Europäisches Patentamt *EP001481668A1* (19) European Patent Office

Office européen des brevets (11) EP 1 481 668 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.7: A61K 31/00, A61K 31/197, 01.12.2004 Bulletin 2004/49 A61K 38/18, A61P 25/08

(21) Application number: 04076366.6

(22) Date of filing: 06.05.2004

(84) Designated Contracting States: (72) Inventor: Ashby, Charles R. Jr. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Sound Beach, NY 11789 (US) HU IE IT LI LU MC NL PL PT RO SE SI SK TR Designated Extension States: (74) Representative: AL HR LT LV MK Winckels, Johannes Hubertus F. et al Vereenigde (30) Priority: 27.05.2003 US 446285 Nieuwe Parklaan 97 2587 BN Den Haag (NL) (71) Applicant: Brookhaven Science Associates Upton, New York 11973 (US)

(54) Use of anti-glaucoma to treat visual field defects associated with the use of a GABAergic agent

(57) The invention provides a method for treating that improves retinal perfusion. Novel compositions visual field defects associated with the use of GABAer- containing a GABAergic and a drug that improves gic drugs in a mammal in need thereof. The method retinal perfusion are also provided. comprises administering an effective amount of a drug EP 1 481 668 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 481 668 A1 2

Description of GABAergic drugs in a mammal. The method includes administering to the mammal an effective amount of a BACKGROUND OF THE INVENTION drug that improves retinal perfusion. [0010] In another embodiment, the invention provides [0001] The invention relates to methods for treating 5 a composition containing a GABAergic drug, and an ef- visual field defects associated with the use of GABAer- fective amount of a drug that improves retinal perfusion. gic drugs, in mammals. [0011] In an alternate embodiment, a method for [0002] GABAergic drugs are known to increase treating visual field defects associated with use of a GABA levels in organs, such as the brain and eye. GABAergic drug in a mammal is provided that compris- These drugs are well known to be effective in the treat- 10 es administering an effective amount of erythropoietin. ment of conditions such as seizure disorders including, [0012] The invention also provides a composition for example, infantile spasms and . comprising a GABAergic drug and an effective amount [0003] Recently, it has been reported that some of erythropoietin. GABAergic drugs such as, for example, gamma-vinyl GABA (GVG), are also effective for treating and prevent- 15 DETAILED DESCRIPTION OF THE INVENTION ing drug addiction. See U.S. Patent Nos. 6,057,368, 6,395,783, and 6,541,520 to Dewey et al., and pending [0013] The present invention is for novel composi- U.S. Patent Application Nos. 09/189,166; 09/362,592; tions and methods for treating visual field defects asso- and 09/853,548. ciated with the use of GABAergic drugs, in a mammal [0004] Typically, GVG functions by irreversibly inhib- 20 in need thereof. iting the GABA-degrading enzyme GABA transaminase [0014] By "treating" is meant administering to a mam- (GABA-T). The inhibition of GABA-T generally results in mal a therapeutically effective amount of a drug that im- an increase in GABA levels. Furthermore, it has been proves retinal perfusion so that the visual field defects shown that GVG-induced