WO2012048871A1 - Mémantine pour l'amélioration de la performance cognitive chez des sujets - Google Patents

Mémantine pour l'amélioration de la performance cognitive chez des sujets Download PDF

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Publication number
WO2012048871A1
WO2012048871A1 PCT/EP2011/005123 EP2011005123W WO2012048871A1 WO 2012048871 A1 WO2012048871 A1 WO 2012048871A1 EP 2011005123 W EP2011005123 W EP 2011005123W WO 2012048871 A1 WO2012048871 A1 WO 2012048871A1
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memantine
subject
cognitive
impairment
suffering
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PCT/EP2011/005123
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English (en)
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Frank Tennigkeit
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Merz Pharma Gmbh & Co. Kgaa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine

Definitions

  • the present invention relates to a use of memantine for improving cognitive performance of a subject with subjective cognitive impairment.
  • Memantine (1-amino-3,5-dimethyl adamantine) is a systemically-active uncompetitive NMDA receptor antagonist having moderate affinity for the receptor and strong voltage dependency and rapid blocking/unblocking kinetics. Memantine has been shown to be useful in alleviation of various progressive neurodegenerative disorders such as dementia in patients with moderate to severe Alzheimer's disease, Parkinson's disease, and spasticity (see, e.g., U. S. Patents No. 5,061 ,703; 5,614,560, and 6,034,134). Memantine is approved for the treatment of moderate to severe Alzheimer's disease (AD) by the FDA and the EMA.
  • AD moderate to severe Alzheimer's disease
  • Memantine has been used to treat age-associated memory impairment, diagnosed by a standardized memory test and the MMSE ContinueA double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI)", Ferris, S. et al., Int J Geriatr Psychiatry 2007; 22(5):448-55).
  • the patients were given a daily dose of 20 mg/day.
  • the criteria for a diagnosis of AAMI include objective evidence of memory problems below the norm compared with healthy young adults (Crook et al. Dev. Neuropsychol. 1986; 2:261- 76.).
  • Memantine has also been used to improve cognition in patients with mild cognitive impairment (MCI) and moderate cognitive impairment diagnosed by the MMSE and a cognitive testing battery (Memantine Improves Cognition in Patients With Mild Cognitive Impairment: Presented at the 9th International Conference on Alzheimer's and Parkinson's Diseases (ADPD); Presentation title: Open-Label, Control-Group Study to Evaluate Effectiveness of Akatinol Memantine in Patients With Non-Dementia Cognitive Impairments. Abstract P413).
  • MCI mild cognitive impairment
  • ADPD Alzheimer's and Parkinson's Diseases
  • Memantine has further been used to improve cognition in patients with cognitive impairment in moderate to severe Alzheimers disease (Reisberg et al. NEJM 2003; 348(14):1333-41 , Winblad et al. Dement Geriatr Cogn Disord 2007; 24(1):20-7.).
  • Subjective cognitive impairment is defined by subjective complaints of memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing) and is defined in accordance with Reisberg et al, Alzheimers & Dementia 2010; 6(1): 11-24.
  • SCI can be a prodromal form of mild cognitive impairment (MCI) and dementia.
  • MCI mild cognitive impairment
  • dementia dementia
  • MCI cognitive disorders
  • cognitive disorders are characterized by memory and/or other cognitive impairments, objectively measured by psychometric tests (e.g. the Mini- Mental State Examination and others, for details see Petersen et al. Neurology 2001 ; 56(9): 1133-42) and below defined norm values.
  • MCI is defined (among other criteria) by "impairment on objective cognitive tasks; and/or evidence of decline over time on objective cognitive tasks. "(Winblad et al. J. Int. Med. 2004; 256:240-246).
  • Criteria for the diagnosis of Alzheimers dementia also include "clinical and neuropsychological evaluation” (McKhann et al. Neurology 1984; 34(7):939-44.).
