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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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans

Definitions

• the present invention relates to the use of the compound escitalopram (INN-name), i.e. (S)- 1 -[3-(dimethylamino)propyl]- 1 -(4-fluorophenyl)-l ,3-dihydro-5- isobenzofurancarbonitrile, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for improving cognition in a condition where the cognitive processes are diminished.
• escitalopram i.e. (S)- 1 -[3-(dimethylamino)propyl]- 1 -(4-fluorophenyl)-l ,3-dihydro-5- isobenzofurancarbonitrile
• Escitalopram is the (S)-enantiomer of the following structure:
• Escitalopram is now marketed as an antidepressant and for the treatment of generalised anxiety disorder (GAD), panic disorder (PD) and social anxiety disorder (SAD).
• GAD generalised anxiety disorder
• PD panic disorder
• SAD social anxiety disorder
• WO0103694 discloses the use of escitalopram for the treatment of neurotic disorders.
• ADHD attention deficit hyperactivity disorder
• Parkinson's disease mild cognitive impairment
• MCI Alzheimer's Disease
• Alzheimer's Disease dementia
• anxiety anxiety
• age associated memory impairment Alzheimer's Disease or post-traumatic stress disorder
• patients taking benzodiazepines or tricyclic antidepressants and in a range of neurodegenerative diseases in addition to Parkinson's Disease and Alzheimer's Disease.
• Diminished cognitive processes refer to the difficulties with attention, learning, memory and executive function (relevant reactions to external stimuli). These can include: deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulty in expressing thoughts and/or difficulty in integrating thoughts, feelings and behaviour and extinction of irrelevant thoughts as well as attention and vigilance, verbal learning and memory, visual learning and memory, speed of processing and social cognition.
• VTA ventral tegmental area
• fluoxetine, citalopram, paroxetine, sertraline and fluvoxamine all may cause a slight inhibition of the firing rate of mesocorticolimbic dopaminergic neurons in the VTA (Prisco and Eposito, 1995, Br J Pharmacol 116:1923-31; Di Masico et al, 1998, Brain Res Bull 46(6): 547- 54, suggesting that these compounds cannot be used in improving cognitive processes. Moreover it has been reported that citalopram as adjunctive therapy to atypical antipsychotic treatment produces no significant cognitive improvement in patients with schizophrenia (Friedman et al, 2005, J. Clinical Psychopharmacology, 25(3), 237-42).
• NRI selective noradrenaline reuptake inhibitors
• reboxetine enhances the excitability of dopaminergic neurons in the VTA with a preferential activation of their burst firing mode (Linner et al, 2001, JPET, 297(2):540-9) and administering of reboxetine has been suggested to have some beneficial effect in the treatment of ADHD.
• APD atypical, but not typical, antipsychotic drugs
• Drugs approved for Alzheimer's dementia also have some effect on diminished cognitive processes, but work via completely different mechanisms, reflecting that cognition problems can have very different pathology, such as acetylcholinesterase inhibitors like donepezil, rivastigmine and galantamine.
• Memantine has weak NMDA antagonistic properties which gives a more "physiological" antagonism of too much background excitation, whereby it increases the signal to noise ratio on glutamate activity.
• EP 474580 discloses that citalopram is useful in the treatment of cerebrovascular disorders and the brain damage and the impairment of memory functions in connection therewith, and that it shows inhibiting action on platelet aggregation. Furthermore EP 474580 suggests that citalopram has an anti-amnesic effect and improves cognitive function in elderly depressed patients having concomitant dementia. It is mentioned that the optical isomers of the compounds may also be used. The effect mentioned in this disclosure suggests a neuroprotective role. Accordingly there is a significant unmet medical need for therapies, which can improve the cognitive symptoms in various diseases and disorders and/or have lowered side effects as compared to known treatments of cognitive symptoms.
• Escitalopram has now been found to increase the firing rate of dopamine cells in the VTA, to stimulate the glutamate-driven burst firing in VTA and to facilitate NMDA- induced currents.
• the present invention relates to the use of escitalopram or a salt thereof for the preparation of a medicament for improving cognition in a condition where the cognitive processes are diminished.
• the present invention relates the use of escitalopram or a pharmaceutically acceptable salt thereof in combination with one or more antipsychotic agents for the preparation of a medicament for improving cognition in a condition where the cognitive processes are diminished.
• the present invention relates the use of escitalopram or a pharmaceutically acceptable salt thereof for the preparation of a medicament to be used in the adjunct treatment with an antipsychotic agent for improving cognition in a condition where the cognitive processes are diminished.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising escitalopram or a pharmaceutically acceptable salt thereof and one or more antipsychotic compounds for improving cognition in a condition where the cognitive processes are diminished.