increases in GABA levels are at least partially and/or substantially completely al- cause a decrease in glutamate decarboxylase (GAD), a 25 leviated in the mammal. GABA synthesizing enzyme. [0015] In addition, treating means administering a [0005] It has been realized, however, that visual dis- therapeutically effective amount of a drug that improves turbances have been associated with the use of retinal perfusion so that the visual field defects are at GABAergic drugs. In particular, there have been reports least partially and/or substantially completely prevented that approximately 25-50% of patients treated with GVG 30 from occurring in the mammal. develop visual field defects (VFDs). Although the mech- [0016] Treating also means administering a therapeu- anism responsible for GVG-induced VFDs is unknown, tically effective amount of erythropoietin so that the vis- it is believed that the VFDs induced by GVG may be ual field defects are at least partially and/or substantially related to elevated levels of GABA within the retina. See, completely alleviated in the mammal. e.g. Comaish, et al., "The effects of on elec- 35 [0017] Treating also means administering a therapeu- trophysiology and visual field in epileptics: a controlled tically effective amount of erythropoietin so that the vis- study with a discussion of possible mechanisms." Doc. ual field defects are at least partially and/or substantially Opthalmol. 104:195-212 (2002). completely prevented from occurring in the mammal. [0006] One proposed method for treating or prevent- [0018] A "GABAergic drug" is any compound that po- ing VFDs associated with the use of GABAergic drugs, 40 tentiates the GABAergic system or increases gamma such as GVG, involves the administration of vitamin B6. amino butyric acid (GABA) levels in the central nervous See U.S. Application No. 10/389,578, filed March 17, system (CNS). According to the invention, the CNS in- 2003. It is believed that vitamin B6 mitigates the visual cludes the spinal cord, brain and midbrain regions. field defects by promoting GABA-T, which in turn de- GABA is a widespread inhibitory neurotransmitter in the grades any excess GABA. 45 CNS. GABA is made in the brain from the amino acid [0007] There exists a need for alternative approaches glutamate with the aid of vitamin B6. to preventing and/or treating VFDs associated with the [0019] GABAergic drugs include compounds that en- use of GABAegic drugs. hance the production or release of GABA in the CNS [0008] It is thus an object of the present invention to and/or increase GABAergic transmission. In addition, a provide compositions and methods for treating and/or 50 GABAergic drug is any compound that directly or indi- preventing VFDs associated with the use of GABAegic rectly augments or facilitates GABAergic neurotrans- drugs, such as GVG. mission in the CNS and/or the retina and/or the optic nerve. SUMMARY OF THE INVENTION [0020] These drugs include, but are not limited to, 55 , valproic acid, , gamma-hydroxy- [0009] These and other objectives have been met by butyric acid, , cetylGABA, , tiagab- the present invention. The invention provides a method ine, acamprosate (homo-calcium-acetyltaurine) or for treating visual field defects associated with the use pharmaceutically acceptable salts thereof, or enantiom-

