include, but are not limited to, genistein, genistin, genista of 6'-0-Mal, genistin of 6'-0 ~ Ac, daidzin, daidzin of 6'-0-Mal, daidzin of 6'- 0-Ac, glycitein, glycitin, 6'-0-Mal glycitin, biochanin A, formononetin, and mixtures thereof (see U.S. Patent No. 6,001,386, which is incorporated herein by reference in its entirety). Examples of anti-inflammatory agents include, but are not limited to, triameinolone, acetamide, and dexamethazone (see U.S. Patent No. 5,770,589, which is incorporated herein by reference in its entirety). Examples of antiangiogenesis compounds include, but are not limited to, thalidomide and immunomodulatory compounds (IMiDs ™, Celgene Corp., N.J.). Examples of interferons include, but are not limited to, interferon-2a. In another embodiment, the second active agent is glutathione (see U.S. Patent No. 5,632,984, which is incorporated herein by reference in its entirety). Examples of growth hormones include, but are not limited to, basic fibroblast growth factor (bFGF) and transforming growth factor b (TGF-b). Examples of neutrotrophic factors include, but are not limited to, the brain-derived neutro- trophic factor (BDNF). Examples of neovascularization regulators include, but are not limited to, type 2 plasminogen activating factor (PAI-2). Additional drugs that can be used for the treatment of MD include, but are not limited to, EYE101 (Eyetech Pharmaceuticals ), LY333531 (Eli Lilly), Miravant and the RETISERT implant (Bausch &Lomb). 4. 3 METHODS FOR TREATMENT AND PREVENTION This invention covers methods for preventing, treating and / or managing various types of D. As used herein, unless otherwise specified, the terms "prevent MD", "treat MD "and" handle the MD "include, but are not limited to, inhibit, or reduce the severity of one or more symptoms associated with the MD. Symptoms associated with MD and related syndromes include, but are not limited to, round, whitish yellowish spots of drusen at the bottom of the eye, disc-shaped scar tissue below the macula. Choroidal neovascularization, retinal pigment epithelium detachment, retinal pigmented epithelium atrophy, abnormal blood vessels arising from the choroid (the tissue layer rich in blood vessels just below the retina), a blurred or distorted area of vision , a central blind spot, pigmentary abnormalities, a continuous layer of fine granular material deposited on the inside of Bruch's membrane, and a thickened and decreased permeability of Bruc's membrane. As used herein, unless otherwise specified, the term "treating MD" refers to the administration of a compound or other active agent after the onset of MD symptoms, while "preventing" is refers to the administration before the onset of symptoms, in particular to patients at risk of MD. Examples of patients at risk for MD include, but are not limited to, people over 60 years of age, and patients suffering from diseases such as, but not limited to, diabetes and leprosy (eg, ENL). Patients with a family history of MD are also preferred candidates for preventive regimens. As used herein, and unless otherwise indicated, the term "managing MD" encompasses preventing the recurrence of MD in a patient who has suffered MD, and / or lengthening the time a patient who has suffered from MD remains in remission. The invention encompasses methods for treating, preventing and managing MD and related syndromes in patients with various stages and specific types of the disease, including, but not limited to, those known as wet MD, dry MD, maculopathy associated with age (ARM), choroidal neovascularization (CWVM), retinal pigment epithelial detachment (PED), and retinal pigment epithelium atrophy (RPE). This also includes methods to treat patients who have been previously treated by MD, do not respond to MD treatments with drugs and not based on drugs, as well as patients who have not been previously treated by MD. Since patients with MD have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on their prognosis. Experienced physicians will be able to easily determine without undue experimentation specific secondary agents and treatments that can be effectively used to treat an individual patient. The methods encompassed by this invention comprise administering one or more selective cytokine inhibitory drugs, or a solvate, hydrate, stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof to a patient suffering or presumably suffering from MD.