  • Subjects with SCI or SMI have a higher probability to progress to MCI and dementia compared to normal control subjects (Reisberg et al., Alzheimers & Dementia 2010; 6(1):11-24; Jessen et al. Arch. Gen. Psych. 2010; 67(4):414 - 422).
  • One object of the invention is to broaden the hitherto known application spectrum of memantine. This and other objects are solved by the subject application.
  • memantine may be used for improving cognitive performance in a subject with subjective cognitive impairment.
  • the invention relates to memantine for use in improving cognitive performance in a subject by administering an effective amount of memantine to said subject, wherein the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia.
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • memantine is administered to a subject that is suffering from subjective cognitive impairment (SCI), as defined by Reisberg et al. in Alzheimer's & Dementia (2010), Volume 6, pages 11 to 24, and/or wherein the subject is suffering from subjective memory impairment (SMI) as defined by Jessen et al.
  • SCI subjective cognitive impairment
  • Jessen et al Jessen et al.
  • GDS Global Deterioration Scale
  • said subject has no clinical symptoms of Alzheimer Dementia (AD-C) but shows an asymptomatic pathophysioloical manifestation of Alzheimer Dementia (AD-P), diagnosed preclinically by the presence of biomarkers as e.g. defined by Sperling et al. in Alzheimer & Dementia (2011), pages 1 to 13.
  • AD-P is defined in three stages, the stages being incorporated herein by reference:
  • Stage 1 The stage of asymptomatic cerebral amyloidosis which is characterized inter alia by high PET amyloid tracer retention and/or low CSF ⁇ 4 2-
  • Stage 2 Amyloid positivity and evidence of synaptic dysfuntion and/or early neurodegeneration characterized inter alia by neuronal dysfunction on FDG- PET/fMRI and/or high CSF tau/p-tau and / or cortical thinning/hippocampal atrophy on sMRI.
  • Stage 3 Amyloid positivity and evidence of neureodegeneration and subtle cognitive decline.
  • said improvement of cognitive performance is or comprises the enhancement of the subject's cognition.
  • said improvement of cognitive performance is or comprises the enhancement of the subject's memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing).
  • other cognitive problems e.g. attention, learning aptitude, concentration, language and speed of information processing.
  • said improvement of cognitive performance is or comprises the slowing down or prevention of cognitive worsening in said subject.
  • memantine is administered to said subject in a dose of below 20 mg/day, e.g. 10 mg/day.
  • the subject application relates to memantine for use in the treatment of a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI) or mild cognitive impairment (MCI), wherein memantine is administered to a subject suffering from said disorder in a dose of below 20 mg/day, e.g. 10 mg/day.
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • memantine is administered to said subject in a twice daily dose, or in a single dose.
  • memantine may be co-administered with one or more other compound known to improve brain function, such as, but not limited to ginkgo extract, piracetam, nimodipine, nicergolin, acetylcholine esterase inhibitors, and mixtures of two or more thereof.
  • the acetylcholine esterase inhibitor is selected from donepezil, rivastigmine and galantamine, and combinations of two or more thereof.
  • memantine is in the form of an over-the-counter preparation.
  • memantine is in the form of a pharmaceutically acceptable salt.
  • the subject is a human being. In another embodiment the subject is at least 6 years and up to 50 years old, e.g. 10 to 50 years or 10 to 30 years old. In another embodiment, the subject is above 50 years to 80 years old.
  • the present application relates to the use of Memantine for improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from, mild cognitive impairment (MCI) to dementia.
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • the subject shows a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2.
  • GDS Global Deteleration Scale
  • the present invention relates to memantine for use in improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia.
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • the term "subject” encompasses both a human being and an animal. In its broadest definition, the subject is one that is not suffering from a "disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia".