2 3 EP 1 481 668 A1 4 ers or racemic mixtures thereof. ture in the methods of the instant invention and such [0021] A GABAergic drug is meant to include the advantages can be readily determined by those skilled pharmaceutically acceptable salts of the drug. As used in the art. herein, pharmaceutically acceptable salts include those [0028] For example, the enantiomer S(+)-gamma-vi- salt-forming acids and bases which do not substantially 5 nyl GABA is more effective at increasing endogenous increase the toxicity of the compound. Some examples intracellular GABA levels than the enantiomer R(-)-gam- of suitable salts include salts of mineral acids such as ma-vinyl GABA. hydrochloric, hydriodic, hydrobromic, phosphoric, met- [0029] Different enantiomers may be synthesized aphosphoric, nitric and sulfuric acids, as well as salts of from chiral starting materials, or the racemates may be organic acids such as tartaric, acetic, citric, malic, ben- 10 resolved by conventional procedures which are well zoic, glycollic, gluconic, gulonic, succinic, arylsulfonic, known in the art of chemistry such as chiral chromatog- e.g. p-toluenesulfonic acids, and the like. raphy, fractional crystallization of diastereomeric salts, [0022] The present invention embraces compositions and the like. which include of GABA or drugs which contain [0030] According to the invention, "a mammal in need GABA as a moiety in its chemical structure. These pro- 15 thereof" is any mammal that has previously taken, is cur- drugs become pharmacologically active when metabol- rently taking, or will be taking, a GABAergic drug, for any ically, enzymatically or non-enzymatically biotrans- condition. formed or cleaved into GABA in the CNS. An example [0031] Such conditions include, for example, seizure of a of GABA is progabide, which upon crossing disorders and drug addiction. Exemplary seizure disor- the blood brain barrier, increases endogenous CNS 20 ders include, but are not limited to epilepsy and West GABA levels. syndrome (i.e. infantile spasms). [0023] A preferred GABAergic drug is gamma vinyl [0032] "Drug addiction" is defined as addiction to one GABA (GVG). GVG is represented by the compound or more drugs of abuse. Drugs of abuse include, but are 4-amino-hex-5-enoic acid, and is sold under the product not limited to, stimulants such as cocaine, ampheta- names Vigabatrin® and Sabril® by Hoechst-Marion 25 mine, pipradol, methylphenidate, and caffeine, Roussel. GVG is an irreversible inhibitor of the pyri- narcotics and pain medications such as and doxal-phoshate dependent enzyme GABA transami- methadone, and central nervous system depressants nase (GABA-T) and is responsible for metabolizing such as , and ethanol. GABA to succinic semialdehyde. GVG is also known to [0033] According to the present invention, addiction inhibit other transaminases, such as, for example, 30 to a combination of one or more drugs of abuse is also alanine aminotransferase and ornithine aminotrans- a condition that is treated by administering a GABAergic ferase. drug. [0024] Not being bound by theory, it is believed that [0034] A "mammal" suitable for the methods of the GVG's action results in an accumulation of GABA within present invention is any mammal, including a human, the nerve terminal, and ultimately, an increase in syn- 35 domestic animal (e.g. cat or dog), laboratory animal (e. aptic GABA levels. GVG has also been reported to pro- g. rat or monkey) or farm animal (e.g. cow, horse or pig). duce changes in the content/level of other amino acids Most preferably the mammal is a human. All humans in the brain such as, for example, a decrease in gluta- are contemplated, including infants, children and adults. mate, aspartate and , and an increase in cer- [0035] In accordance with the invention, "visual field ebrospinal fluid levels of homocarnosine. 40 defects" associated with the use of a GABAergic drug [0025] GVG does not bind to any receptor or reuptake include any disturbance of the visual field. For example, complex, but typically increases endogenous intracellu- visual field defects include loss of visual acuity, loss of lar GABA levels by selectively and irreversibly inhibiting peripheral vision, visual field constrictions, reduction in GABA-transaminase (GABA-T), the enzyme that nor- retinal cone function, bilateral concentric defect and op- mally catabolizes GABA. 45 tic neuropathy. Typically, visual field defects are associ- [0026] As used herein, GVG includes the racemic ated with the retina. compound or mixture which contains equal amounts of [0036] Not being bound by theory, it is believed that S(+)-gamma-vinyl GABA, and R(-)-gamma vinyl GABA. GABAergic drugs may produce visual field defects by This racemic compound of GVG is available as Viga- directly or indirectly altering blood flow to the retina. For batrin® from Hoechst Marion Roussel and can be ob- 50 example, the GABAergic drug may increase intraocular tained from Marion Merell Dow of Cincinnati, Ohio. pressure in the eye by, for instance, decreasing or pre- [0027] GVG contains asymmetric carbon atoms and venting fluid draining from the eye. An increase in in- thus is capable of existing as enantiomers. The present traocular pressure can, for example, decrease blood invention embraces any enantiomeric form of GVG in- flow to the retina. A decrease in retinal blood flow can cluding the racemates or racemic mixture of GVG. In 55 lead to a degeneration of optic nerve function, thus elic- some cases there may be advantages, i.e. greater effi- iting visual field defects. cacy, to using a particular enantiomer when compared [0037] The visual field defects associated with use of to the other enantiomer or the racemate or racemic mix- GABAergic drugs such as, for example, GVG, may also