• the present invention relates to a method of improving cognition in a condition where the cognitive processes are diminished comprising administering escitalopram or a pharmaceutically acceptable salt thereof.
• FIG. 2 Escitalopram stimulates the glutamate-driven burst firing in VTA dopamine cells in vivo more potently than citalopram and R-citalopram blocks the effect of escitalopram.
• Figure 3 Effect of risperidone (atypical antipsychotic), citalopram, escitalopram, and reboxetine (NRI) on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex in vitro.
• a novel use of escitalopram or a pharmaceutically acceptable salt thereof, namely for the preparation of a medicament for improving cognition in a condition where the cognitive processes are diminished is provided.
• escitalopram increases the firing rate of dopamine cells in the VTA in vivo, an effect blocked by R-citalopram. Additionally it has been found escitalopram compared with citalopram more potently and also dose-dependently stimulates the glutamate-driven burst firing in VTA dopamine cells in vivo, an effect that is blocked by R-citalopram. Moreover it has been found that escitalopram and reboxetine but not citalopram facilitate NMDA-induced currents in pyramidal cells of the medial prefrontal cortex in vitro.
• the present findings indicate that escitalopram in similarity with NRIs, such as reboxetine, enhance the excitability of the dopaminergic system. Additionally the present findings indicate that escitalopram in similarity with atypical, but not typical antipsychotic drugs, as well as reboxetine facilitates prefrontal glutaminergic neurotransmission.
• escitalopram can be used for improving cognition in a condition where the cognitive processes are diminished as well as augmenting the response to exposure therapy. Additionally the present findings also strongly suggest escitalopram may be used as adjunct treatment to typical antipsychotic drugs for improving cognition in a condition where the cognitive processes are diminished and in the treatment of schizophrenia and other related diseases and disorders.
• the phrase "diminished cognitive processes” refers to the difficulties with attention, learning, memory and executive function (relevant reactions to external stimuli). These can include: deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulty in expressing thoughts and/or difficulty in integrating thoughts, feelings and behaviour and extinction of irrelevant thoughts as well as attention and vigilance, verbal learning and memory, visual learning and memory, speed of processing and social cognition.
• One embodiment of the present invention relates to the use of escitalopram or a pharmaceutically acceptable salt thereof for the preparation of a medicament for improving cognition in a condition where the cognitive processes are diminished wherein the condition is associated with schizophrenia.
• the condition is associated with Parkinson's Disease.
• the condition is associated with dementia, such as AIDS dementia.
• the condition is associated with an anxiety disorder.
• the condition is associated with age associated memory impairment.
• the condition is associated with depression, including major depression, in particular in elderly.
• the condition is associated with the use of benzodiazepines.
• the condition is associated with the use of tricyclic antidepressants.
• the condition is associated with Alzheimer's Disease. In another embodiment of the invention the condition is associated with attention deficit hyperactivity disorder (ADHD). In another embodiment of the invention the condition is associated with post-traumatic stress disorder (PTSD).
• the medicament is for administration as a unit dose. In further embodiment of the invention the unit dose is containing escitalopram in an amount from 1.0 mg to 50 mg, more preferred 5 mg/day to 20 mg/day, most preferably 10 mg. In a further embodiment the unit dose is given once daily. In a further embodiment the daily doses are, 5, 10 or 20 mg.
• Another embodiment of the present invention relates to the use of escitalopram or a pharmaceutically acceptable salt thereof in combination with one or more antipsychotic compounds for the preparation of a medicament for improving cognition in a condition where the cognitive processes are diminished wherein the condition is associated with schizophrenia.
• the condition is associated with Parkinson's Disease.
• the condition is associated with dementia, such as AIDS dementia.
• the condition is associated with an anxiety disorder.
• the condition is associated with age associated memory impairment.
• the condition is associated with depression, including major depression, in particular in elderly.
• the condition is associated with the use of benzodiazepines.
• condition is associated with the use of tricyclic antidepressants.
• condition is associated with Alzheimer's Disease.
• condition is associated with attention deficit hyperactivity disorder (ADHD).
• ADHD attention deficit hyperactivity disorder
• condition is associated with post-traumatic stress disorder (PTSD).
• antipsychotic compound is a compound approved for the treatment of a psychotic condition.
• the antipsychotic compound is selected from the list of Asenapine, Blonanserin, Iloperidone, Paliperidone, Bifeprunox, Lurasidone, Ocaperidone, Talnetant, ACP 104, SLV 310, ACR 16, YKP 1358, GW 773812, RGH 188, SLV 314, Y-931, BL 1020, Chlorpromazine, Levomepromazine, Promazine, Acepromazine, Trifiupromazine, Cyamemazine, Chlorproethazine, Dixyrazine, Fluphenazine, Perphenazine, Prochlorperazine, Thiopropazate, Trifluoperazine, Acetophenazine, Thioproperazine, Butaperazine, Perazine, Periciazine, Thioridazine, Mesoridazine, Pipotiazine, Haloperidol, Trifluperidol,
• a further embodiment of the present invention relates to the use of escitalopram or a pharmaceutically acceptable salt thereof for the preparation of a medicament to be used in the adjunct treatment with an antipsychotic compound for improving cognition in a condition where the cognitive processes are diminished wherein the condition is associated with schizophrenia.
• the condition is associated with Parkinson's Disease.
• the condition is associated with dementia, such as AIDS dementia.
• the condition is associated with an anxiety disorder.
• the condition is associated with age associated memory impairment.
• the condition is associated with depression, including major depression, in particular in elderly.
• the condition is associated with the use of benzodiazepines.
• condition is associated with the use of tricyclic antidepressants.
• condition is associated with Alzheimer's Disease.
• condition is associated with attention deficit hyperactivity disorder (ADHD).
• ADHD attention deficit hyperactivity disorder
• condition is associated with post-traumatic stress disorder (PTSD).
• antipsychotic compound is a compound approved for the treatment of a psychotic condition.
• the antipsychotic agent is selected from the list of Asenapine, Blonanserin, Iloperidone, Paliperidone, Bifeprunox, Lurasidone, Ocaperidone, Talnetant, ACP 104, SLV 310, ACR 16, YKP 1358, GW 773812, RGH 188, SLV 314, Y-931, BL 1020, Chlorpromazine, Levomepromazine, Promazine, Acepromazine, Triflupromazine, Cyamemazine, Chlorproethazine, Dixyrazine, Fluphenazine, Perphenazine, Prochlorperazine, Thiopropazate, Trifluoperazine, Acetophenazine, Thioproperazine, Butaperazine, Perazine, Periciazine, Thioridazine, Mesoridazine, Pipotiazine, Haloperidol, Trifluperidol, Melper
• a further embodiment of the present invention relates to a method of improving cognition in a condition where the cognitive processes are diminished comprising administering escitalopram or a pharmaceutically acceptable salt thereof wherein the condition is associated with schizophrenia.
• the condition is associated with Parkinson's Disease.
• the condition is associated with dementia, such as AIDS dementia.
• the condition is associated with an anxiety disorder.
• the condition is associated with age associated memory impairment.
• the condition is associated with depression, including major depression, in particular in elderly.
• the condition is associated with the use of benzodiazepines.
• the condition is associated with the use of tricyclic antidepressants.
• the condition is associated with Alzheimer's Disease.
• the condition is associated with attention deficit hyperactivity disorder (ADHD).
• PTSD post-traumatic stress disorder
• a further embodiment of the present invention relates to the use of escitalopram for the preparation of a medicament for the treatment of schizophrenia wherein the negative and cognitive symptoms are improved.
• a further embodiment of the present invention relates to the use of escitalopram for the preparation of a medicament for the treatment of attention deficit hyperactivity disorder (ADHD).
• ADHD attention deficit hyperactivity disorder
• escitalopram the facilitation of the glutamatergic neurotransmission in prefrontal cortex, likely means that escitalopram can be used to enhance the effect of psychotherapy, e.g. exposure-based therapies.
• Escitalopram could affect anxiety disorders, both directly through the SRI component and through facilitation of e.g. extinction processes during psychotherapy.
• a further embodiment of the present invention relates to the use of escitalopram for the preparation of a medicament useful in facilitating psychotherapy, cognitive behavioural therapy and exposure -based therapy.
• the present invention thus provides a significant improvement in the treatment of cognition in conditions where the cognitive processes are diminished.
• the advantages of the invention, compared to known treatments are better efficacy and potentionally lowered side-effects.
• some patients groups that could not be treated at all before might, by the use of escitalopram according to the present invention, experience improved effects on cognitive processes.
• escitalopram or a pharmaceutically acceptable salt thereof may be administered in any suitable way e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
• the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
• Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine.
• adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colourings, flavourings, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
• Escitalopram is preferably used in the form of the oxalate salt thereof, escitalopram as the base or as the HBr salt or the likes or any other pharmaceutically acceptable salt thereof could also be used.
• Escitalopram is most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in a dose from about 1.0 mg to 50 mg, more preferred 5 mg/day to 20 mg/day, most preferably 10 mg. Such a unit dose is preferably given once daily. Preferred daily doses are, 5, 10 or 20 mg.
• oxalate of escitalopram may be prepared as described in US Patent No 4,943,590 and the base and other pharmaceutically acceptable salts may be obtained from the base by standard procedures.
• the acid addition salts used according to the invention may be obtained by treatment of escitalopram with the acid in an inert solvent followed by precipitation, isolation and optionally re-crystallisation by known methods and if desired micronisation of the crystalline product by wet or dry milling or another convenient process, or preparation of particles from a solvent-emulsification process.