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • AAMI age-associated memory impairment
  • dementia any disorder being associated with a cognitive condition as defined above. This definition includes these conditions per se, i.e. as the sole condition under which the subject is suffering. It also includes conditions, where AAMI, MCI or dementia are the result or a side effect of a different, underlying disease, such as Parkinson's disease, Multiple Sclerosis, depression, schizophrenia, bipolar disorder, brain cancer (tumors), aphasia, and stroke.
  • MCI cognitive impairment
  • MCI mild cognitive impairment
  • AAMI age associated memory impairment
  • the subject is one that is suffering from subjective cognitive impairment (SCI) as defined in Reisberg et al., Alzheimer's and Dementia (2010), 6, pages 11-24.
  • condition subjective cognitive impairment is synonymous with a rating of Global Deterioration Scale (GDS) of 2.
  • GDS Global Deterioration Scale
  • the subject is suffering from subjective memory impairment (SMI) as defined by Jessen et al. in Arch Gen Psychiatry (2010) 67, pages 414 to 422.
  • SI subjective memory impairment
  • the subject has a rating within the Global Deterioration Scale (GDS) as defined by Reisberg et al. in Am J Psych, (1982) 139, pages 1136 to 1139 of lower than 3.
  • GDS Global Deterioration Scale
  • the respective GDS ratings are defined as follows, the definition being incorporated herein by reference:
  • this subject is of GDS stage 2 or lower, e.g. GDS stage 1 or 2. Again, it is to note that this definition is meant to not include subjects suffering from AAMI.
  • the subject is of GDS stage 2 and be up to 50 years old, e.g. 6 to 50 or 10 to 30 years old.
  • the subject is of GDS stage 2 or lower, and the dosing of memantine is less than 20 mg/day, e.g. 10 mg/day.
  • This definition includes subjects of GDS stage 1 or 2, which are being dosed as defined hereinabove. Again this definition does not include subjects suffering from a disorder being or being accompanied by AAMI.
  • the term "improving cognitive performance” as used for the purpose of this application defines the ability of memantine to enhance the cognitive performance of a subject in comparison to placebo or in comparison to the non- administration of memantine.
  • the term “improvement of cognitive performance” means in its broadest meaning an enhancement of the subject's cognition, including but not limited to the enhancement of the subject's memory, attention, learning aptitude, concentration, language and speed of information processing or any combination of two or more thereof. It also encompasses the slowing down or prevention of cognitive worsening in said subject.
  • the above defined “improvement of cognitive performance” may potentially be corroborated by cognitive effects objectively measurable by a neuropsychological testing battery and effects on higher activities of daily living.
  • Examples are computerized testing batteries such as the
  • CogState (cf. e.g. Collie A, Maruff P, Darby DG, et al. The effects of practice on the cognitive test performance of neurologically normal individuals assessed at brief test-retest intervals, J Int Neuropsychol Soc. 2003 Mar;9(3):419-28 and Pietrzak RH, Maruff P, Mayes LC, et al. An examination of the construct validity and factor structure of the Groton Maze Learning Test, a new measure of spatial working memory, learning efficiency, and error monitoring, Arch Clin Neuropsychol. 2008 Jul;23(4):433-45),
  • CANTAB Cosmetic Neuropsychological Test Automated Battery
  • Sahakian BJ Owen AM Computerized assessment in neuropsychiatry using CANTAB: discussion paper, J R Soc Med. 1992 Jul;85(7):399-402 and Egerhazi A, Berecz R, Bartok E, Degrell I Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease, Prog Neuropsychopharmacol Biol Psychiatry. 2007 Apr 13;31(3):746-51. Epub 2007 Jan 16),
  • CDR Cognitive Drug Research Computerized Assessment System
  • COGDRAS Cognitive Drug Research Computerized Assessment System
  • testing batteries may be used, such as the
  • MMSE cf e.g. Folstein, M.F., Folstein, S.E., McHugh, P.R. Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician, J. Psychiatr. Research 12, 189-198, 1975
  • ADAS cog Alzheimer's Disease Assessment Scale
  • NTB (cf e.g. Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological test battery for use in Alzheimer disease clinical trials, Arch Neurol. 2007 Sep;64(9): 1323-9) or the
  • Everyday Cognition 39 item version (Ecog 39) (cf e.g. Farias ST, Mungas D, Reed BR, et al. The measurement of everyday cognition (ECog): scale development and psychometric properties, Neuropsychology 2008 Jul;22(4):531-44) battery. [0066] In one embodiment improvement of cognitive performance is thus assessed via the CogState as defined above.