3 5 EP 1 481 668 A1 6 be idiopathic in nature, i.e. no known cause can be iden- preferred. tified. [0048] Systemic administration can be achieved by [0038] According to the invention, improving retinal any means known to the skilled practitioner, including perfusion means increasing blood flow to the retina, enteral and parenteral administration. The drug can also which was altered (e.g., decreased) directly or indirectly 5 be suitably administered nasally, transdermally or by by the use of GABAergic drugs. The improvement in ret- nebulizer. Sustained release formulations are also con- inal perfusion can prevent, diminish or eliminate visual templated by the invention, and are discussed below. field defects associated with the use of a GABAergic [0049] According to the invention, an "effective drug. amount" of a drug that improves retinal perfusion is ad- [0039] The drug can be any drug that improves retinal 10 ministered to a mammal. An effective amount of the drug perfusion. Drugs that improve retinal perfusion include is an amount that is effective to treat and/or prevent vis- any drug that increases blood flow to the retina. Exam- ual defects associated with the use of a GABAergic ples of drugs that increase blood flow to the retina in- drug. clude, but are not limited to pentoxifylline, puerarin de- [0050] An effective amount of the drug easily be de- rivatives, nitropyrazole derivatives, inhibitors of nitric ox- 15 termined by the skilled practitioner. Exemplary dosages ide synthase, and anti-glaucoma drugs. of optical solutions of the following drugs are provided. [0040] Anti-glaucoma drugs include, for example, be- [0051] For example, betaxolol (sold as Betoptic®) is ta-blockers, prostaglandin analogs, adrenergic ago- administered in a concentration of approximately 0.25% nists, cholinergic , carbonic anhydrase inhibi- to 0.5%, twice daily. Carteolol (sold as Ocuporess®) is tors, and alpha-adrenergic agonists. 20 administered in a concentration of approximately 1.0%, [0041] Beta-blockers and adrenergic agonists essen- twice daily. Levobubulol (sold as Betagan®) is adminis- tially block beta adrenergic substances such as adren- tered in a concentration of approximately 0.25% to 0.5% aline (e.g. epinephrine). Some examples of beta-block- once or twice daily. Timolol (sold as Timoptic®/Beti- ers include betaxolol, cartelol, levobunolol, meti- mol®) is administered in a concentration of approxi- pranolol, timolol, levobetaxolol, and . Exam- 25 mately 0.25% to 0.5% twice daily. Levobetaxolol (sold ples of adrenergic agonists include epinephrine and as Betaxon®) is administered in a concentration of ap- dipivefrin proximately 0.50% twice daily. [0042] Prostaglandin analogs lower intraocular pres- [0052] Epinephrine (sold as Epifren®) is administered sure by increasing the outflow of the fluid that the eye in a concentration of approximately 0.1% to 0.2% once continually makes called the aqueous humor. Examples 30 or twice daily. Dipivefrin (sold as Propine®) is adminis- of prostaglandin analogs include latanoprost, unopros- tered in a concentration of approximately 0.10% every tone, bimatoprost, and travopost. 12 hours. [0043] Cholinergic drugs act by mimicking the effects [0053] (sold as Diamox®) is adminis- of the chemical acetylcholine, which controls the pro- tered in a concentration of approximately 250mg four duction of fluid in the eye. Examples of cholinergic ag- 35 times a day or 250mg, sustained release, twice a day. onists include pilocarpine, carbochol, demacrium, Methazolamide (soled as Neptazane®) is administered echothiophate iodide, and physostigmine. in a concentration of approximately 25 to 100 mg three [0044] Carbonic anyhdrase inhibitors work by inhibit- times a day. ing the ciliary process in the eye which decreases the [0054] Pilocarpine (sold as Isopto Carpine®, Pilo- aqueous humor secretion, presumably by slowing down 40 car®, or Pilostat®) is administered in a concentration of the formation of bicarbonate ions with the subsequent approximately 0.25% to 10% two to four times daily. Car- reduction in sodium and fluid transport. Examples of car- bachol (sold as Isopto Carbachol® or Carboptic®) is ad- bonic anhydrase inhibitors include dorzolamide, brin- ministered in a concentration of approximately 0.75% to zolamide, acetazolamide, and methazolamide. 3% three times daily. Demacarium (sold as Humursol®) [0045] Alpha-adrenergic agonists work by lowering 45 is administered in a concentration of approximately intraocular pressure by reducing the production of aque- 0.125% to 0.25% twice daily. ous flow. Examples of alpha-adrenergic agonists in- [0055] Echothiophate Iodide (sold as Phosholine Io- clude apraclonidine, brimonidine. dide©) is administered in a concentration of approxi- [0046] The drug that improves retinal perfusion can mately 0.03% to 0.25% twice daily. Physostigmine (sold be used alone or in combination with another drug that 50 as Isopto Eserine®) is administered in a concentration also improves retinal perfusion. For example, a beta- of approximately 0.25% to 0.5% three to four times daily. blocker can be used in combination with a prostaglandin [0056] Dorzolamide (sold as Trusopt®) is adminis- analog. Alternatively, two different beta-blocker drugs tered in a concentration of approximately 2% three times can be used in combination. daily. Brinzolamide (sold as Azopt®) is administered in [0047] The drug that improves retinal perfusion is ad- 55 a concentration of approximately 1% three times daily. ministered in any form including tablet, caplet, and liquid [0057] Latanoprost (sold as Xalatan®) is adminis- formulations. The drug can be administered systemical- tered in a concentration of approximately 0.01% once ly or optically (e.g., eye drops). Optical administration is daily. Unoprostone (sold as Resula®) is administered in

