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WO1989009600A1 - Procede et composition de traitement de troubles neurologiques - Google Patents

Procede et composition de traitement de troubles neurologiques Download PDF

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Publication number
WO1989009600A1
WO1989009600A1 PCT/US1989/001402 US8901402W WO8909600A1 WO 1989009600 A1 WO1989009600 A1 WO 1989009600A1 US 8901402 W US8901402 W US 8901402W WO 8909600 A1 WO8909600 A1 WO 8909600A1
Authority
WO
WIPO (PCT)
Prior art keywords
choline
composition
aminopyridine
source
potassium channel
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1989/001402
Other languages
English (en)
Inventor
Richard J. Wurtman
Rifat Levent Buyukuysal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Massachusetts Institute of Technology
Original Assignee
Massachusetts Institute of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Massachusetts Institute of Technology filed Critical Massachusetts Institute of Technology
Publication of WO1989009600A1 publication Critical patent/WO1989009600A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Exogenous choline is known to be required for acetylcholine (ACh) synthesis and to be supplied to cholinergic neurons, as choline or one of its precursors, from a variety of sources (e.g., circulation, breakdown of released ACh, efflux of free choline from the intra- cellular space of brain cells, hydrolysis of choline- containing membrane phospholipids) .
  • sources e.g., circulation, breakdown of released ACh, efflux of free choline from the intra- cellular space of brain cells, hydrolysis of choline- containing membrane phospholipids.
  • acetylcholine production and/or release appear to be affected.
  • Alzheimer's disease is accompanied by a cholinergic defect in specific areas of the brain; and a specific defect in choline acetyl- transferase, the enzyme which catalyzes acetylcholine production from choline and acetyl-coenzyme A, has been identified in autopsy material from patients with Alzheimer's. Summers, .K.. et_al. , the New England Journal of Medicine, 315:1241-1245 (1986) Davies, P. and Maloney, A.J.F., Lancet, 2 ⁇ :1403 (1976). Loss of cholin ⁇ ergic function is believed to contribute to the intel ⁇ lectual impairment, memory deficits and dementia which characterize Alzheimer's disease.
  • Cholinergic deficiency states are also believed to be the basis for other neurological disorders. For example, it is thought that cholinergic deficiency states are present in such neurological disorders as Tourette's disease, Freidreich's ataxia, Huntington's Chorea amyoletrophic lateral scerosis, familiar dysautonomia, post-stroke, post-traumatic, or post-toxic syndromes affecting memory of cognition and tardive dyskinesia. S. Bajada, Alz ⁇ heimer's Disease: A Report of Progress. In: Aging, S. Corkin, ⁇ t al. , (ed.) £:427, Raven Press, New York, NY (1982) .
  • This invention relates to a composition and a process for the treatment of neurological degenerative disorders by increasing acetylcholine levels in the brain. It is based on the discovery that administration of a combination of choline or a choline source or precursor and a drug which blocks neural voltage- dependent potassium channels (i.e., potassium channel blockers) dramatically increases the synthesis and release of acetylcholine in neurons.
  • the potentiation of the combined effect of choline or a choline source and a potassium channel blocker is greater than the simple additive effects of choline or a choline precursor and a drug which is a potassium channel blocker.
  • This combination provides distinct advantages in the treatment of diseases associated with decreased acetyl ⁇ choline production and/or release.
  • it enables surviving neurons to liberate large amounts of acetylcholine and thus, in effect, "substitutes" for the damaged neurons.
  • the combination of the invention can be administered to an individual in an amount effective to substantially increase acetylcholine release by the neurons, to reduce the symptoms of the neurological disorder.
  • a combination of choline, which is a precursor of acetylcholine, and 4-aminopyridine, which blocks voltage dependent potassium channels in excitable membranes is administered to an individual in a quantity sufficient to substantially increase the release of acetylcholine by the neurons.
  • choline (or a source thereof) sufficient to double blood choline levels in an individual is administered with at least one drug which is a potassium channel blocker.
  • Administration of choline or a choline source and at least one potassium channel blocker according to the method of the invention is beneficial to individuals suffering from neurological disorders, because it results in replacement or replenishment of acetylcholine lacking or not made/released by affected neurons.
  • the Figure is a graphic representation of the relationship between release of acetylcholine from superfused slices of rat striatum and addition to the medium of choline alone, 4-aminopyridine alone or choline and 4-aminopyridine in combination.
  • the invention relates to a composition to be ad- ministered to enhance the synthesis and release of acetylcholine from neurons, as well as to a method of administering choline (or a choline source) and at least one potassium channel blocker to individuals for treat ⁇ ment of neurological disorders which selectively involve cholinergic neurons.
  • the composition of the invention comprises choline or a choline source and at least one potassium channel blocker.
  • Choline itself can be used in the composition.
  • a choline source such as phosphatidyl- choline, glycerophosphocholine or commercial lecithin, can be used.
  • the potassium channel blocker enhances the release of acetylcholine.
