WO2004089351A2 - Methodes et moyens de traitement de troubles neurologiques progressifs - Google Patents

Methodes et moyens de traitement de troubles neurologiques progressifs Download PDF

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WO2004089351A2
WO2004089351A2 PCT/GB2004/001546 GB2004001546W WO2004089351A2 WO 2004089351 A2 WO2004089351 A2 WO 2004089351A2 GB 2004001546 W GB2004001546 W GB 2004001546W WO 2004089351 A2 WO2004089351 A2 WO 2004089351A2
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mice
treatment
creatine
tacrine
moclobemide
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PCT/GB2004/001546
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English (en)
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WO2004089351A3 (fr
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Anne Jennifer Morton
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Cambridge University Technical Services Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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

Definitions

  • the present invention relates to therapeutic compositions and methods for the treatment of neurological disorders, in particular Huntington's disease (HD) .
  • HD Huntington's disease
  • Huntington's disease is a progressive adult-onset movement disorder (Harper PS, (1996) Huntington's Disease 2nd Edn London, Saunders) .
  • the disorder also has serious psychiatric symptoms, including mood disorders, depression, and progressive cognitive decline into dementia .
  • HD is caused by an abnormally expanded CAG repeat in the HD gene.
  • R6/2 transgenic mice carry the human HD mutation in the first exon of the gene (Mangiarini, L. et al (1996) Cell 87, 493-506) and display a progressive neurological phenotype similar to HD in which overt symptoms appear around 8-10 weeks of age.
  • motor and cognitive deficits can be measured several weeks earlier than this (Carter, R. J. et al (1999) J Neurosci. 19, 3248-3257, Lione, L.A. et al . J. Neurosci .23 , 10428- 10437 (1999) ) suggesting that deleterious neuronal dysfunction occurs before symptoms are observed.
  • a first aspect of the present invention provides a composition comprising a first agent which is a monoamine oxidase inhibitor and a second agent which is an acetylcholine esterase inhibitor.
  • Monoamine oxidase inhibitors prevent or reduce the breakdown of norepinephrine (NE) , serotonin (5- hydroxytryptamine) and dopamine in the brain of a subject.
  • An inhibitor for use in accordance with the present invention may be an irreversible or, more preferably, a reversible inhibitor of monoamine oxidase, such as brofaromine .
  • a suitable monoamine oxidase inhibitor may be non- selective or may be specific for either the MAO-A or the MAO-B isoform of monoamine oxidase.
  • irreversible MAO-B inhibitors examples include deprenyl (selegiline) and rasagiline.
  • irreversible MAO-A inhibitors include phenelzine and isocarbazid.
  • the monoamine oxidase inhibitor is a reversible and selective inhibitor of MAO-A isoenzyme
  • Suitable monoamine oxidase inhibitors include moclobemide (M) .
  • Suitable acetylcholine esterase inhibitors which prevent or reduce the breakdown of ACh in the brain of a subject, include tacrine (T) , donazepil, rivastigmine and galantamine .
  • the first agent is moclobemide (M) and the second agent is tacrine (T) .
  • Moclobemide (4-chloro-N- [2- (4-morpholinyl) -ethyl] benzamide) is an antidepressant (see No: 6309, Merck Index 12th edition (Merck __ Co, Whitehouse Station NJ 1996) and references therein, Fulton & Benfield (1996) Drugs 52 (6) 869) .
  • the term ⁇ moclobemide' or M' as used herein encompasses variants and derivatives of moclobemide which possess the same pharmacological properties .
  • Tacrine (1, 2, 3, 4-Tetrahydro-9-acridinamine) is an irreversible ACh esterase inhibitor that prevents the breakdown of ACh (see No: 9199, Merck Index 12th edition (Merck & Co, Whitehouse Station, NJ 1996) and references therein) .
  • the term ⁇ tacrine' or ⁇ T' as used herein also encompasses variants and derivatives of tacrine which possess the same pharmacological properties .
  • Creatine N- (aminoiminomethyl) -N-methylglycine : see No: 2637, Merck Index 12th edition (Merck & Co, Whitehouse Station NJ 1996) and references therein)
  • Creatine is a naturally occurring compound found in mammalian tissues such as the brain, muscles, retina and heart. It is phosphorylated in vivo by creatine kinase to generate phosphocreatine. The adminstration of creatine has been shown to increase brain phosphocreatine levels and improve the motor symptoms and survival of R6/2 mice (Ferrante et al (2000) J.
  • compositions of the present invention may additionally comprise creatine (C) .
  • Another aspect of the invention provides a combination of a first agent which is a monoamine oxidase inhibitor and a second agent which is an acetylcholine esterase inhibitor, and optionally, creatine, for example for use in the treatment of a progressive neurological condition such as HD .
  • compositions and combinations of the present invention may additionally comprise anti-depressant agent.
  • anti-depressant agent may elevate global biogenic amine levels.
  • Suitable antidepressants include selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine and fluvoxamine and inhibitors of NE and serotonin uptake such as clomiphamine (see Merck Index (1996) supra) .
  • Compositions, combinations and methods of the present invention may further include agents which act on motor symptoms of HD.