In one embodiment, the recommended daily dosage range of a selective cytokine inhibitory drug is from about 1 mg, to once a day, individually, or preferably in divided doses throughout the day. More specifically, the daily dose is administered twice a day in evenly divided doses. Specific daily dosage ranges are from about 1 mg to about 5,000 mg per day, from about 10 mg to about 2,500 mg per day, from about 100 mg to about 800 mg per day, from about 100 mg to about 1,200 mg per day , or from about 25 mg to about 2,500 mg per day. In handling a patient, therapy should be initiated at a low dose, perhaps from about 1 mg to about 2,500 mg, and if necessary increased to about 200 mg to about 5,000 mg per day either as a single dose or dose divided, depending on the overall response of the patient. In a particular embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide is administered in an amount of about 400, 800, 1,200, 2,500, 5,000 or 10,000 mg per day as two separate doses. The treatment lasts from about two to about twenty weeks, about four to about sixteen weeks, about eight to about twelve weeks, until the therapeutic effect is achieved, or chronically to maintain the desired effect. 4.3.1 Combination Therapy with a Second Active Agent The specific methods of the invention comprise administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with a second active agent or active ingredient. Examples of selective cytokine inhibitory drugs are described herein (see for example, section 4.1); and examples of second active agents are also described here (see, for example, section 4.2). The administration to a patient of a selective cytokine inhibitory drug and a second optional active agent, may occur simultaneously or sequentially, by means of the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (for example, if it can be administered orally, decomposition before entering the bloodstream) and the disease being treated. A preferred route of administration for selective cytokine inhibitory drugs is oral or ophthalmic. Preferred routes of administration for the second agents or active ingredients of the invention are known to those of ordinary skill in the art, for example, in the Physicians' Desk Reference (57th ed, 2003). In one embodiment, the second active agent is administered orally, intravenously, intramuscularly, subcutaneously, mucosally, topically, or transdermally and once or twice a day in an amount of from about 1 to about 2,500 mg, from about 1 to about 2,000. mg, from about 10 mg to about 1,500 mg, from about 50 mg to about 1,000 mg, from about 100 mg to about 750 mg, or from about 250 mg to about 500 mg. In other modalities, the second active agent is administered weekly, monthly, every two months or annually. The specific amount of the second active agent may depend on the specific agent used, the type of MD that is treated or prevented, the severity and stage of the MD, and the amounts of inhibitory drugs of the selective cytokine and any other agent (s) (s) optional (s) administered concurrently to the patient. In a particular modality, the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotropic factor, a neovascularization regulator, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound, or an antiangiogenesis compound, or a combination thereof. 4.3.2 Use with Surgical Interventions This invention encompasses a method for treating, preventing and / or managing MD, which comprises administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug. acceptable from it, in conjunction with (for example, before, during or after) surgical interventions. Examples of surgical interventions include, but are not limited to, light or laser therapy, radiation therapy, transplantation of the pigmented epithelium of the retina, and foveal displacement. The combined use of selective cytokine inhibitory drugs and surgical interventions provides a unique treatment regimen that may be unexpectedly effective in certain patients. Without being limited by theory, it is believed that selective cytokine inhibitory drugs can provide additive or synergistic effects when administered concurrently with surgical interventions. In a specific embodiment, the invention encompasses methods for treating, preventing and / or managing MD, which comprise administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug, or a salt, solvate, hydrate. , stereoisomer, clathrate, or pharmaceutically acceptable prodrug thereof, in combination with light or laser therapy. Examples of light or laser therapy include, but are not limited to, laser photocoagulation therapy or photodynamic therapy. The selective cytokine inhibitory drug can be administered simultaneously or sequentially with the surgical intervention. In one embodiment, the selective cytokine inhibitory drug is administered prior to light or laser therapy. In another embodiment, the selective cytokine inhibitory drug is administered after light or laser therapy. In one embodiment, the selective cytokine inhibitory drug is administered during light or laser therapy. The compound can be administered at least four weeks before, two weeks before, one week before, or just before laser surgery, or just after laser surgery for a total treatment of approximately 12-16 weeks. 4.3.3 Cyclic therapy In certain modalities, prophylactic or therapeutic agents are cyclically administered to a patient. Cyclic therapy involves the administration of a first agent for a period of time, followed by the administration of the agent and / or a second agent for a period of time and repeating this sequential administration. Cyclic therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment. In a specific embodiment, the prophylactic or therapeutic agents are administered in a cycle of about 6 months, approximately once or twice each day. A cycle can comprise the administration of a therapeutic or prophylactic agent and at least one or three weeks of rest. The number of cycles administered can be from about one to about 12 cycles, about two to about 10 cycles, or about two to about eight cycles. 4.4 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS UNITARY Pharmaceutical compositions can be used in the preparation of individual, simple, unit dosage forms. The pharmaceutical compositions and dosage forms of the invention comprise selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof. The pharmaceutical compositions and dosage forms of the invention may further comprise one or more excipients. The pharmaceutical compositions and dosage forms of the invention may also comprise one or more active agents. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise the active agents described herein (e.g., selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second active agent). Examples of additional, optional active agents are described herein (see for example, section 4.2). The unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), or parenteral (e.g., subcutaneous, intravenous, bolus, intramuscular, or intraarterial) administration. ), topical (for example, eye drops), ophthalmic, transdermal or transcutaneous, to a patient. Examples of dosage forms include, but are not limited to: tablets, capsules; capsules, such as soft gelatin capsules; capsules; tablets; pills; suppositories; powder; aerosols (for example, nasal sprays or inhalers); eye drops; gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. The composition, form and type of the dosage forms of the invention will typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active agents of which it comprises a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active agents than it comprises a dosage form used to treat the same disease. These and other ways in which the specific dosage forms encompassed by this invention will vary from one another, will be readily apparent to those skilled in the art. See, for example, Remington, s Pharmaceutical Sciences, 18th ed. , Mack Publishing, Easton PA (1990). Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a joint excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the manner in which the dosage form will be administered to the patient. For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active agents in the dosage form. For example, the decomposition of some active agents can be accelerated by some excipients such as lactose, or when exposed to water. Active agents comprising primary or secondary amines are particularly susceptible to such accelerated decomposition. Accordingly, this invention encompasses pharmaceutical compositions and dosage forms containing few mono or disaccharides, if any, other than lactose. As used herein, the term "lactose free" means that the amount of lactose present, if any, is insufficient to substantially increase the rate of degradation of an active agent. The lactose-free compositions of the invention may comprise excipients that are well known in the art and are listed, for example, in the United States Pharmacopeia (USP) 25-NF20 (2002). In general, the lactose-free compositions comprise active agents, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Lactose-free dosage forms comprise the active agents, microcrystalline cellulose, pregelatinized starch, and magnesium stearate. This invention also encompasses pharmaceutical compositions and anhydrous dosage forms comprising the active agents, since water can facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage to determine characteristics such as storage shelf life or stability of formulations with time, see, for example, Jens T. Carstensen, Drug Stability: Principies &; Practice, 2d. Ed., Marcel Dekker, NY, Y, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on a formulation can be of great importance since moisture is commonly encountered during manufacturing, package handling, storage, shipping, and use of the formulations. The pharmaceutical compositions and the anhydrous dosage forms of the invention can be prepared using anhydrous ingredients or containing low moisture and low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active agent comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture is expected during manufacture, packaging, and / or storage. An anhydrous pharmaceutical composition will be prepared and stored in such a way as to maintain its anhydrous nature. Accordingly, the anhydrous compositions are preferably packaged using materials known to prevent exposure to water, so that these may be included in forms equipment. Examples of suitable packages include, but are not limited to, tightly sealed metal foils, unit dose containers (e.g., jars), bubble pack, and strip packaging. The invention further encompasses pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate through which an active agent will be decomposed. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants, such as ascorbic acid, H-buffers, or saline buffers. As the amounts and types of excipients, the amounts and specific types of active agents in a dosage form may differ depending on factors such as, but not limited to, the route by means of which they should be administered to patients. However, typical dosage forms comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount of from about 1 to about 10,000 mg. Typical dosage forms comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in an amount of about 1, 2, 5, 10, 25, 50, 10, 200, 400, 800, 1,200, 2,500, 5,000 or 10,000 mg. In a particular embodiment, a preferred dosage form comprises 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide in an amount of about 400 , 800 or 1,200 mg. Typical dosage forms comprise the second active agent in an amount of from about 1 to about 2,500 mg, from about 1 mg to about 2,000 mg, from about 10 mg to about 1,500 mg, from about 50 mg to about 1,000 mg, from about about 100 mg to about 750 mg, or from 250 mg to about 500 mg. Of course, the specific amount of the second active agent will depend on the specific agent used, the type of MD that is being treated or handled, and the amount (s) of the selective cytokine inhibitory drug and any additional active agents, optionals administered concurrently to the patient. 4.1.1 Oral Dosage Forms Pharmaceutical compositions of the invention that are suitable for oral administration may be present as discrete dosage forms, such as, but not limited to, tablets (eg, chewable tablets), capsules, and liquids ( for example, flavored syrups)). Such dosage forms contain predetermined amounts of active agents, and can be prepared by pharmacy methods well known to those skilled in the art. see generally Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing, Easton PA (1990). Typical oral dosage forms are prepared by combining the active agents in an intimate mixture with at least one excipient according to conventional pharmaceutical combination techniques. The excipients may take a variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, and capsules) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case the solid excipients are employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of the pharmacy. In general, the pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active agents with the liquid carriers, the finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active agents in a suitable machine, in a free-flowing form such as powders or granules, optionally mixed with an excipient. The molded tablets can be manufactured by molding in a suitable machine a mixture of the pulverized compound moistened with an inert liquid diluent. Examples of excipients that may be used in oral dosage forms include, but are not limited to, filler binders, disintegrators, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid , other alginates, powdered tragacanth, guar gum, cellulose and their derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose ( for example, Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-195 (available from FMC Corporation, American Viseose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. The excipients or additives anhydrous and low humidity or include, AVICEL-PH-103 ™ and Starch 1500 LM. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin , mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the invention are typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or the dosage form. Disintegrators are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain a lot of disintegrant can disintegrate in storage, while those that contain very little may not disintegrate at a desired rate under the desired conditions. Therefore, a sufficient amount of disintegrant should be used which is neither too much nor too little to detrimentally alter the release of the active agents, to form the oral dosage forms of the invention, the amount of disintegrator used varies based on the type of formulation, and is easily discernible by those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent disintegrant, preferably from about 1 to about 5 weight percent disintegrator. Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato starch p tapioca, other starches, pregelatinized starch, other starches, clays, other algin, other celluloses, gums, and mixtures thereof. Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, sodium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium laurel sulfate, talc, hydrogenated vegetable oil, (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate , ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a siloid silica gel (AEROSIL200, manufactured by WR Grace Co. of Baltimore, MD), a synthetic silica coagulated aerosol (marketed by Degussa Co. of Plano, TX), CAB-O- SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, MA.), And mixtures thereof. If used in any way, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms in which they are incorporated. A preferred solid oral dosage form comprises a selective cytokine inhibitory drug, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, anhydrous colloidal silica, and gelatin. 4.4.2 Release Dosage Forms. Delayed Active agents of the invention can be administered by controlled release means or delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active gons using, for example, idropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Controlled release formulations known to those of ordinary skill in the art, including those described herein, can be easily selected for use with the active agents of the invention. The invention further encompasses individual unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps or gel capsules, and capsules that are adapted for controlled release. All pharmaceutical products have the common goal of improving drug therapy in addition to that achieved by their non-controlled counterparts. Ideally, the use of a controlled release preparation optimally designed in medical treatment is characterized by a minimum of the drug substance used to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency, and increased compliance of the patient. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can therefore affect the occurrence of side effects (eg, adverse). Most controlled release formulations are designed to initially release a quantity of drug (the active agent) that promptly produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain this level of therapeutic effect or prophylactic for a prolonged period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug to be metabolized and excreted from the body. The controlled release of an active agent can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological or compound conditions. 4.4.3 Parenteral Dosage Forms Dosage forms can be administered to patients by several routes including, but not limited to, intravitreal, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since their administration typically eludes the natural defenses of patients against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable carriers that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Inger Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer Injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that increase the solubility of one or more of the active agents described herein can also be incorporated into the parenteral dosage forms of the invention, for example, the cyclodextrin and its derivatives can be used to increase the solubility of the inhibitory drugs of the invention. selective cytokine and its derivatives, see, for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference. 4.4.4 Topical and Mucosal Dosage Forms The topical and mucosal dosage forms of the invention include, but are not limited to, eye drops, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to an experienced person. in the technique. see ,. for example, Remington's Pharmaceutical Sciences, 16th and 18th eds. , ack Publishing, Easton ?? (1980 &1990); e Jntroduction to Pharmaceutical Dosage Forms, 4th ed. , Read & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissues within the oral cavity can be formulated as mouth rinses or as oral gels. Such suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the topical and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that in mind, typical excipients include, but are not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures of the same for forms solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. If desired, humidifiers or humectants may also be added to the pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art, see, for example, Remington's Phar aceutical Sciences, 16a and 18a eds. , Mack Publishing, Easton PA (1980 &1990). The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the administration of one or more active agents. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve administration. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active agents to improve administration. In this regard, stearates can serve as a lipid carrier for the formulation, as an emulsifying agent or surfactant, and as an agent that improves administration or improves penetration. Different salts, hydrates or solvates of the active agents can be used to further adjust the properties of the resulting composition. 4.4.5 Equipment Typically, the active agents of the invention are preferably not administered to a patient at the same time or by the same route of administration. This invention therefore encompasses equipment that, when used by physicians, can simplify the administration of the appropriate amounts of effective agents to a patient.