4 7 EP 1 481 668 A1 8 a concentration of approximately 0.15% twice daily. Bi- Med., Vol. 347, No. 24 (Dec. 12, 2002). It is believed matoprost (sold as Lumigan®) is administered in a con- that EPO provides neuroprotective effects to the retina. centration of approximately 0.03% once daily. Trav- [0067] EPO can be used alone or in combination with aprost (sold as Travatan®) is administered in a concen- one or more drugs that improve retinal perfusion such tration of approximately 0.004% once daily. 5 as those drugs discussed above. [0058] Apraclonidine (sold as Iopidine®) is adminis- [0068] EPO is administered in any form including tab- tered in a concentration of approximately 0.5% to 0.20% let, caplet, and liquid formulations. The drug can be ad- three times daily. Brimonidine (sold as Alphagan®) is ministered systemically, or preferably, optically (e.g., administered in a concentration of approximately 0.20% eye drops). Systemic administration can be achieved by three times daily. 10 any means known to the skilled practitioner, including [0059] Dorzolamide, also known as timilol (both are enteral and parenteral administration. The drug is also sold as Cosopt®) are administered in concentrations of be suitably administered nasally, transdermally or by approximately 2% and 0.5%, respectively, two times nebulizer. Sustained release formulations are also con- daily. Epinephrine (sold as EP®), also known as pilo- templated by the invention, and are discussed below. carpine (sold as E-Pilo®), are administered in concen- 15 [0069] An effective amount of EPO is any amount that trations of approximately 1% once daily, and 1-6% four effectively provides neuroprotective effects to the retina. times daily, respectively. Such amounts are readily determined by the skilled [0060] According to the invention, the drug can be ad- practitioner. ministered prior to, simultaneously with, or after, admin- [0070] EPO, according to the invention, includes any istration of a GABAergic drug. For example, prior to be- 20 form of EPO that is effective in providing neuroprotective ginning treatment with a GABAergic drug, a mammal effects to the retina. For example, recombinant human can begin to take a drug that improves retinal perfusion. EPO also known as epoetin alfa, (sold as Procrit ® by [0061] Prior administration of the drug can begin at Ortho Biotech Products, and Epogen® by Amgen) is any time before commencement of treatment with a suitable for the methods and compositions of the inven- GABAergic drug. Preferably, the drug is administered 25 tion. from about one month, more preferably about two [0071] An effective amount of EPO is approximately weeks, and even more preferably about one day, before 0.45 µg/kg two to three times per week. Preferably, an commencement of treatment with a GABAergic drug. Si- effective amount of EPO is less than 0.45 µg/kg two to multaneous administration is accomplished by begin- three times per week. More preferably, the EPO is ad- ning treatment of the GABAergic drug at the same time 30 ministered in an eye drop formulation in which the effec- treatment with the drug is commenced. tive % amount of EPO in the solution can be determined [0062] Commencement of the administration of the by the skilled practitioner. drug can occur at any time after treatment with a [0072] According to the invention, the EPO can be ad- GABAergic drug. Preferably, commencement the drug ministered prior to, simultaneously with, or after, admin- is administered within about one year after treatment 35 istration of a GABAergic drug. For example, prior to be- with a GABAergic drug, more preferably within about six ginning treatment with a GABAergic drug, a mammal months, even more preferably within about one month, can begin to take EPO. and most preferably within about one day after treat- [0073] Prior administration of the EPO can begin at ment with a GABAergic drug. any time before commencement of treatment with a [0063] The mammal may or may not continue treat- 40 GABAergic drug. Preferably, the EPO is administered ment with the drug after treatment with the GABAergic from about one month, more preferably about two drug ends. Such continued treatment can last for any- weeks, and even more preferably about one day, before time up to about one year after treatment with the commencement of treatment with a GABAergic drug. Si- GABAergic drug ceases. Alternatively, the mammal can multaneous administration is accomplished by begin- cease taking the drug at the same time the GABAergic 45 ning treatment of the GABAergic drug at the same time drug is ceased. treatment with the EPO is commenced. [0064] In another embodiment of the invention, a [0074] Commencement of the administration of the method for treating visual field defects associated with EPO can occur at any time after treatment with a use of a GABAergic drug is provided that comprises ad- GABAergic drug. Preferably, commencement of the ministering an effective amount of erythropoietin (EPO). 50 EPO is administered within about one year after treat- [0065] EPO is a multifunctional protein of about 40kD ment with a GABAergic drug, more preferably within that is produced and secreted mainly by the kidney in about six months, even more preferably within about adults and by the during fetal stages and that is one month, and most preferably within about one day present in the serum. It is believed that EPO can cross after treatment with a GABAergic drug. the blood-brain barrier and blood-retina barrier. 55 [0075] The mammal may or may not continue treat- [0066] It is known that hypoxia induces the expression ment with the EPO after treatment with the GABAergic of EPO in the retina. See Becerra, et al. "Erythropoietin drug ends. Such continued treatment can last for any- - An Endogenous Retinal Survival Factor," N. Engl. J. time up to about one year after treatment with the