  • agents which act on motor symptoms of HD may include novel classes of agents such as endocanabinoid uptake inhibitors (Lasrtres-Becker et al, (2002) Synapse 44, 23-35) such as AM404, agents with dual muscarinic receptor agonist/dopamine receptor antagonist properties (Veinbergs et al, (2001) Society for Neurosciences 31 st Annual Meeting, San Diego, Abstract 549) that improve abnormal spontaneous and drug-induced locomotor symptoms without impairing cognition, and cannabinoids, including endogenous cannabinoids such as anandamide .
  • endocanabinoid uptake inhibitors Lasrtres-Becker et al, (2002) Synapse 44, 23-35
  • AM404 agents with dual muscarinic receptor agonist/dopamine receptor antagonist properties
  • cannabinoids including endogenous cannabinoids such as anandamide .
  • compositions and combinations may include, in addition to tacrine, moclobemide and optionally other active ingredients such as creatine as described above, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient .
  • a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient .
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous .
  • compositions and combinations of the present invention may be useful in a method of treatment of the human or animal body, in particular a method for the treatment of a neurological disorder, in particular a progressive neurological disorder such as Huntington's Disease (HD) , AIDS dementia, Parkinson's disease and Alzheimer's disease.
  • a neurological disorder in particular a progressive neurological disorder such as Huntington's Disease (HD) , AIDS dementia, Parkinson's disease and Alzheimer's disease.
  • HD Huntington's Disease
  • AIDS dementia dementia
  • Parkinson's disease Alzheimer's disease
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications) , in which a desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, and amelioration of the condition or its symptoms, in particular behavioural symptoms such as cognitive deterioration and/or degeneration.
  • Treatment as a prophylactic measure i.e. prophylaxis
  • prophylaxis is also included.
  • compositions may in particular be useful in the alleviation or amelioration of symptoms associated with progressive neurological disorders such as Huntington's disease, in particular cognitive deterioration or degeneration.
  • compositions or combinations as described above in the manufacture of a medicament for use in the treatment of a progressive neurological disorder or dementia, such as HD, and the use of tacrine, moclobemide and optionally creatine in the manufacture of a medicament for use in the treatment of a progressive neurological disorder or dementia, such as HD. Examples of methods of treating progressive dementias using such medicaments are described below.
  • Another aspect of the present invention provides a method for treatment of a progressive neurological disorder or dementia, such as Huntington's disease, comprising administering a therapeutically effective amount of tacrine and a therapeutically effective amount of moclobemide to an individual in need thereof .
  • a progressive neurological disorder or dementia such as Huntington's disease
  • Such a method may further comprise administering a therapeutically effective amount of creatine to said individual .
  • terapéuticaally-effective amount pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
  • Methods of the present invention may further comprise the administration of other agents, such as anti-depressants and agents which act on motor symptoms of dementia, as described above .
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations within the brain which achieve the desired effect . Further details of appropriate dosages are found in the British National Formulary (2000) Pub: British Medical Association & Royal Pharmacological Society of Great Britain.
  • Administration in vivo can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • the active compounds or composition comprising the active compounds may be administered to a subject by any convenient route of administration.
  • Routes of administration include, but are not limited to, oral, for example by ingestion, parenteral, for example, by cutaneous, subcutaneous or intravenous injection; or by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
  • tacrine and moclobemide While it is possible for tacrine and moclobemide to be administered separately (i.e. as discrete compositions administered separately to the same patient) , it is preferable to present them together as a single pharmaceutical composition (e.g., formulation) comprising both active ingredients together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials well known to those skilled in the art and optionally other therapeutic agents, which may include, for example, creatine.
  • a single pharmaceutical composition e.g., formulation
  • pharmaceutically acceptable carriers e.g., excipients, buffers, adjuvants, stabilisers, or other materials well known to those skilled in the art and optionally other therapeutic agents, which may include, for example, creatine.
  • the present invention further provides methods of making a pharmaceutical composition comprising admixing tacrine and moclobemide, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein. Methods may further comprise admixing creatine together with the other ingredients .
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g., human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • compositions of the present invention may conveniently be formulated in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations may, for example, be in the form of liquids, solutions, suspensions, emulsions, tablets, capsules, cachets, pills or ampoules.
