WO2004105756A2 - Combinaison contenant un agent neuroprotecteur et un agent se fixant a la gadph, et utilisation pharmaceutique associee - Google Patents

Combinaison contenant un agent neuroprotecteur et un agent se fixant a la gadph, et utilisation pharmaceutique associee Download PDF

Info

Publication number
WO2004105756A2
WO2004105756A2 PCT/EP2004/005792 EP2004005792W WO2004105756A2 WO 2004105756 A2 WO2004105756 A2 WO 2004105756A2 EP 2004005792 W EP2004005792 W EP 2004005792W WO 2004105756 A2 WO2004105756 A2 WO 2004105756A2
Authority
WO
WIPO (PCT)
Prior art keywords
combination according
neurodegenerative disorders
disease
pharmaceutically acceptable
combination
Prior art date
Application number
PCT/EP2004/005792
Other languages
English (en)
Other versions
WO2004105756A3 (fr
Inventor
Enrique Carrazana
Nigel Scott Cook
Bettina Nauli
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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 Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2004105756A2 publication Critical patent/WO2004105756A2/fr
Publication of WO2004105756A3 publication Critical patent/WO2004105756A3/fr

Links

Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61P25/28—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 combinations suitable for the treatment of neurodegenerative disorders, in particular amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's Disease (AD).
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson's disease
  • AD Alzheimer's Disease
  • the effect of a combination which comprises (a) a neuroprotectant having an inhibitory effect on glutamate release or the effect of i ⁇ activation of voltage-dependent sodium channels or the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors, and (b) an active ingredient binding to GADPH is greater than the additive effect of the single components (a) or (b).
  • the effect of a combination which comprises riluzole and a dibenzo-oxepine on neurodegenerative disorders is greater than the additive effect of the single drugs.
  • the combinations disclosed herein can be used to treat neurodegenerative disorders, which are refractory to mono therapy employing one of the combination partners alone.
  • the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises (a) a neuroprotectant having an inhibitory effect on glutamate release or the effect of inactivation of voltage-dependent sodium channels or the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors, and (b) an active ingredient binding to GADPH, in particular a combination comprising riluzole and a dibenzo-oxepine, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use, especially in the treatment of neurodegenerative disorders.
  • a neuroprotectant having an inhibitory effect on glutamate release or the effect of inactivation of voltage-dependent sodium channels or the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors
  • an active ingredient binding to GADPH in particular a combination comprising riluzole and a dibenzo-oxepine, in
  • the invention relates to a combination suitable for synergistic action of the active components against neurodegenerative disorders which consists of synergistically effective amounts of (a) at least one neuroprotectant having an inhibitory effect on glutamate release or the effect of inactivation of voltage-dependent sodium channels or the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors, and (b) at least one active ingredient binding to GADPH, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, for simultaneous, separate or sequential use.
  • neurodegenerative disorders includes, but is not restricted to, ALS, PD, cerebral ischemia, AD, glaucoma, Huntington's chorea, fronto temporal lobe dementia, Lewy body dementia, retinitis pigmentosa and other retinal neurodegenerative disorders, mild cognitive impairment, progressive supranuclear palsy or atrophy, multiple sclerosis, multiple system atrophy, spinocerebellar atrophy, and also general, degenerative or diabetic peripheral neuropathies.
  • the term “neurodegenerative disorders” relates to ALS, PD and AD.
  • ALS sometimes called Lou Gehrig's disease
  • the disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons.
  • the disease causes weakness with a wide range of disabilities.
  • ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. ALS most commonly strikes people between 40 and 60 years of age, but younger and older people also can develop the disease.
  • ALS neoplasm originating from a specific genetic defect that leads to mutation of the enzyme known as superoxide dismutase 1 (SOD1 ).
  • SOD1 superoxide dismutase 1
  • the earliest symptoms of ALS may include twitching, cramping, or stiffness of muscles; muscle weakness affecting an arm or a leg; slurred and nasal speech; or difficulty chewing or swallowing. In some cases, symptoms initially affect one of the legs, and patients experience awkwardness when walking or running or they notice that they are tripping or stumbling more often.
  • Parkinson's patients notice speech problems. To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.
  • PD is a chronic, degenerative neurological disorder that affects both voluntary and involuntary movement. Tremor, rigidity and freezing in place, pain, muscle cramps, swallowing difficulty, balance problems and dementia are only some of the symptoms of Parkinson's which can cause severe debilitation. There is no cure at present. The various treatment options can offer Parkinson's patients temporary relief from symptoms.
  • AD is a progressive neurodegenerative disease characterized by distinct pathologies including fibhllary tangles, neuritic plaques, neuronal atrophy, dendritic pruning and neuronal death. AD is causing impaired memory, thinking and behavior.
  • the disease to be treated is ALS, especially ALS which is caused by a genetic defect that leads to mutation of the superoxide dismutase 1.
  • the disease to be treated is PD.
  • riluzole refers to 2-amino-6-(trifluoromethoxy) benzothiazole.
  • the term “riluzole” also comprises active ingredients having at least one pharmacological property also observed with riluzole selected from an inhibitory effect on glutamate release, inactivation of voltage-dependent sodium channels and the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
  • active ingredients having at least one pharmacological property also observed with riluzole selected from an inhibitory effect on glutamate release, inactivation of voltage-dependent sodium channels and the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
  • riluzole in ALS is described in US 5,527,814, the compound and its preparation is disclosed in EP 050551.
  • Other neuroprotectant compounds can be prepared as described, e.g., by Yagupolskii et al in Zhurnal Obschei Khimii 33 (7), 2301-7 (1963
  • dibenzo-oxepine as used herein includes, but is not limited to, the compounds disclosed in US 5,780, 500, the disclosure of which is incorporated by reference into the present patent specification, in particular the claimed chemical compounds and final products of the working examples.