• the amount of the above-mentioned compounds actually administered will be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
• Electrodes were pulled in a Narishige vertical puller from borosilicate glass capillaries with outer and inner diameters of 1.50 and 1.17 mm, respectively, and filled with 2% Pontamine Sky Blue in 2 M NaCl.
• the electrodes were broken under microscope to yield an impedance of 2-4 M ⁇ at 135 Hz and then slowly lowered into a hole drilled in the skull above the VTA (3.2 ⁇ 0.3 mm anterior of the interaural line and 0.7 ⁇ 0.2 mm lateral to the midline by using a hydraulic microdrive.
• Extracellular electrical activity was amplified, filtered (band pass 0.3-3 kHz), discriminated and monitored on an oscilloscope and an audiomonitor.
• Discriminated spikes were fed via a CED 1401 interface to a computer running CED Spike 2 software. After the experiment the recording site was marked by iontophoresis of Pontamine Sky Blue into the tissue. The rat was killed with an overdose of anesthetic, and the brain was removed and placed in 25% sucrose 10% paraformaldehyde solution. Sections of the VTA were cut (50 ⁇ M) and stained with Neutral Red and the recording sites were verified by light microscopy.
• a single slice containing mPFC was then transferred to a recording chamber (32 0 C), in which it was held submerged in-between two nylon nets.
• the chamber was continuously perfused by aerated Ringer's solution at a flow rate of 2 ml/min.
• Standard intracellular and single-electrode voltage-clamp techniques were used to record pyramidal cells in layers V and VI of the mPFC in slice preparations as described previously. Briefly, electrodes were pulled from borosilicate glass capillaries by using a horizontal electrode puller. Recording electrodes were filled with 2 M Potassium Acetate (the tip resistance was between 20 and 160 M ⁇ ) and used for recording the mPFC neurons with an Axoclamp 2A amplifier.
• Single electrode voltage-clamp (holding potential - 60 mV) was performed in the discontinuous mode with a sampling rate of 5-6.2 kHz.
• the voltage recordings were acquired using a digital/analogue sampling and acquisition software.
• glycine (1 ⁇ M,to enhance the NMDA-induced responses
• bicucculine 5 ⁇ M,to block the ⁇ - aminobutyric acid type A (GABA A ) responses
• GABA A ⁇ - aminobutyric acid type A
• the effects of the drugs or drug combinations on the NMDA-induced currents were calculated by dividing the NMDA-induced currents after the bath application of the drugs by the control NMDA-induced currents. The results shown in the figure are presented as mean ⁇ S.E.M.
• Figure 1 describes the effect of citalopram and each of its enantiomers on firing rate of dopamine cells in the VTA. It is shown that citalopram at the tested doses (0-1280 ⁇ g/kg) does not increase the firing rate. On the other hand escitalopram elevates firing rate statistically significant at 320 ⁇ g/kg and this effect appears to be maintained at the higher dose (640 ⁇ g/kg). Furthermore it is shown that the firing rate is unaffected by R-citalopram and that the effect of escitalopram (320 ⁇ g/kg) can be blocked by pre-treatment with 320 ⁇ g/kg of R-citalopram, thus further substantiating that this effect is specific to escitalopram.
• Figure 2 describes the effect of citalopram and each of its enantiomers on burst firing of the dopaminergic cells recorded in the in the VTA. It was shown that escitalopram increases burst firing statistically significant dose-dependently at doses equal to and above 160 ⁇ g/kg. At the highest dose tested (640 ⁇ g/kg) escitalopram causes a burst difference of about 20%. Citalopram also appear to increase burst firing, allthough this only reaches significance at the 640 ⁇ g/kg dose, and the maximal response appears to be approximately 10% burst difference. Further it is shown that R- citalopram alone has no effect on burst firing and that R-citalopram (320 ⁇ g/kg) significantly inhibits the effect of escitalopram (320 ⁇ g/kg).
• Figure 3 describes the effect of risperidone (atypical antipsychotic), citalopram, escitalopram and reboxetine (NRI) on NMDA-induced currents in pyramidal cells of the prefrontal cortex. It has previously been shown that atypical antipsychotics increase NMDA-induced currents in this preparation. This is examplified by risperidone. It is shown that reboxetine (NRI) but not citalopram (SSRI), nor fluoxetine (data not shown) increases NMDA-induced currents. Surprisingly escitalopram facilitates the NMDA-induced currents to similar extent as the risperidone and reboxetine. It is furthermore shown that this effect is likely mediated through the dopamine Dl receptor as a dopamine Dl receptor antagonist (SCH 23390) reverses the effect of escitalopram.
• SCH 23390 dopamine Dl receptor antagonist

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