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GABAergic drug ceases. Alternatively, the mammal can the United States. cease taking the EPO at the same time the GABAergic [0087] A composition containing progabide will in- drug is ceased. clude progabide in an amount from about 250mg to [0076] In another embodiment, the invention provides about 2g/day. Progabide is available as Gabrene® from a novel composition containing a GABAergic drug and 5 Synthelabo, France. The chemical formula of progabide a drug that improves retinal reperfusion, in a suitable is C17 H16 N2 O2. pharmaceutical carrier (vehicle) or excipient as under- [0088] A composition containing fengabine will in- stood by practitioners in the art. clude fengabine in an amount from about 250mg to [0077] Exemplary drugs that improve retinal reper- about 4g/day. Fengabine is available as SL 79229 from fusion are discussed above. Any of these aforemen- 10 Synthelabo, France. The chemical formula of fengabine tioned drugs is suitable for the composition. is C17 H17 C12 NO. [0078] Additionally, the invention provides a novel [0089] A composition containing gamma-hydroxybu- composition containing a GABAergic drug and EPO in tyric acid will include gamma-hydroxybutyric acid in an a suitable pharmaceutical carrier (vehicle) or excipient amount from about 5mg/kg to about 100mg/kg/day. as understood by practitioners in the art. EPO and ac- 15 Gamma-hydroxybutyric acid is available from Sigma ceptable forms of EPO are discussed above. Chemical. The chemical formula of gamma-hydroxybu- [0079] Examples of pharmaceutically acceptable car- tyric acid is C4 H7 O3 Na. riers and excipients include starch, milk, sugar, certain [0090] The amount of a drug that improves retinal per- types of clay, gelatin, stearic acid or salts thereof, mag- fusion in the composition can vary and may depend up- nesium or calcium stearate, talc, vegetable fats or oils, 20 on the amount of GABAergic drug administered and the gums and glycols. mammal being treated. Examples of suitable amounts [0080] The compositions of the invention may be ad- of drugs that improve retinal reperfusion have been dis- ministered by methods known in the art, typically, sys- closed above, and can be further determined by those temically. Systemic administration can be enteral or skilled in the art during pre-clinical and clinical trials. parenteral. Enteral administration is a preferred route of 25 [0091] The amount of EPO in the composition can delivery of the compositions. Liquid or solid (e.g., tab- vary and may depend upon the amount of GABAergic lets, gelatin capsules) formulations can be employed. drug administered and the mammal being treated. Ex- [0081] Administration can also be accomplished by a amples of suitable amounts of EPO have been dis- nebulizer or liquid mist. Optical administration is pre- closed above, and can be further determined by those ferred (e.g. eye drops). Parenteral administration of the 30 skilled in the art during pre-clinical and clinical trials. compositions of the invention (e.g., intravenous, intra- muscular, subcutaneous injection) is also contemplat- ed. Formulations using conventional diluents, carriers, Claims etc. such as are known in the art can be employed to deliver the compound. 35 1. A method for treating visual field defects associated [0082] The compositions may be in a sustained re- with the use of a GABAergic drug in a mammal in lease formulation, as is known in the art. Sustained re- need thereof comprising administering to the mam- lease administration, as discussed above, allows one to mal an effective amount of a drug that improves ret- achieve a certain level of the drug over a particular pe- inal perfusion. riod of time. 40 [0083] Preferably, the composition contains a 2. A method according to claim 1, wherein the GABAergic drug in an amount which is effective for the GABAergic drug is gamma vinyl GABA. purpose intended, such as treatment of seizure disorder or drug addiction, but has little or no adverse effects. For 3. A method according to claim 1, wherein the drug example, the amount of GVG in the composition is from 45 that improves retinal perfusion is a . about 15mg/kg to about 2g/kg or from about 15mg/kg to about 600mg/kg. 4. A method according to claim 1, wherein the drug [0084] A composition containing gabapentin will in- that improves retinal perfusion is a prostaglandin clude gabapentin in an amount from about 500mg to analog. about 2g/day. Gabapentin is available as Neurontin® 50 from Parke-Davis in the United States. 5. A method according to claim 1, wherein the drug [0085] A composition containing valproic acid will in- that improves retinal perfusion is a adrenergic ago- clude valproic acid in an amount from about 5mg/kg to nist. about 100 mg/kg/day. Valproic acid is available as De- pakene® from Abbott in the United States. 55 6. A method according to claim 1, wherein the drug [0086] A composition containing topiramate acid will that improves retinal perfusion is a cholinergic ag- include topiramate in an amount from about 50mg to onist. about 1g/day is available as Topamax® from McNeil in