  • a suitable combination comprises an active ingredient binding to GADPH, like the dibenzo-oxepines mentioned herein, and a neuroprotectant having an inhibitory effect on glutamate release or the effect of inactivation of voltage- dependent sodium channels or the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors, in particular selected from the group consisting of riluzole, lubeluzole, lubeluzole-N-oxide and 6-hydroxylubeluzole.
  • the active ingredient binding to GADPH is selected from the dibenzo-oxepines mentioned herein, rasagiline, selegiline and desmethyl-deprenyl.
  • the combination comprises the dibenzo- oxepine N-methyl-N-2-propynyldibenz[b,f]oxepin-10-methanamine, also disclosed in US 5,780, 500.
  • the combination comprises a pharmaceutically acceptable salt of N-methyl-N-2-propynyldibenz[b,f]oxepin-10-methan- amine, especially the hydrogen maleate, as disclosed, e.g., in WO97/45422.
  • Riluzole can be administered, e.g., in the form as marketed, e.g. under the trademark RILUTEKTM.
  • Dibenzo-oxepines may be administered, e.g., in the form as described in US 5,780, 500.
  • a combined preparation defines especially a "kit of parts" in the sense that the first and second active ingredient as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the ingredients, i.e., simultaneously or at different time points.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the active ingredients.
  • the ratio of the total amounts of the active ingredient 1 to the active ingredient 2 to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • there is at least one beneficial effect e.g., a mutual enhancing of the effect of the first and second active ingredient, in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutic effect in a non- effective dosage of one or both of the first and second active ingredient, and especially a strong synergism the first and second active ingredient.
  • references to the active ingredients are meant to also include the pharmaceutically acceptable salts. If these active ingredients have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the active ingredients having an acid group (for example COOH) can also form salts with bases.
  • the active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • a pharmaceutical combination which comprises riluzole and a dibenzo-oxepine, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, if at least one salt-forming group is present, will be referred to hereinafter as a COMBINATION OF THE INVENTION.
  • the pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be evidenced in preclinical studies known as such.
  • the pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be demonstrated in a clinical study.
  • Such clinical studies are preferably randomized, double- blind, clinical studies in patients with ALS with either familial or sporadic ALS.
  • Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION.
  • the beneficial effects on ALS can be determined directly through the results of these studies, e.g. by the time to tracheostomy or death in patients taking the COMBINATION OF THE INVENTION compared to placebo, or by changes in the study design which are known as such to a person skilled in the art.
  • the studies are, in particular, suitable to compare the effects of a mono therapy using the active ingredients and a COMBINATION OF THE INVENTION.
  • a further benefit is that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects, e.g. those observed with riluzole, e.g. nausea, an increase of the liver transaminase level, head aches, vomiting, dizziness, pancreatitis or neutropenia. This is in accordance with the desires and requirements of the patients to be treated.
  • the COMBINATIONS OF THE INVENTION can be used, in particular, for the treatment of ALS, AD or PD which is refractory to mono therapy.
  • It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against neurodegenerative disorders, comprising the COMBINATION OF THE INVENTION and at least one pharmaceutically acceptable carrier.
  • the first and second active ingredient can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms.
  • the unit dosage form may also be a fixed combination.
  • the present invention provides a pharmaceutical composition consisting of a quantity, which is jointly therapeutically effective against neurodegenerative disorders, of (a) at least one neuroprotectant having an inhibitory effect on glutamate release or the effect of inactivation of voltage-dependent sodium channels or the ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors, and (b) at least one active ingredient binding to GADPH, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.
  • compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active ingredient, alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
  • enteral such as oral or rectal and parenteral administration to mammals (warm-blooded animals), including man
  • a therapeutically effective amount of at least one pharmacologically active ingredient alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
  • the preferred route of administration of the dosage forms of the present invention is orally.
  • the novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients.
  • Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, eye-drops, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils or alcohols; or carriers such as starches, sugars, microcristalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
  • a therapeutically effective amount of each of the active ingredients of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of treatment of diseases according to the invention may comprise (i) administration of the first active ingredient in free or pharmaceutically acceptable salt form and (ii) administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described herein.
  • the individual active ingredients of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • administering also encompasses the use of a prodrug of an active ingredient that convert in vivo to the active ingredient as well as the use of active metabolites.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the present invention relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of neurodegenerative disorders.
  • the present invention provides a method of treating a warm-blooded animal having neurodegenerative disorders comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against said neurodegenerative disorders and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.
  • the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential use thereof in the treatment of neurodegenerative disorders, preferably amyotrophic lateral sclerosis.
  • the COMBINATION OF THE INVENTION is used for the treatment of neurodegenerative disorders which are refractory to monotherapy.
  • the effective dosage of each of the active ingredients employed in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the severity-of the neurodegenerative disorder being treated.
  • the dosage regimen the COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.
  • riluzole can be applied in a dosage of 20 to 50 mg, preferably about 25 to 35 mg, every 12 hours.
  • RILUTEK tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related decrease in bioavailability.