  • improvement of cognitive performance is thus assessed via the CANTAB as defined above.
  • improvement of cognitive performance is thus assessed via the CDR (COGDRAS) as defined above.
  • improvement of cognitive performance is thus assessed via the MMSE as defined above.
  • improvement of cognitive performance is thus assessed via the ADAS cog as defined above.
  • improvement of cognitive performance is thus assessed via the NTB as defined above.
  • improvement of cognitive performance is thus assessed via the Ecog 39 as defined above.
  • the subject to be treated may be one with a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2.
  • GDS Global Deteleration Scale
  • Improvement of cognitive performance can also be assessed based on subjective assessment, e.g. by answering the question "Check the number that best describes how your memory, concentration, or attention problems are now, compared to how it was before you began taking medication"".
  • the subject to be treated may be one with a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2.
  • GDS Global Deteleration Scale
  • the improvement of cognitive performance is or comprises the enhancement of the subject's cognition.
  • Cognition is the scientific term for "the process of thought”. Cognition encompasses the ability of the brain to think, to process, communicate and store information, and to solve problems. Cognition is a high level of behavior, preferably unique to humans.
  • the term “cognitive” encompasses functions or processes such as perception, introspection, memory, creativity, communication, concentration, attention, in other words, things which can be performed with the mind.
  • said method comprises the enhancement of the subject's memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing). [0080] In another embodiment, said method is the enhancement of the subject's memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing.
  • memory encompasses an organism's ability to store, retain, and recall information.
  • speed information processing refers to the prediction of how fast an individual can process information in a given amount of time and under given conditions.
  • the term "attention” is the cognitive process of selectively concentrating on one aspect of the environment while ignoring other things.
  • concentration is the cognitive process of selectively concentrating on one aspect of the environment for a longer time period while ignoring other things.
  • language is the cognitive process of understanding and communicating thoughts, percepts and other cognitive concepts.
  • learning aptitude refers to the prediction of how well an individual can learn in a given amount of time and under given conditions.
  • the "forgetfulness” also called “forgetting" within a subject to be treated is improved.
  • the term u forgetfulness'T forgetting" refers to apparent loss of information already encoded and stored in an individual's long term memory. Stated differently, it is a persistent failure to remember.
  • said memantine is administered to said subject in a dose which is not sufficient to treat a mental disorder or cognitive disorder.
  • said memantine is administered to said subject in a dose which is less than 20 mg/day.
  • the dose is 10 mg/day.
  • said memantine is administered to said subject in a daily dose.
  • said memantine is administered to said subject in a single dose.
  • said memantine is administered to said subject in an oral dose.
  • said subject prior to the administration of said memantine to said subject, said subject is not up-titrated with a dose of memantine that exceeds 10 mg/day.
  • not up-titrated means that memantine is not administered to the subject prior to the administration of memantine according to the method according to the invention in one or more doses of less than 20 mg/day.
  • a concomitant administration with a medication or medications to said subject is excluded which have an effect on an brain syndrome or mental disorder or cognitive disorder.
  • memantine is the sole compound to be administered to the subject. Accordingly, memantine is not administered to said subject concomitantly to or in combination with a medication which has an effect on a mental disorder or cognitive disorder. In a further embodiment, memantine is not administered to said subject prior to, simultaneously to, or subsequently to said medication.