  • Drugs which are potassium channel blockers include tetraethylammonium, guane- thidine, cesium ions (Cs ) , tetrahydroaminoacridine (THA) , aminopyridine compounds, apamin, quinine, quinidine, charybdotoxin, calcium channel blockers which block transient potassium currents and neurotrans itter agonists which regulate potassium channels (e.g., alpha-1 agonists which act on dorsal raphe serotoninergic neurons and cholinergic neurons) .
  • Cs cesium ions
  • TAA tetrahydroaminoacridine
  • aminopyridine compounds aminopyridine compounds
  • apamin aminopyridine compounds
  • quinine quinidine
  • charybdotoxin charybdotoxin
  • calcium channel blockers which block transient potassium currents and neurotrans itter agonists which regulate potassium channels (e.g., alpha-1 agonists
  • the agents or drugs can be administered orally, by subcutaneous or other injection, intravenously, parenterally, transdermally, rectally or via an implanted reservoir containing choline or a choline source and the potassium channel blocker(s) .
  • the form in which the drugs will be administered e.g. powder, tablet, capsule, solution, emulsion
  • the quantity of the drugs to be administered will be determined on an individual basis, and will be based at least in part on consideration of the individual's size, the severity of the symptoms to be treated and the result sought.
  • quantities of choline or a choline source sufficient to double blood choline levels will be administered (Blood choline levels generally range from 7-9 nanomoles/ml.) .
  • Bood choline levels generally range from 7-9 nanomoles/ml.
  • approximately 9 gm. of pure phosphaphotidylcholine a day (given in one dose or a number of smaller doses) will be adequate in most individuals to produce the desired doubling.
  • 3-100 gm. of phosphatidylcholine will be given in conjunction with the potassium channel blocker(s) .
  • lecithin is not available in pure form and is available as a mixture of lecithin and other phospholipids; typically 20-30 weight percent of such mixtures is lecithin.
  • compositions such as these in which lecithin is one component are referred to as commercial lecithin.
  • the composition of the present invention can option ⁇ ally include, in addition to choline or a choline source and potassium channel blocker(s) , other components.
  • the components included in a particular composition are de- termined primarily by the manner in which the composition is to be administered.
  • a composition to be administered orally in tablet form can include, in addition to the drugs, a filler (e.g. lactose) , a binder (e.g.carboxymethyl cellulose, gum arabic, gelatin), an adjuvant, a flavoring agent, a coloring agent and a coating material (e.g. wax or a plasticizer) .
  • a compo ⁇ sition to be administered in liquid form can include the combination of drugs of the present invention, and, optionally, an emulsifying agent, a flavoring agent and/or a coloring agent.
  • composition of the present invention is administered to an individual periodically as neces ⁇ sary to improve symptoms of the disease being treated.
  • the length of time during which the drugs are adminis- tered and the dosage will depend on the disease being treated, the type and severity of the symptoms, and the physical condition of the individual being treated.
  • the composition of the present invention can be used to treat neurological disorders which are characterized by degeneration of cholinergic neurons or other neuro ⁇ logical disorders which cause deficiencies in acetyl ⁇ choline release.
  • diseases include Alzheimer's disease, post-polio syndrome, myasthenia gravis, Huntington's disease, age-related memory disorders, post- traumatic, post-stroke or post-toxic syndromes affecting memory or cognition, dysautonomia or any other disorder affecting memory or cognition.
  • the potassium channel blocker enhances the release of acetylcholine, and the choline source provides a source of free choline.
  • extra ⁇ cellular choline can influence the synthesis and release of acetylcholine, the synthesis of phophatidylcholine and levels of phosphatidylcholine in membranes.
  • extra ⁇ cellular choline is inadequate, choline in membrane phosphatidylcholine can be mobilized to serve as a precursor for acetylcholine synthesis. This can be problematic, however, because neuron membrane phospho- lipid ⁇ can be depleted. This depletion can be reduced by supplying choline to the neurons. Ulus and Wurtman, The New England Journal of Medicine, 318 (3) : 191 (1988).
  • a preferred choline source is choline.
  • Other useful compounds, which serve as choline sources are, for example, phosphatidylcholine, glycerophosphocholine and commercial lecithin.
  • a preferred potassium blocker is 4- aminopyidrine (4-AP) .
  • 4-AP 4- aminopyidrine
  • the combination of 4-AP with choline results in a potentiation of the release of acetylcholine which is much greater than the sum of each compound acting alone.
  • the synergi ⁇ tic effect of the combination will be useful in treating Alzheimer's disease and/or other neurological disorders involving cholinergic neurons.
  • the invention is illustrated by the following exemplification, which is not to be seen as limiting in any way.
  • the slices were transferred to a superfusion chamber (volume 0.7 ml). The chamber was maintained at 37°C in a water-bath.
  • a peristaltic pump (Sage Instruments, type 375A, Cambridge, MA) delivered the pre-heated physiological solution (constantly bubbled with a mixture of 95% 0 and 5% CO ) containing 20 uM eserine salicylate. Drugs were added to the superfusion medium, as indicated in the text.
  • the slices (approximately 90 mg wet weight) were equilibrated for 30 min in superfusion medium, flowing at a rate of 0.5 ml.min . At the end of this equilibration period, the perfusate was collected at 10 minute intervals in glass tubes kept on ice. At the end of the 1 hour collection period, the slices were removed from the superfusion chamber and homogenized for determination of DNA contents.
  • acetylcholine ACh
  • rat striatum a brain region rich in ACh-releasing neurons