Landscapes

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

Abstract

L'invention concerne des combinaisons adaptées pour le traitement des maladies neurodégénératives, en particulier la sclérose latérale amyotrophique, la maladie de Parkinson et la maladie d'Alzheimer. Ces combinaisons contiennent : (a) un agent neuroprotecteur présentant un effet inhibiteur de la libération de glutamate, ou l'effet d'inactiver des canaux sodiques dépendants du potentiel, ou la capacité d'interférer avec les événements intracellulaires ultérieurs à la fixation d'émetteurs au niveau de récepteurs d'acides aminés excitateurs, en particulier ceux choisis parmi le riluzole, le lubeluzole, le lubeluzole-N-oxyde et le 6-hydroxylubeluzole ; et (b) un principe actif se fixant à la GADPH. L'invention concerne également : l'utilisation de ces combinaisons dans la préparation d'un médicament destiné au traitement des maladies neurodégénératives ; des emballages commerciaux contenant lesdites combinaisons ; une composition pharmaceutique contenant lesdites combinaisons ; ainsi qu'une méthode permettant de traiter un animal à sang chaud souffrant d'une maladie neurodégénérative.
PCT/EP2004/005792 2003-05-29 2004-05-28 Combinaison contenant un agent neuroprotecteur et un agent se fixant a la gadph, et utilisation pharmaceutique associee WO2004105756A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47429203P 2003-05-29 2003-05-29
US60/474,292 2003-05-29

Publications (2)

Publication Number Publication Date
WO2004105756A2 true WO2004105756A2 (fr) 2004-12-09
WO2004105756A3 WO2004105756A3 (fr) 2005-02-10

Family

ID=33490710

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/005792 WO2004105756A2 (fr) 2003-05-29 2004-05-28 Combinaison contenant un agent neuroprotecteur et un agent se fixant a la gadph, et utilisation pharmaceutique associee

Country Status (1)

Country Link
WO (1) WO2004105756A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016085998A1 (fr) 2014-11-26 2016-06-02 Medicinova, Inc. Association d'ibudilast et de riluzole, et méthode d'utilisation de cette dernière
AU2021201034B2 (en) * 2014-11-21 2023-07-06 Biohaven Pharmaceutical Holding Company Ltd Sublingual formulation of riluzole