A typical equipment of the invention comprises a dosage form of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The equipment encompassed by this invention may further comprise one or more additional active agents or a combination thereof. Examples of additional active agents are described, (see for example, section 4.2). The equipment of the invention may further comprise the devices that are used to administer the active agents. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. An equipment of the invention may further comprise an Amsler grid useful for detecting or diagnosing MD. The kits of the invention may further comprise pharmaceutically acceptable carriers which may be used to administer one or more active agents. For example, if an active agent is provided in a solid form that must be reconstituted for parenteral administration, the device may comprise a sealed container of a suitable vehicle in which the active agent can be dissolved to form a sterile solution free of charge. particles that is suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Injection of Dextrose and Sodium Chloride, and Lactated Ringer's Injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. 5. EXAMPLES The following examples are intended to further illustrate the invention without limiting its scope. 5.1 IN VITRO PHARMACOLOGICAL STUDIES One of the biological effects typically exerted by selective cytokine inhibitor drugs is the reduction of TNF-a synthesis. Specific selective cytokine inhibitory drugs enhance the degradation of TNF- mRNA. TNF- may play a pathological role in the degeneration of the macula. In a specific embodiment, the pharmacological properties of 3- (3, -dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide are characterized in in vitro studies. Studies examine the effects of compounds on the production of several cytosines. The inhibition of TNF-a production following the stimulation of human PBMC and whole blood by the compound is investigated in vitro. In vitro studies suggest that a pharmacological activity profile for 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-l-yl) -propionamide is five fifteen times more potent than thalidomide. The pharmacological effects of 3 - (3, 4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide can be derived from its action as an inhibitor of the generation of the inflammatory cytosines. 5.2 CLINICAL STUDIES IN PATIENTS WITH MD The selective cytokine inhibitor drugs of the invention are administered in an amount of about 20 to about 1,200 mg per day to patients with macular degeneration. In a specific modality, clinical studies are carried out with forty patients with degeneration of the macula, who were divided into two groups. The first group receives conventional treatment to close the choroidal vessels with effusions (characteristic of this disease) by means of photodynamic therapy with verteporfin. Ophthalmol 1999 (117): 1329-1345. The second group receives the same conventional therapy with verteporfin and (+) 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethyl] -4-acetylaminoisoindoline-1,3-dione in an amount of about 20 mg / day as an auxiliary for 20 weeks. The neovascular cascade is sufficiently hindered in the group receiving (+) 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethyl] -4-acetylaminoisoindoline-1,3-dione to prolong the effects indefinitely of photodynamic therapy. However, the first group without (+) 2- [l- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethyl] -4-acetylamino-isoindoline-1,3-dione undergoes progressive reperfusion of the excised vessels several weeks after the treatment. Progressive visual loss continues, which requires that photodynamic therapy be repeated. In another preferred embodiment, the (+) 2 - [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethyl] -4-acetylaminoisoindoline-1,3-dione is administered in an amount of about 1 to about 200. mg / day, preferably about 10 to about 50 mg / day, or a higher dose, generally about 1.5 to 2.5 times the daily dose each day. Auxiliary therapy is applicable for other types of conventional therapies used to prevent MD, including but not limited to surgical interventions, including laser photocoagulation. The embodiments of the invention described herein are only illustrative of the scope of the invention, a number of references have been cited, the complete contents of which have been incorporated herein by reference.