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On a mis au point des compositions utiles dans le traitement de troubles dégénératifs neurologiques affectant les neurones cholinergiques, ainsi que des procédés d'utilisations prévus à cet effet. Lesdites compositions comprennent un bloqueur de potassium dépendant de la tension neuronale ainsi que de la choline ou une source de choline combinés.
PCT/US1989/001402 1988-04-08 1989-04-04 Procede et composition de traitement de troubles neurologiques Ceased WO1989009600A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17959088A 1988-04-08 1988-04-08
US179,590 1988-04-08

Publications (1)

Publication Number Publication Date
WO1989009600A1 true WO1989009600A1 (fr) 1989-10-19

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EP (1) EP0408650A1 (fr)
JP (1) JPH03505868A (fr)
WO (1) WO1989009600A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014439A1 (fr) * 1992-12-18 1994-07-07 Canadian Spinal Research Organization Utilisation de 4-aminopyridine dans le traitement d'une pathologie neurologique
WO1994025872A1 (fr) * 1993-05-03 1994-11-10 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Test effectue sur des cellules pour diagnostiquer la maladie d'alzheimer
US5399587A (en) * 1993-12-13 1995-03-21 Merck & Co., Inc. Biologically active compounds
WO1998030243A1 (fr) * 1997-01-08 1998-07-16 Warner-Lambert Company Inhibiteurs d'acetylcholinesterase en combinaison avec des agonistes muscariniques utilises dans le traitement de la maladie d'alzheimer
US5792743A (en) * 1995-04-19 1998-08-11 Acorda Therapeutics Method for promoting neural growth comprising administering a soluble neural cell adhesion molecule
US5976816A (en) * 1993-05-03 1999-11-02 The United States Of America As Represented By The Department Of Health And Human Services Cell tests for alzheimer's disease
EP1190708A1 (fr) * 2000-09-21 2002-03-27 Tinnitus Forschungs- und Entwicklungs GmbH Utilisation médicale de substances
EP1511474A4 (fr) * 2002-05-14 2008-02-20 Inst Medical W & E Hall Procede de traitement
FR2918281A1 (fr) * 2007-09-25 2009-01-09 Assist Publ Hopitaux De Paris Medicament pour le traitement de la maladie de parkinson.
WO2013052575A1 (fr) 2011-10-04 2013-04-11 Acorda Therapeutics. Inc. Procédés de traitement d'une déficience sensorimotrice liée à un accident vasculaire cérébral à l'aide d'aminopyridines
WO2014172266A1 (fr) 2013-04-15 2014-10-23 Acorda Therapeutics, Inc. Procédés permettant de traiter des troubles sensori-moteurs associés à certains types d'accidents vasculaires cérébraux à l'aide d'aminopyridines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346084A (en) * 1980-02-29 1982-08-24 Massachusetts Institute Of Technology Process and composition for treating disorders by administering lithium and choline
US4385053A (en) * 1981-03-11 1983-05-24 Barry Reisberg Treatment for human memory impairment associated with aging
US4386095A (en) * 1982-02-22 1983-05-31 Cornell Research Foundation, Inc. Diaminopyridines to improve cognition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346084A (en) * 1980-02-29 1982-08-24 Massachusetts Institute Of Technology Process and composition for treating disorders by administering lithium and choline
US4385053A (en) * 1981-03-11 1983-05-24 Barry Reisberg Treatment for human memory impairment associated with aging
US4386095A (en) * 1982-02-22 1983-05-31 Cornell Research Foundation, Inc. Diaminopyridines to improve cognition

