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WO 2010/015037 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 11 February 2010 (11.02.2010) WO 2010/015037 Al (51) International Patent Classification: (74) Agents: MUTIMER, Helen, P. et al; Davies Collison A61K 31/4184 (2006.01) A61P 25/16 (2006.01) Cave, 1 Nicholson Street, Melbourne, VIC 3000 (AU). A61K 31/4741 (2006.01) A61P 25/00 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 31/198 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, PCT/AU2009/001012 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 7 August 2009 (07.08.2009) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (25) Filing Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (30) Priority Data: TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/087,497 !August 2008 (08.08.2008) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): kind of regional protection available): ARIPO (BW, GH, HOWARD FLOREY INSTITUTE [AU/AU]; Gate 11, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Royal Parade, The University of Melbourne, Parkville, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Victoria 3010 (AU). TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors; and MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (75) Inventors/Applicants (for US only): AUMANN, Timo¬ TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, thy, Douglas [AU/AU]; Gate 11, Royal Parade, The Uni ML, MR, NE, SN, TD, TG). versity of Melbourne, Parkville, Victoria 3010 (AU). HORNE, Malcolm [AU/AU]; Gate 11, Royal Parade, Published: The University of Melbourne, Parkville, Victoria 3010 — with international search report (Art. 21(3)) (AU). (54) Title: THERAPEUTIC METHODS AND COMPOSITIONS (57) Abstract: The present invention is generally directed to the field of neurological therapy. More particularly, the present in vention contemplates therapeutic protocols for neurological conditions associated with dopamine deficiency including pharmaceu tical compositions for use in such therapeutic protocols. THERAPEUTIC METHODS AND COMPOSITIONS This application is associated with and claims priority from United States Patent Application No. 61/087,497, filed on 8 August, 2008, the entire contents of which, are incorporated herein by reference. FIELD The present invention is generally directed to the field of neurological therapy. More particularly, the present invention contemplates therapeutic protocols for neurological conditions associated with abnormal levels of dopamine including pharmaceutical compositions for use in such therapeutic protocols. BACKGROUND Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that this prior art forms part of the common general knowledge in any country. Dopamine is a hormone and neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, dopamine functions as a neurotransmitter, activating the five types of dopamine receptor, Dl, D2, D3, D4 and D5, and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and hypothalamus. Dopamine is associated with many neurological activities, including having important roles in behavior and cognition, motor activity, motivation and reward, regulation of milk production, sleep, mood, attention and learning. Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is dopamine) are present in the ventral tegmental area (VTA) of the midbrain, substantia nigra pars compacta, arcuate nucleus of the hypothalamus, olfactory bulb and retina. Accordingly, abnormal levels of dopamine (i.e. either too much or too little) has a major impact on the health of an individual. For example, based on its neurological pleiotrophy, dopamine deficiency is associated with such symptoms as resting tremor, rigidity, bradykinesia (slowing of physical movement), postural instability, physical fatigue, overt fatigue and lethargy, negative behavioral feelings, concentration deficit, weight gain, addictive behavior, reduced libido and/or impotence, depression, alcoholism and attention deficit and hyperactivity disorder (ADHD). One disease associated with dopamine deficiency is Parkinson's disease (also known as "Parkinson disease" or "PD"). PD is a chronic and progressive degenerative disorder of the central nervous system that impairs movement, speech and other functions. PD is characterized by motor symptoms including muscle rigidity, tremor, bradykinesia and, in extreme cases, a loss of physical movement (akinesia). Non-motor symptoms include pain/discomfort, anxiety, depression, slowness of thinking, memory deficits, tiredness, disturbed sleep, constipation, bladder problems, sexual difficulties, speech and swallowing difficulties. The primary motor symptoms are the result of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain, particularly those in the substantia nigra. PD is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise and nutrition. At present, there is no cure for PD, but medications or surgery can provide some relief from the motor symptoms, at least in the short- to medium-terms (5-10 years on average). Neurological disease and disorders contribute immense distress to families and potential injuries to patients, and represent a major cost burden to the community and the healthcare system. There is a need to further develop therapeutic protocols to treat neurological disease conditions such as those associated with dopamine deficiency. SUMMARY Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The present invention relates generally to neurological therapy, and in particular the treatment or prevention of neurological conditions which include neurological diseases and disorders as well as neurodegenerative conditions associated with abnormal levels of dopamine. By "abnormal" dopamine levels it is meant a deficiency or elevation in the level of dopamine. This is generally determined relative to a subject regarded as healthy i.e. with no symptoms of a neurological disorder. It may also be determined by a standardized control based in the measurement of a range of subjects over time. In cases where there is a deficiency in the level of dopamine, the present invention contemplates promoting recruitment of new dopaminergic cells. Examples of nneurological diseases and conditions associated with a dopamine deficiency contemplated for treatment herein include Parkinson's Disease (PD), dystonia, Tourettes syndrome, restless legs, certain psychoses, attention deficit and hyperactivity disorder (ADHD), cognition disorders, motor control disorders, abnormal lactation, sleep disorders, memory deficit, attention deficit, problem solving deficit, learning deficit, abnormal moods, social disorders, abnormal libido, anhedonia and eating disorders. In cases where there is an elevated level of dopamine, the present invention provides for decreasing the number of dopaminergic cells. Such neurological diseases and conditions associated with enhanced levels of dopamine include schizophrenia, drug addiction, obsessive compulsive disorder, mania and certain psychoses. Accordingly, the present invention is directed, in one aspect, to a method for treating or preventing a neurological disease or disorder associated with decreased dopamine levels in a subject, the method comprising administering to the subject an agent which modulates neuronal cell excitability, thereby increasing dopaminergic cells. Also contemplated herein is the use of an agent which modulates neuronal excitability in the manufacture of a medicament for treating a neurological condition, and in particular, a neurological condition associated with dopamine deficiency. "Modulates" refers to targeting different cell surface molecules to either decrease or increase neuronal excitability thereby altering the number of dopaminergic cells. The present invention also contemplates a method of preventing or treating a neurological condition associated with enhanced levels of dopamine, the method comprising administering to a subject an agent which modulates neuronal cell excitability, thereby decreasing the number of dopaminergic cells. Also contemplated is the use of an agent which modulates neuronal excitability in the manufacture of a medicament for treating a neurological condition, and in particular, a neurological
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