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7. A method according to claim 1, wherein the drug 21. A method according to claim 20, wherein the eryth- that improves retinal perfusion is a carbonic anhy- ropoietin is recombinant human erythropoietin. drase inhibitor. 22. A composition comprising a GABAergic drug and 8. A method according to claim 1, wherein the drug 5 an effective amount of erythropoietin. that improves retinal perfusion is a alpha-adrener- gic .

9. A method according to claim 1, wherein the drug that improves retinal perfusion is selected from the 10 group consisting of pentoxifylline, puerarin deriva- tives, notropyrazole derivatives, inhibitors of nitric oxide synthase and combinations thereof.

10. A method according to claim 1, wherein the mam- 15 mal is a human.

11. A composition comprising a GABAergic drug and an effective amount of a drug that improves retinal perfusion. 20

12. A composition according to claim 11, wherein the drug that improves retinal perfusion is a beta block- er. 25 13. A composition according to claim 11, wherein the drug that improves retinal perfusion is a prostaglan- din analog.

14. A composition according to claim 11, wherein the 30 drug that improves retinal perfusion is a adrenergic agonist.

15. A composition according to claim 11, wherein the drug that improves retinal perfusion is a cholinergic 35 agonist.

16. A composition according to claim 11, wherein the drug that improves retinal perfusion is a carbonic anhydrase inhibitor. 40

17. A composition according to claim 11, wherein the drug that improves retinal perfusion is a alpha- adrenergic agonist. 45 18. A composition according to claim 11, wherein the drug that improves retinal perfusion is selected from the group consisting of pentoxifylline, puerarin de- rivatives, notropyrazole derivatives, inhibitors of ni- tric oxide synthase and combinations thereof. 50

19. A composition according to claim 11, wherein the GABAergic drug is gamma vinyl GABA.

20. A method for treating visual field defects associated 55 with use of a GABAergic drug in a mammal in need thereof comprising administering to the mammal an effective amount of erythropoietin.

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