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2160590C2 (ru) * 1992-12-18 2000-12-20 Канэдиан Спайнал Рисерч Организейшн Способ лечения боли и спастичности
WO1994014439A1 (fr) * 1992-12-18 1994-07-07 Canadian Spinal Research Organization Utilisation de 4-aminopyridine dans le traitement d'une pathologie neurologique
US5545648A (en) * 1992-12-18 1996-08-13 Canadian Spinal Research Organization Use of 4-aminopyridine in the reduction of chronic pain and spasticity in a spinal cord injured patient
AU676251B2 (en) * 1992-12-18 1997-03-06 Canadian Spinal Research Organization The use of 4-aminopyridine in the treatment of a neurological condition
US5580748A (en) * 1993-05-03 1996-12-03 The United States Of America As Represented By The Department Of Health And Human Services Diagnostic tests for alzheimers disease
US5976816A (en) * 1993-05-03 1999-11-02 The United States Of America As Represented By The Department Of Health And Human Services Cell tests for alzheimer's disease
US6080582A (en) * 1993-05-03 2000-06-27 The United States Of America As Represented By The Department Of Health And Human Services Cell tests for Alzheimer's disease
WO1994025872A1 (fr) * 1993-05-03 1994-11-10 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Test effectue sur des cellules pour diagnostiquer la maladie d'alzheimer
US5399587A (en) * 1993-12-13 1995-03-21 Merck & Co., Inc. Biologically active compounds
US5792743A (en) * 1995-04-19 1998-08-11 Acorda Therapeutics Method for promoting neural growth comprising administering a soluble neural cell adhesion molecule
WO1998030243A1 (fr) * 1997-01-08 1998-07-16 Warner-Lambert Company Inhibiteurs d'acetylcholinesterase en combinaison avec des agonistes muscariniques utilises dans le traitement de la maladie d'alzheimer
EP1190708A1 (fr) * 2000-09-21 2002-03-27 Tinnitus Forschungs- und Entwicklungs GmbH Utilisation médicale de substances
EP1511474A4 (fr) * 2002-05-14 2008-02-20 Inst Medical W & E Hall Procede de traitement
FR2918281A1 (fr) * 2007-09-25 2009-01-09 Assist Publ Hopitaux De Paris Medicament pour le traitement de la maladie de parkinson.
WO2013052575A1 (fr) 2011-10-04 2013-04-11 Acorda Therapeutics. Inc. Procédés de traitement d'une déficience sensorimotrice liée à un accident vasculaire cérébral à l'aide d'aminopyridines
CN104220072A (zh) * 2011-10-04 2014-12-17 阿索尔达治疗公司 利用氨基吡啶治疗中风相关的感觉运动损伤的方法
EA029558B1 (ru) * 2011-10-04 2018-04-30 Акорда Терапьютикс, Инк. Способы лечения связанной с инсультом сенсорно-двигательной недостаточности с использованием аминопиридинов
CN108451953A (zh) * 2011-10-04 2018-08-28 阿索尔达治疗公司 利用氨基吡啶治疗中风相关的感觉运动损伤的方法
WO2014172266A1 (fr) 2013-04-15 2014-10-23 Acorda Therapeutics, Inc. Procédés permettant de traiter des troubles sensori-moteurs associés à certains types d'accidents vasculaires cérébraux à l'aide d'aminopyridines
EP3243516A1 (fr) 2013-04-15 2017-11-15 Acorda Therapeutics, Inc. Procédés permettant de traiter des troubles sensori-moteurs associés à certains types d'accidents vasculaires cérébraux à l'aide d'aminopyridines
EP3427735A1 (fr) 2013-04-15 2019-01-16 Acorda Therapeutics, Inc. Procédés permettant de traiter des troubles sensori-moteurs associés à certains types d'accidents vasculaires cérébraux à l'aide d'aminopyridines

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Publication number Publication date
JPH03505868A (ja) 1991-12-19
EP0408650A1 (fr) 1991-01-23

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