  • memantine is administered together with other compounds that are capable of improving brain function, including but not limited to ginkgo extract, piracetam, nimodipine, nicergolin and acetylcholine esterase inhibitors, such as those disclosed in EP 1 509 232 A2, e.g. Donepezil, Rivastigmine, Galantamine, and combinations of two or more thereof.
  • memantine is not administered concomitantly to isosorbide dinitrate (ISDN), or in combination with ISDN.
  • ISDN isosorbide dinitrate
  • memantine is not administered prior to, simultaneously to, or subsequently to ISDN.
  • said memantine is administered to said subject in an over-the-counter preparation.
  • over-the-counter preparation encompasses a pharmaceutical formulation which is available without prescription.
  • the OTC may be prepared by procedures known in the art.
  • memantine can be formulated into tablets, capsules, powders, suspensions, solutions for oral administration, with common and conventional carriers, binders, diluents, and excipients.
  • Inert pharmaceutically acceptable excipients useful to form over-the- counter formulations in accordance with the present invention include starch, mannitol, calcium sulfate, dicalcium phosphate, magnesium stearate, silicic derivatives, and/or sugars such as sucrose, lactose, and glucose.
  • Binding agents include carboxymethyl cellulose and other cellulose derivatives, gelatin, natural and synthetic gums including alginates such as sodium alginate, polyethylene glycol, waxes and the like.
  • Diluents include a suitable oil, saline, sugar solutions such as aqueous dextrose or aqueous glucose, and glycols such as polyethylene or polypropylene glycol.
  • excipients include lubricants such as sodium oleate, sodium acetate, sodium stearate, sodium chloride, sodium benzoate, talc, and magnesium stearate, and the like; disintegrating agents including agar, calcium carbonate, sodium bicarbonate, starch, xanthan gum, and the like; and adsorptive carriers such as bentonite and kaolin. Coloring and flavoring agents may also be added to the over-the counter formulations.
  • lubricants such as sodium oleate, sodium acetate, sodium stearate, sodium chloride, sodium benzoate, talc, and magnesium stearate, and the like
  • disintegrating agents including agar, calcium carbonate, sodium bicarbonate, starch, xanthan gum, and the like
  • adsorptive carriers such as bentonite and kaolin. Coloring and flavoring agents may also be added to the over-the counter formulations.
  • said over-the-counter preparation is a tablet, capsule, powder, suspension, or solution.
  • said memantine is in the form of a pharmaceutically acceptable salt.
  • the term “pharmaceutically acceptable salts” refers to salts of memantine that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable salt means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • Conversion of memantine to a pharmaceutically acceptable salt thereof is accomplished in conventional fashion by admixture of the base with at least one molecular equivalent of a selected acid in an inert organic solvent. Isolation of the salt is carried out by techniques known to the art such as inducing precipitation with a non-polar solvent (e.g. ether) in which the salt has limited solubility.
  • a non-polar solvent e.g. ether
  • the nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • Examples of pharmaceutically acceptable salts are those formed with hydrochloric, hydrobromic, methanesulfonic, acetic, succinic, maleic, citric acid, and related acids.
  • Further pharmaceutically acceptable salts include, but are not limited to, acid addition salts, such as those made with hydroiodic, perchloric, sulfuric, nitric, phosphoric, propionic, glycolic, lactic, pyruvic, malonic, fumaric, tartaric, benzoic, carbonic, cinnamic, mandelic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid.
  • said pharmaceutically acceptable salt is the hydrochloride.
  • said subject is a human being.
  • said subject is a member of a group of people preparing for oral and/or written examinations.
  • said subject is a member of a group of people attending a school.
  • said subject is a pupil or a student.
  • said subject is a member of a group of people attempting to enhance cognition with regard to complex information such as new technical developments.
  • said subject did not learn said complex information at school, or said complex information have not been available when said subject visited school.
  • said subject is from 50 to 80 years old, or from 10 to 30 years old.
  • Memantine-HCI immediate release tablets with 10mg memantine-HCI ( 8.31 mg memantine) were administered to a first subject group once daily.
  • the dosage form is a 10mg film-coated lactose-free tablets (1 tablet/day) with the following excipients:
  • Excipients of tablet core microcrystalline cellulose, sodium croscarmellose,
  • colloidal anhydrous silica colloidal anhydrous silica, magnesium stearate.
  • Excipients of tablet coat Hypromellose, titanium dioxide E171 , Macrogol 400, iron oxide yellow E172.
  • matching placebo tablets are administered as film coated tablets to the second subject group.
  • the subject rates the development of his/her memory, concentration or attention problems on a 7-point scale from 1 (very much improved) to 7 (very much worsened) to measure the change compared to the baseline situation (day 0).
  • the scale presents seven tick boxes which are associated to the numeric values. [00126] It turns out that subjects receiving memantine in a dose of 10 mg/day over 12 weeks show a statistically significant improvement according to the above rating compared to a subject group which receives placebo.

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Abstract

La présente invention concerne la mémantine destinée être utilisée pour améliorer la performance cognitive chez un sujet par administration d'une quantité efficace de mémantine au dit sujet, caractérisée en ce que le sujet ne souffre pas d'un trouble qui est un trouble cognitif ou qui s'accompagne d'un trouble cognitif dont la gravité va d'un trouble cognitif léger (MCI), à la démence en passant par un trouble de la mémoire lié à l'âge (TMLA).
PCT/EP2011/005123 2010-10-12 2011-10-12 Mémantine pour l'amélioration de la performance cognitive chez des sujets WO2012048871A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061703A (en) 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
US5614560A (en) 1991-04-04 1997-03-25 Children's Medical Center Corporation Method of preventing NMDA receptor-mediated neuronal damage
US6034134A (en) 1997-06-30 2000-03-07 Merz + Co. Gmbh & Co. 1-Amino-alkylcyclohexane NMDA receptor antagonists
CA2558708A1 (fr) * 2002-05-31 2003-09-16 H. Lundbeck A/S Combinaison d'un antagoniste nmda et d'agents inhibiteurs d'acetylcholinesterase pour le traitement de la maladie d'alzheimer
EP1509232A1 (fr) 2002-05-31 2005-03-02 H. Lundbeck A/S Combinaison d'un antagoniste de n-methyl d-aspartate et d'inhibiteurs de l'esterase d'acetylcholine pour le traitement de la maladie d'alzheimer
WO2006096194A2 (fr) 2004-06-17 2006-09-14 Merz Pharma Gmbh & Co. Kgaa Formulations a liberation immediate de formes de dosage oral de memantine
US20060205822A1 (en) * 2004-12-22 2006-09-14 Forest Laboratories, Inc. 1-Aminocyclohexane derivatives for the treatment of multiple sclerosis, emotional lability and pseudobulbar affect
WO2007094755A2 (fr) * 2005-02-04 2007-08-23 Massachusetts Institute Of Technology Compositions et procédés de modulation de la fonction cognitive

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061703A (en) 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
US5614560A (en) 1991-04-04 1997-03-25 Children's Medical Center Corporation Method of preventing NMDA receptor-mediated neuronal damage