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045515A2 (fr) * 2002-11-15 2004-06-03 Teva Pharmaceutical Industries, Ltd. Utilisation de rasagiline, avec ou sans riluzole, pour traiter la sclerose laterale amyotrophique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045515A2 (fr) * 2002-11-15 2004-06-03 Teva Pharmaceutical Industries, Ltd. Utilisation de rasagiline, avec ou sans riluzole, pour traiter la sclerose laterale amyotrophique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE EMBASE [Online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 2002, DESPORT J-C ET AL: "Oxydative stress in neurodegenerative diseases" XP002296879 Database accession no. EMB-2003029691 & NUTRITION CLINIQUE ET METABOLISME 2002 FRANCE, vol. 16, no. 4, 2002, pages 253-259, ISSN: 0985-0562 *
DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; October 2000 (2000-10), SAGOT Y ET AL: "An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease." XP002296878 Database accession no. NLM11030721 & BRITISH JOURNAL OF PHARMACOLOGY. OCT 2000, vol. 131, no. 4, October 2000 (2000-10), pages 721-728, ISSN: 0007-1188 *
DEIGNER H-P ET AL: "APOPTOSIS MODULATORS IN THE THERAPY OF NEURODEGENERATIVE DISEASES" EXPERT OPINION ON INVESTIGATIONAL DRUGS, ASHLEY PUBLICATIONS LTD., LONDON, GB, vol. 9, no. 4, April 2000 (2000-04), pages 747-764, XP001012423 ISSN: 1354-3784 *
KRAGTEN E ET AL: "Glyceraldehyde-3-dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl" JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 273, no. 10, March 1998 (1998-03), pages 5821-5828, XP002141410 ISSN: 0021-9258 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2021201034B2 (en) * 2014-11-21 2023-07-06 Biohaven Pharmaceutical Holding Company Ltd Sublingual formulation of riluzole
WO2016085998A1 (fr) 2014-11-26 2016-06-02 Medicinova, Inc. Association d'ibudilast et de riluzole, et méthode d'utilisation de cette dernière
EP3223815A4 (fr) * 2014-11-26 2018-06-27 MediciNova, Inc. Association d'ibudilast et de riluzole, et méthode d'utilisation de cette dernière
US10258611B2 (en) 2014-11-26 2019-04-16 Medicinova, Inc. Combination of ibudilast and riluzole and methods of using same
US11278531B2 (en) 2014-11-26 2022-03-22 Medicinova, Inc. Combination of ibudilast and riluzole and methods of using same

Also Published As

Publication number Publication date
WO2004105756A3 (fr) 2005-02-10

Similar Documents

Publication Publication Date Title
US20030109504A1 (en) Treatment of movement disorders with metabotropic glutamate receptors antagonist
US11318144B2 (en) Compositions and methods for treating Alzheimer's disease and Parkinson's disease
US20040029941A1 (en) Zonisamide use in obesity and eating disorders
EP1435943B1 (fr) Utilisation de derives de 2-oxo-1-pyrrolidine pour la preparation d'un medicament pour traiter la dyskinesie
JP2007517901A (ja) 体重の減少に作用する鎮痙剤及び抗精神病剤の組成物
JP2009517393A (ja) 不安症の治療方法
KR20150080013A (ko) 운동성 질환에 걸린 환자의 치료용 조성물
JP2011037877A (ja) ジスキネジーの治療
WO2000002542A2 (fr) Agent a effet antidepressif
CA3183560A1 (fr) Compositions et methodes de traitement de la maladie d'alzheimer et de la maladie de parkinson
EP1397138B1 (fr) ASSOCIATION DE PRINCIPES ACTIFS (par ex. de la galanthamine ou la désoxypéganine avec de l'acamprosate ou la mémantine) DESTINEE AU TRAITEMENT D'UNE INTOXICATION A DES SUBSTANCES ENTRAINANT UNE DEPENDANCE OU A DES STUPEFIANTS
JPH07505646A (ja) 神経伝達速度の減損を伴う障害，特に糖尿病性ニューロパシーに対するアンギオテンシンｉｉアンタゴニスト
US20070287685A1 (en) Medicinal composition containing FBPase inhibitor
JP5175015B2 (ja) ジスキネジーの治療
WO2004105756A2 (fr) Combinaison contenant un agent neuroprotecteur et un agent se fixant a la gadph, et utilisation pharmaceutique associee
EP1345610B1 (fr) Quetiapine pour le traitement de la dyskinesie dans des patients non-psychotique
AU2003267557B2 (en) Treatment of dyskinesia
EP3570841A1 (fr) Agoniste de ppary pour le traitement de la maladie de huntington
MX2014014316A (es) Método de reducción de peso.
CA2521274A1 (fr) Combinaisons de medicaments anti-epileptiques permettant de traiter des troubles neurologiques
EP3319603B1 (fr) Utilisation du méthylphénidate pour le traitement d'une altération de la démarche et déficience des membres secondaires au trouble du cortex pré-frontal
JP2002500181A (ja) ジスキネジーの処置
PL231163B1 (pl) Kombinacja i kompozycja farmaceutyczna do zastosowania w leczeniu i/lub zapobieganiu bólowi z powodu umiarkowanych do ciężkich neuralgii o różnorodnym umiejscowieniu
US20240293435A1 (en) Methods and Compositions for Treating Human Disorders Using D-Cycloserine and a Psychedelic Agent
AU761978B2 (en) Use of 2-amino-6- trifluoromehthoxy- benzothiazole for preventing or treating cerebellum dysfunction

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase