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 drugs 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 drug 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 epilepsy. 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 vigabatrin 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 gabapentin, valproic acid, progabide, gamma-hydroxy- [0009] These and other objectives have been met by butyric acid, fengabine, cetylGABA, topiramate, 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 prodrugs 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 prodrug 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, nicotine and caffeine, Roussel. GVG is an irreversible inhibitor of the pyri- narcotics and pain medications such as morphine and doxal-phoshate dependent enzyme GABA transami- methadone, and central nervous system depressants nase (GABA-T) and is responsible for metabolizing such as barbiturates, chlordiazepoxide 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.