  • parenteral administration e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal
  • the active ingredients will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, or Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • the concentration of the active ingredient in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound particular organs, such as the brain.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) , surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • a pharmaceutical composition produced by a method described herein may be used for treating a progressive neurological condition such as Huntington's disease (HD) .
  • a progressive neurological condition such as Huntington's disease (HD) .
  • kits for use in the treatment of a progressive neurological condition such as Huntington's disease, comprising (a) tacrine and moclobemide, preferably provided as a single pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the composition and/or active compounds.
  • Figure 1 shows performance of R6/2 and WT mice in the Morris water maze (vehicle-treated WT (light circles) , WT triple treated (dark circles) , R6/2 vehicle treated (dark diamonds) R6/2 triple treated (light diamonds) ) . Mice were trained over 4 sessions using a visible platform
  • Figure 2 shows the effects of triple drug therapy on the performance of R6/2 mice in a T-maze alternation test (WT mice: light circles, vehicle treated R6/2 mice: dark diamonds, triple treated R6/2 mice: light diamonds).
  • WT mice light circles
  • vehicle treated R6/2 mice dark diamonds
  • triple treated R6/2 mice light diamonds
  • the total number of trials taken to reach criterion (a) , the total number of errors made (b) and the percentage of these errors that were perseverative (c) are shown.
  • Figure 3 shows the effect of triple treatment (tacrine/moclobemide/creatine) on various measures of the R6/2 phenotype.
  • WT vehicle treated mice light circles
  • triple treated WT mice dark circles
  • vehicle treated R6/2 mice dark diamonds
  • triple treated R6/2 mice light diamonds
  • mice A colony of R6/2 transgenic mice was established in the Department of Pharmacology, University of Cambridge and maintained by backcrossing onto CBAxC57/BL6 FI mice. Mice were housed in cages of mixed genotype with 12 hours light and dark cycles in a temperature controlled room. All cognitive testing was performed on female mice.
  • mice Weights of mice were recorded from 5 weeks either twice weekly (creatine treatment) or daily (all other treatments) .
  • Tacrine (Sigma) was used at 2 doses (2.7 mg/kg and 3.2 mg/kg) and prepared in 0.9% saline. During our pilot studies we found that tacrine at the 3.2 mg/kg dose was associated with acute side effects (reduced locomotor activity) that appeared for 30 min after the drug was given. Therefore for most of the studies described here, a lower dose of 2.7 mg/kg was used.
  • Moclobemide (10 mg/kg: Roche (manerix) ) was prepared in a small volume of ethanol and saline. Tacrine and moclobemide were administered via the intraperitoneal route. Creatine, which is readily available from commercial sources, was added to the diet by dissolving it in the water used to prepare the wet mash. Drugs were administered as single, double (tacrine/creatine, moclobemide/creatine, tacrine/moclobemide) or triple (tacrine/moclobemide/creatine) treatments .
  • T-maze alternation was used as previously described (Lione et al 1999 supra) . Briefly, a T-maze was formed by blocking 5 arms of an 8 arm radial maze to form a T-shape. Mice were habituated in the maze for 6 mins over 3 consecutive days, so they would run reliably and find banana flavoured food pellets (20 mg) in wells placed at the end of each arm. All mice were trained for 2 days to perform 15 forced alternations. During the testing phase mice were placed in the start arm with both side arms baited. When a mouse entered an arm (defined when all four feet were inside the arm) , it was confined to its chosen arm by lowering a guillotine door. Mice were then returned to the start arm and the mice had to perform 10 alternations each session. An error was noted when a mouse returned to the arm it had previously visited, a perseverative error was recorded when the same error was made more than once .
  • a circular white pool (diameter, 120 cm; height 50 cm) was filled to a depth of 25 cm with water and rendered opaque with nontoxic white paint. Four positions were designated N, S, E, W around the pool.
  • a circular platform (diameter, 10 cm) was submerged 0.5 cm below the surface of the water. Mice were given 4 trials each day over 17 sessions from 9.3- 12 weeks of age. On the first 4 sessions mice were trained to swim to the submerged platform made visible by a high contrast black marker placed on the platform.
  • Both the start position (N, S ,E ,W) and the position of the platform (NE, SE, SW, NW) were psuedorandomised across trials. Mice were allowed 60 seconds to find the platform, and those that did not reach the platform were placed on the platform by hand. From sessions 5-13 mice the high contrast marker was removed, and the platform placed in the SE quadrant. From sessions 14-17 the high contrast marker was reintroduced to identify the platform location, and as before placed in different locations across trials. All trials were analysed using HVS software (HVSImage, Buckingham, UK) .
  • Training consisted of placing mice aged 4.5 weeks on the rotarod at 24 rpm for 4 trials over 3 consecutive days . Mice were tested at speeds of 5, 8, 15, 24, 33 and 44 rpm at weekly intervals from 5 weeks of age.
  • mice were fasted for 12 hours and then given a glucose challenge 1.5 g/kg intraperitoneally. Blood samples were taken before glucose was administered, and then 1 hour after the challenge. A drop of blood collected from the anaesthetised tail tip and blood glucose was measured using an automated glucometer (Bayer Diagnostics, Newbury, UK) .
  • the improvement in the performance of the tacrine/moclobemide/creatine-treated mice is likely to be due to a change in strategy used to find the hidden platform.
  • R6/2 mice exhibited significantly more thigmotaxis (swimming around the perimeter of the pool) than wild-type mice (P ⁇ 0.001) (figure Id) . This activity reduced the probability of the R6/2 mice locating the platform and accounted for the increase in path length and latency.
  • the combined treatment with tacrine and moclobemide produced beneficial effects equivalent to triple (tacrine/moclobemide/creatine) treatment. No additional benefit was observed when creatine was also administered.
  • mice were treated from 4 weeks of age, but this time, cognitive performance was assessed in a T- maze alternation task between 5.5 and 10 weeks of age.
  • R6/2 mice showed significant impairments in this task (Fig 2a) .
  • WT mice gradually improved their performance with time (P ⁇ 0.001)
  • R6/2 mice deteriorated across test sessions, with the mice needing progressively more trials to complete the task (P ⁇ 0.001).
  • Analysis of the first 10 trials showed that R6/2 mice displayed a gradual deterioration in the alternation task (Fig. 2b) , until by 8 weeks of age, mice were performing at just below chance level.
  • Tacrine/moclobemide/creatine treatment also improved performance in the Morris water maze via a change in strategy used to find the hidden platform, since thigmotaxis was significantly reduced by tacrine/moclobemide/creatine treatment.
  • thigmotaxis was significantly reduced by tacrine/moclobemide/creatine treatment.
  • the absence of thigmotaxis in fimbria fornix lesioned rats points towards a non- hippocampal origin of this type of behaviour (Devan & White (1999) J " . Neuroscience 7, 2789-2798)
  • lesions of the medial striatum but not the dorsal striatum were associated with increased thigmotaxis.
  • Obsessive compulsive disorder arguably considered as a type of perseverative behaviour, is also found in HD patients (Harper, 1996 supra, Anderson, K.E. et al (2001 Am. J. Psychiatry 158, 799-801) .
  • mice showed normal growth until about 11 weeks of age when body weight dropped dramatically irrespective of drug treatment (transgene x days P, 0.001; drug, transgene x drug and transgene x drug x days all n.s. )
  • tacrine/moclobemide/creatine did not simply delay glycosuria onset, rather there was a slowing of appearance of diabetes.
  • R6/2 mice treated with tacrine/moclobemide/creatine or creatine alone displayed higher blood glucose concentrations but no other differences were found between R6/2 groups (Fig. 3c) .
  • the delayed in onset of glycosuria produced by tacrine/moclobemide/creatine is unlikely to underlie the improvement in cognitive function, since (i) double treatment with tacrine and moclobemide enhanced cognition without affecting glycosuria, (ii) the onset of glycosuria did not correlate with deterioration of cognitive performance or changes in synaptic plasticity (Murphy, K. P. et al (2000) J Neurosci. 20, 5115-5123) and (iii) there was no difference in the number of mice that developed diabetes between R6/2 groups.
  • mice treated with the drugs No histopathological changes were observed in brains of mice treated with the drugs. However, this was also expected, since all mice were used for survival studies and therefore died of their phenotype.
  • tacrine and moclobemide In contrast to tacrine and moclobemide, the role of creatine in the beneficial effects observed after tacrine/moclobemide/creatine treatment is not clear.
  • the combination of tacrine and moclobemide is responsible for the cognitive enhancing effects, since tacrine/moclobemide produced equivalent improvements to the triple treatment in the Morris water maze, and creatine is not essential.
  • no deleterious effects of creatine were observed either alone or in combination with any other drug and this is significant because it indicates that tacrine and moclobemide could be used safely in patients who were independently taking creatine supplements.

Abstract

La présente invention se rapporte à des compositions et à des méthodes de traitement de troubles neurologiques progressifs, notamment la maladie de Huntington. L'administration d'un inhibiteur de la monoamine oxydase, notamment moclobémide, en combinaison avec un inhibiteur d'acétylcholine estérase, notamment tacrine, et éventuellement créatine, a montré améliorer les symptômes dans des systèmes de modèles murins.
PCT/GB2004/001546 2003-04-10 2004-04-07 Methodes et moyens de traitement de troubles neurologiques progressifs WO2004089351A2 (fr)

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WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2008143553A1 (fr) 2007-05-23 2008-11-27 Viktor Ivanovich Roschin Médicament servant au traitement de patients souffrant de maladies provoquées par l'activité excessive de la monoaminooxydase et méthode de traitement de patients souffrant de maladies provoquées par l'activité excessive de la monoaminooxydase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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