Claims

CLAIMS 1. A method for treating, preventing or managing macular degeneration, which is characterized in that it comprises administering to a patient in need of such treatment, prevention or management, a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. The method of claim 1, characterized in that it further comprises administering to the patient a therapeutically or prophylactically effective amount of a second active agent. The method of claim 2, characterized in that the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound. 4. The method of claim 2, characterized in that the second active agent is thalidomide, verteporfin, purlitin, an angiostatic steroid, rhuFab, interferon-2a or pentoxifylline, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 5. The method of claim 4, characterized in that the antiangiogenesis compound is thalidomide. 6. The method of claim 1, characterized in that degeneration of the macula is wet macular degeneration, dry macular degeneration, macular degeneration associated with age, maculopathy associated with age, choroidal neovascularization, retinal pigment epithelium detachment, atrophy of the pigmented epithelium of the retina, Best's disease, vitelliform, Stargardt's disease, juvenile macular dystrophy, fundus flavimaculus, Sorsby's disease, Doyne's disease, honeycomb dystrophy, or condition of damage to the macula. The method of claim 1, characterized in that the selective cytokine inhibitory drug is stereomerically pure. 8. A method for treating, preventing or managing degeneration of the macula which is characterized in that it comprises administering to a patient in need of such treatment, prevention or management, a therapeutically or prophylactically effective amount of 3- (3,4 -dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 9. The method of claim 8, characterized in that 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide is enantiomerically pure. 10. A method for treating, preventing or managing degeneration of the macula, which is characterized in that it comprises administering to a patient in need of such treatment, prevention or management, a therapeutically or prophylactically effective amount of. { 2- [1- (3-Ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl-amide of cyclopropanecarboxylic acid, or a salt , pharmaceutically acceptable solvate or stereoisomer thereof. 11. The method of claim 10, characterized in that the. { 2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-OXO-2,3-dihydro-lH-isoindol-4-yl-amide of cyclopropanecarboxylic acid is enantiomerically pure. The method of claim 1, characterized in that the selective cytokine inhibitory drug is of the formula (I): 0) where n has a value of 1, 2, or 3; R5 is o-phenylene, unsubstituted or substituted by 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, and halo; R7 is (i) phenyl or phenyl substituted with one or more substituents each independently selected from the others from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) unsubstituted benzyl or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbotoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (iv) benzyloxy; R12 is -OH, alkoxy of 1 to 12 carbon atoms, or R is hydrogen or alkyl of 1 to 10 carbon atoms; and hydrogen, alkyl of 1 to 10 carbon atoms, COR10, or -SO2R10, wherein R10 is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl. The method of claim 12, characterized in that the selective cytokine inhibitory drug is enantiomerically pure. The method of claim 1, characterized in that the selective cytokine inhibitory drug is of the formula (II): (?) wherein each of R1 and R2, when taken independently of each other, is hydrogen, lower alkyl, or R1 and R2 when taken together with the carbon atoms to which each is bonded, is o-phenylene, or -naphthylene, or cyclohexen-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; R3 is phenyl substituted with from one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, cycloalkylidenemethyl of C4-C6, alkylidenemethyl of C3-C10, indanyloxy, and halo; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; R4 'is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is -C¾, -CH2-CO-, S02-, -S-, or - HCO-; and n has a value of 0, 1, or 2. 15. The method of claim 14, characterized in that the selective cytokine inhibitory drug is enantiomerically pure. 16. The method of claim 1, characterized in that, the selective cytokine inhibitory drug is of the formula (III): wherein the designated carbon atom * constitutes a center of chirality; Y is C = 0, CH2, S02, or C¾C = 0; each of R1, R2, R3, and R4, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR8R9; or any two of R1, R2, R3, and R4 in adjacent carbon atoms, together with the represented phenylene ring are naphthylidene; each of R5 and Re, independently of each other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms; R7 is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR8'R9 '; each of R8 and R9 taken independently of one another is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R8 and Rs is hydrogen and the other is -COR10 or -S02R10, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene, or -CH2CH2 1CH2CH2- wherein X1 is -O-, -S- or - H-; and each of R8 'and R9' taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R8 'and R9 is hydrogen and the other is -COR10 or -S02R10' , or R8 and R9 'taken together are tetramethylene, pentamethylene, hexamethylene, or -CH2CH2X2CH2CH2- in which X2 is -0-, -S-, or - H-. 17. The method of claim 16, characterized in that the selective cytokine inhibitory drug is enantiomerically pure. 18. A method for treating, preventing or managing degeneration of the macula, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitor drug or a salt, solvate or pharmaceutically acceptable stereoisomer thereof, before, during or after surgical interventions aimed at reducing or avoiding a symptom of degeneration of the macula in the patient. 19. The method of claim 17, characterized in that the surgical intervention is light therapy, laser therapy, radiation therapy, transplantation of the pigmented epithelium of the retina, or displacement of the fovea. 20. A pharmaceutical composition, characterized in that it comprises a selective inhibitory drug of the cytokine, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a second active agent capable of reducing or preventing a symptom of degeneration of the macula. The pharmaceutical composition of claim 20, characterized in that the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotropic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an anti-angiogenesis compound. The pharmaceutical composition of claim 20, characterized in that the second active agent is thalidomide, verteporfin, purlitin, an angiostatic steroid, rhuFab, interferon-2 or pentoxifylline, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.