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Methods of Treating Fragile X Syndrome

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(19) TZZ __T (11) EP 2 578 216 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 10.04.2013 Bulletin 2013/15 A61K 31/195 (2006.01) A61K 31/428 (2006.01) A61K 31/215 (2006.01) A61P 25/00 (2006.01) (2006.01) (21) Application number: 12184579.6 A61P 43/00 (22) Date of filing: 21.11.2007 (84) Designated Contracting States: • Roberts, Kathryn AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Fairfield, CT Connecticut CT 06824 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE •Bear,Mark F SI SK TR Boston, MA Massachusetts MA 02118 (US) Designated Extension States: AL BA HR MK RS (74) Representative: Kirkham, Nicholas Andrew et al Graham Watt & Co. LLP (30) Priority: 22.11.2006 US 860733 P St. Botolph’s House 02.11.2007 US 1567 P 7-9 St. Botolph’s Road Sevenoaks, Kent TN13 3AJ (GB) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 07862184.4 / 2 083 811 •This application was filed on 14-09-2012 as a divisional application to the application mentioned (71) Applicant: Seaside Therapeutics, Inc. under INID code 62. Cambridge, MA 02139 (US) •Claims filed after the date of filing of the application (Rule 68(4) EPC). (72) Inventors: • Carpenter, Randall L Boston, MA Massachusetts MA 02116 (US) (54) Methods of treating fragile x syndrome (57) Subjects having at least one condition selected a GABA(B) agonist, such as baclofen. GABA (B) agonists from the group consisting of mental retardation, Down’s can be used in combination with Group I mGluR antag- syndrome, fragile X syndrome and autism are treated onists and MI muscarinic receptor antagonists in meth- with a composition that includes gamma-am inobutyric ods of treating humans. acid agonists and/or MI muscarinic receptor antagonists. The gamma-am inobutyric acid agonist (GABA) can be EP 2 578 216 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 578 216 A1 Description RELATED APPLICATIONS 5 [0001] This application claims the benefit of U.S. Provisional Application No. 60/860,733, filed on November 22, 2006, and U.S. Provisional Application entitled "Use of M1 Muscarinic Antagonists to Treat Disorders of Brain Development," by Randall L. Carpenter, filed November 2, 2007, Attorney Docket No.: 3933.1007-000. The entire teachings of the above applications are incorporated herein by reference. 10 BACKGROUND OF THE INVENTION [0002] Mental retardation, Down’s syndrome, fragile X syndrome and autism are developmental and genetic disorders that affect day to day functioning, including learning, memory, speech, social skills and behavior. Currently available treatment regimens for humans with mental retardation, Down’s syndrome, fragile X syndrome and to assist in day-to- 15 day functioning, include, for example, behavioral modifications and treatment with a range of medications including anti- depressant and anti-psychotic drugs. However, such regimens frequently are not effective or may produce undesirable side-effects with long term use, particularly the use of anti-psychotic drugs. Thus, there is a need to develop new, improved and effective methods to treat mental retardation, Down’s syndrome, fragile X syndrome and autism. 20 SUMMARY OF THE INVENTION [0003] The present invention relates to a method of treating humans having mental retardation, Down’s syndrome, fragile X syndrome and autism. [0004] In one embodiment, the invention is a method of treating a human, comprising the step of administering to a 25 human having at least one condition selected from the group consisting of Down’s.syndrome, fragile X syndrome and autism a composition that includes a gamma-aminobutyric acid agonist. [0005] In another embodiment, the invention is a method of treating a human, comprising the step of administering to a human having at least one condition selected from the group consisting of Down’s Syndrome, fragile X syndrome and autism a composition that includes Formula I: 30 35 40 [0006] In yet another embodiment, the invention is a method of treating a human, comprising the step of administering 45 to a human having at least one condition selected from the group consisting of mental retardation, Down’s syndrome, fragile X syndrome and autism a composition that includes baclofen, wherein the baclofen is administered to the human at a dose of about 2 mg per day for days 1, 2 and 3 of treatment, a dose of about 4 mg per day for days 4, 5 and 6 of treatment, a dose of about 6 mg per day for days 7, 8 and 9 of treatment, a dose of about 10 mg per day for days 10, 11 and 12 of treatment, a dose of about 20 mg per day for days 13, 14 and 15 of treatment, a dose of about 30 mg per 50 day for days 16, 17 and 18 of treatment and a dose between about 30 mg to about 80 mg per day for the duration of the treatment. [0007] In an additional embodiment, the invention is a method of treating a human, comprising the step of administering to a human having at least one condition selected from the group consisting of mental retardation, Down’s syndrome, fragile X syndrome and autism a composition that includes baclofen, wherein the baclofen is administered to the human 55 at a dose of about 15 mg for days 1, 2 and 3 of treatment, a dose of about 30 mg for days 4, 5 and 6 of treatment, a dose of about 45 mg for days 7, 8 and 9 of treatment, a dose of about 60 mg for days 10, 11 and 12 of treatment and a dose between about 60 mg to about 80 mg per day for the duration of the treatment. [0008] In still another embodiment, the invention is a method of treating a human, comprising the step of administering 2 EP 2 578 216 A1 to a human having at least one condition selected from the group consisting of mental retardation, Down’s syndrome, fragile X syndrome and autism a composition that includes at least about 51 mole percent S-baclofen relative to the total S-baclofen and R-baclofen in the composition administered to the human. [0009] In a further embodiment, the invention is a method of treating a human, comprising the step of administering 5 to a human having at least one condition selected from the group consisting of mental retardation, Down’s syndrome, fragile X syndrome and autism a composition that includes at least about 51 mole percent R-baclofen relative to the total R-baclofen and S-baclofen in the composition administered to the human. [0010] An additional embodiment of the invention is a method of treating a human, comprising the step of administering to a human having at least one condition selected from the group consisting of mental retardation, Down’s syndrome, 10 fragile X syndrome and autism a composition that includes baclofen, wherein the baclofen is administered to the human at a dosing regimen of at least one member selected from the group consisting of about 1 mg twice a day, about 2 mg twice a day, about 3 mg twice a day, about 5 mg twice a day, about 10 mg twice a day and about 10 mg three times a day. [0011] In yet another embodiment, the invention is a method of treating a subject, comprising the step of administering to a subject having at least one condition selected from the group consisting of mental retardation, Down’s syndrome, 15 fragile X syndrome and autism a composition that includes at least one M1 muscarinic antagonist. [0012] Advantages of the claimed invention can include, for example, treatment of mental retardation, Down’s syn- drome, fragile X syndrome and autism in a manner that can improve symptoms (e.g., reduce anxiety and irritability; increase cognitive function, communication and/or social interaction), efficacy or reduce side effects and thereby improve tolerability for use over a relatively long period of time wit hout significant side effects. The methods of the invention can 20 provide an effective manner to treat a subject having mental retardation, Down’s syndrome, fragile X syndrome and/or autism. BRIEF DESCRIPTION OF THE DRAWINGS 25 [0013] Figure 1 depicts the effects of racemic baclofen on the inhibition of marble-burying behavior in fragile X (Fmrl) knock out (KO) mice (n = 7-8 mice/group). Data are expressed as the mean 6 SEM number of marbles buried. Figure 2 depicts the effects of R(+)-baclofen on marble-burying behavior in Fmrl KO mice (n = 10-16 mice/group). 30 Data are expressed as the mean marbles buried 6 SEM. An asterik (*) indicates data for the 10 mg/kg dose was significantly less (p < 0.05) than all other groups. Figure 3 depicts the effects S(-)-baclofen on marble-burying behavior of Fmr1 KO mice (n = 11-15 mice/group). Data are expressed as the mean number of marbles buried 6 SEM. The # symbol indicates that the data for the 1 mg/kg dose was significantly greater than the 0 mg/kg dose. The asterik (*) indicates that the 50 mg/kg dose was 35 significantly different (p< 0.05) than all other groups. Figure 4 depicts the effect of R(+)-baclofen and S(-)-baclofen on audiogenic seizures in Fmr1 KO mice (n = 9-10 mice/group). Data are expressed as a percentage of mice treated with vehicle (0 mg/kg), (+)-R or S(-)-baclofen, that exhibited audiogenic seizures. Figure 5 depicts the effect of R(+)- and S(-)-baclofen on open-field activity of Fmr1 KO male mice.
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  • Tourette's Syndrome