US6034134A (en) 1997-06-30 2000-03-07 Merz + Co. Gmbh & Co. 1-Amino-alkylcyclohexane NMDA receptor antagonists
CA2558708A1 (fr) * 2002-05-31 2003-09-16 H. Lundbeck A/S Combinaison d'un antagoniste nmda et d'agents inhibiteurs d'acetylcholinesterase pour le traitement de la maladie d'alzheimer
EP1509232A1 (fr) 2002-05-31 2005-03-02 H. Lundbeck A/S Combinaison d'un antagoniste de n-methyl d-aspartate et d'inhibiteurs de l'esterase d'acetylcholine pour le traitement de la maladie d'alzheimer
WO2006096194A2 (fr) 2004-06-17 2006-09-14 Merz Pharma Gmbh & Co. Kgaa Formulations a liberation immediate de formes de dosage oral de memantine
US20060205822A1 (en) * 2004-12-22 2006-09-14 Forest Laboratories, Inc. 1-Aminocyclohexane derivatives for the treatment of multiple sclerosis, emotional lability and pseudobulbar affect
WO2007094755A2 (fr) * 2005-02-04 2007-08-23 Massachusetts Institute Of Technology Compositions et procédés de modulation de la fonction cognitive

Non-Patent Citations (33)

* Cited by examiner, † Cited by third party
Title
COLLIE A, MARUFF P, DARBY DG ET AL.: "The effects of practice on the cognitive test performance of neurologically normal individuals assessed at brief test-retest intervals", J INT NEUROPSYCHOL SOC., vol. 9, no. 3, March 2003 (2003-03-01), pages 419 - 28
CROOK ET AL., DEV. NEUROPSYCHOL., vol. 2, 1986, pages 261 - 76
EGERHAZI A, BERECZ R, BARTOK E: "Degrell 1 Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease", PROG NEUROPSYCHOPHARMACOL BIOL PSYCHIATRY, vol. 31, no. 3, 13 April 2007 (2007-04-13), pages 746 - 51, XP022002958, DOI: doi:10.1016/j.pnpbp.2007.01.011
FARIAS ST, MUNGAS D, REED BR ET AL.: "The measurement of everyday cognition (ECog): scale development and psychometric properties", NEUROPSYCHOLOGY, vol. 22, no. 4, July 2008 (2008-07-01), pages 531 - 44
FERRIS STEVEN ET AL: "A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI)", INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, JOHN WILEY AND SONS, CHICHESTER, GB, vol. 22, no. 5, 1 May 2007 (2007-05-01), pages 448 - 455, XP009143808, ISSN: 0885-6230, [retrieved on 20061120], DOI: DOI:10.1002/GPS.1711 *
FERRIS, S. ET AL., INT J GERIATR PSYCHIATRY, vol. 22, no. 5, 2007, pages 448 - 55
FOLSTEIN, M.F., FOLSTEIN, S.E., MCHUGH, P.R.: "Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician", J. PSYCHIATR. RESEARCH, vol. 12, 1975, pages 189 - 198
HARRISON J, MINASSIAN SL, JENKINS L, BLACK RS, KOLLER M, GRUNDMAN M: "A neuropsychological test battery for use in Alzheimer disease clinical trials", ARCH NEUROL., vol. 64, no. 9, September 2007 (2007-09-01), pages 1323 - 9, XP002675391, DOI: doi:10.1001/archneur.64.9.1323
JESSEN ET AL., ARCH GEN PSYCHIATRY, vol. 67, 2010, pages 414 - 422
JESSEN ET AL., ARCH GEN PSYCHIATRY, vol. 67, no. 4, 2010, pages 414 - 422
JESSEN ET AL., ARCH. GEN. PSYCH., vol. 67, no. 4, 2010, pages 414 - 422
JESSEN FRANK ET AL: "Prediction of Dementia by Subjective Memory Impairment Effects of Severity and Temporal Association With Cognitive Impairment", ARCHIVES OF GENERAL PSYCHIATRY, AMERICAN MEDICAL ASSOCIATION, US, vol. 67, no. 4, 1 April 2010 (2010-04-01), pages 414 - 422, XP009143688, ISSN: 0003-990X *
MCKHANN ET AL., NEUROLOGY, vol. 34, no. 7, 1984, pages 939 - 44
PETERSEN ET AL., ARCH NEUROL., vol. 56, 1999, pages 303 - 307
PETERSEN ET AL., NEUROLOGY, vol. 56, no. 9, 2001, pages 1133 - 42
PIETRZAK RH, MARUFF P, MAYES LC ET AL.: "An examination of the construct validity and factor structure of the Groton Maze Learning Test, a new measure of spatial working memory, learning efficiency, and error monitoring", ARCH CLIN NEUROPSYCHOL., vol. 23, no. 4, July 2008 (2008-07-01), pages 433 - 45, XP022705549, DOI: doi:10.1016/j.acn.2008.03.002
REISBERG B ET AL: "Outcome over seven years of healthy adults with and without subjective cognitive impairment", ALZHEIMER'S & DEMENTIA: THE JOURNAL OF THE ALZHEIMER'SASSOCIATION, ELSEVIER, NEW YORK, NY, US, vol. 6, no. 1, 1 January 2010 (2010-01-01), pages 11 - 24, XP026834727, ISSN: 1552-5260, [retrieved on 20100107] *
REISBERG B ET AL: "THE GLOBAL DETERIORATION SCALE FOR ASSESSMENT OF PRIMARY DEGENERATIVE DEMENTIA", AMERICAN JOURNAL OF PSYCHIATRY, AMERICAN PSYCHIATRIC ASSOCIATION, WASHINGTON, DC, US, vol. 139, no. 9, 1 January 1982 (1982-01-01), pages 1136 - 1139, XP009096908, ISSN: 0002-953X *
REISBERG ET AL., ALZHEIMER'S & DEMENTIA, vol. 6, 2010, pages 11 - 24
REISBERG ET AL., ALZHEIMERS & DEMENTIA, vol. 6, no. 1, 2010, pages 11 - 24
REISBERG ET AL., ALZHEIMER'S AND DEMENTIA, vol. 6, 2010, pages 11 - 24
REISBERG ET AL., AM J PSYCH, vol. 139, 1982, pages 1136 - 1139
REISBERG ET AL., AM J. PSYCH, vol. 139, 1982, pages 1136 - 1139
REISBERG ET AL., NEJM, vol. 348, no. 14, 2003, pages 1333 - 41
REISBERG ET AL.: "The Brief Cognitive Rating Scale (BCRS", PSYCHOPHARMACOL BULL, vol. 24, 1988, pages 629 - 36
ROSEN, W.G., MOHS, R.C., DAVIS, K.L.: "A New Rating Scale for Alzheimer's Disease", AM. J. PSYCHIATRY, vol. 141, 1984, pages 1356 - 1364
SAHAKIAN BJ, OWEN AM: "Computerized assessment in neuropsychiatry using CANTAB: discussion paper", J R SOC MED., vol. 85, no. 7, July 1992 (1992-07-01), pages 399 - 402, XP008063491
SIMPSON PM, SURMON DJ, WESNES KA, WILCOCK GK: "The Cognitive Drug Research computerised assessment system for demented patients: a validation study", INT J GERIATR PSYCHIATRY, vol. 6, 1991, pages 95 - 102
SINGH B ET AL: "When should drug treatment be started for people with dementia?", MATURITAS, ELSEVIER SCIENCE PUBLISHERS IRELAND LTD, IR, vol. 62, no. 3, 20 March 2009 (2009-03-20), pages 230 - 234, XP026073994, ISSN: 0378-5122, [retrieved on 20090206], DOI: DOI:10.1016/J.MATURITAS.2008.12.022 *
SPERLING ET AL., ALZHEIMER & DEMENTIA, 2011, pages 1 - 13
USPENSKAYA O V ET AL: "Memantine hampers the progression of cognitive dysfunction and conversion to dementia in amnestic MCI patients", JOURNAL OF THE NEUROLOGICAL SCIENCES, vol. 285, no. Suppl. 1, October 2009 (2009-10-01), & 19TH WORLD CONGRESS OF NEUROLOGY; BANGKOK, THAILAND; OCTOBER 24 -30, 2009, pages S275, XP002619447, ISSN: 0022-510X *
WINBLAD ET AL., DEMENT GERIATR COGN DISORD, vol. 24, no. 1, 2007, pages 20 - 7
WINBLAD ET AL., J. INT. MED., vol. 256, 2004, pages 240 - 246

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