    Tourette's Syndrome

    Tourette’s Syndrome CHRISTOPHER KENNEY, MD; SHENG-HAN KUO, MD; and JOOHI JIMENEZ-SHAHED, MD Baylor College of Medicine, Houston, Texas Tourette’s syndrome is a movement disorder most commonly seen in school-age children. The incidence peaks around preadolescence with one half of cases resolving in early adult- hood. Tourette’s syndrome is the most common cause of tics, which are involuntary or semi- voluntary, sudden, brief, intermittent, repetitive movements (motor tics) or sounds (phonic tics). It is often associated with psychiatric comorbidities, mainly attention-deficit/hyperac- tivity disorder and obsessive-compulsive disorder. Given its diverse presentation, Tourette’s syndrome can mimic many hyperkinetic disorders, making the diagnosis challenging at times. The etiology of this syndrome is thought to be related to basal ganglia dysfunction. Treatment can be behavioral, pharmacologic, or surgical, and is dictated by the most incapacitating symp- toms. Alpha2-adrenergic agonists are the first line of pharmacologic therapy, but dopamine- receptor–blocking drugs are required for multiple, complex tics. Dopamine-receptor–blocking drugs are associated with potential side effects including sedation, weight gain, acute dystonic reactions, and tardive dyskinesia. Appropriate diagnosis and treatment can substantially improve quality of life and psychosocial functioning in affected children. (Am Fam Physician. 2008;77(5):651-658, 659-660. Copyright © 2008 American Academy of Family Physicians.) ▲ Patient information: n 1885, Georges Gilles de la Tourette normal context or in inappropriate situa- A handout on Tourette’s described the major clinical features tions, thus calling attention to the person syndrome, written by the authors of this article, is of the syndrome that now carries his because of their exaggerated, forceful, and provided on p.