[go: up one dir, main page]

WO2005049039A1 - Combinaisons comprenant des antagonistes de recepteurs ampa, utilisees dans le traitement de troubles affectifs et de troubles deficitaires de l'attention - Google Patents

Combinaisons comprenant des antagonistes de recepteurs ampa, utilisees dans le traitement de troubles affectifs et de troubles deficitaires de l'attention Download PDF

Info

Publication number
WO2005049039A1
WO2005049039A1 PCT/EP2004/012145 EP2004012145W WO2005049039A1 WO 2005049039 A1 WO2005049039 A1 WO 2005049039A1 EP 2004012145 W EP2004012145 W EP 2004012145W WO 2005049039 A1 WO2005049039 A1 WO 2005049039A1
Authority
WO
WIPO (PCT)
Prior art keywords
affective
aliphatic
combination according
attention disorders
combination
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/EP2004/012145
Other languages
English (en)
Inventor
Kurt LINGENHÖHL
Ferenc Martenyi
Silvio Ofner
Mary Ann Karolchyk
Hans O. Kalkman
David Aitken
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.)
Novartis Pharma GmbH Austria
Novartis AG
Original Assignee
Novartis Pharma GmbH Austria
Novartis AG
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 Pharma GmbH Austria, Novartis AG filed Critical Novartis Pharma GmbH Austria
Publication of WO2005049039A1 publication Critical patent/WO2005049039A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • 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

Definitions

  • the present invention relates to combinations suitable for the treatment of neurological / psychiatric disorders, in particular affective and attention disorders.
  • the effect of a combination which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics is greater than the additive effect of the combined drugs.
  • the combinations disclosed herein can be used to treat affective and attention disorders which is refractory to monotherapy employing one of the combination partners alone.
  • the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics, 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.
  • a combination such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics, 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
  • cognitivo and attention disorders includes, but is not limited to bipolar disorder, e.g. manic-depressive psychoses, mania with or without psychotic feature, attention deficit hyperactivity disorder (ADHD), and other attention disorders, e.g. autism, as well as those behavioural states characterized by social withdrawal, e.g., negative symptoms.
  • bipolar disorder e.g. manic-depressive psychoses, mania with or without psychotic feature
  • ADHD attention deficit hyperactivity disorder
  • autism e.g. autism
  • lithium as used herein includes, but is not limited to lithium acetate, lithium carbonate, lithium chloride, lithium citrate and lithium sulfate.
  • conventional antipsychotics as used herein includes, but is not limited to haloperidol and fluphenazine.
  • typically antipsychotics as used herein includes, but is not limited to olanzapine, quetiapine and risperidone.
  • antagonists as used herein includes, but is not limited to tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI's), or selective serotonin and norepinephrine reuptake inhibitors (SNRI-s).
  • a tricyclic antidepressant suitable for the present invention is especially selected from amitriptyline, butriptyline, clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline, trimipramine, maprotiline, mianserin, and mirtazepine.
  • An SSRI suitable for the present invention is especially selected from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram and escitalopram, and an SNRI selected from venlafaxine and duloxetine.
  • anti-epileptics includes, but is not limited to barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, succinimides, valproic acid and other fatty acid derivates, AMPA antagonists and other anti-epileptic drugs, 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.
  • the term "barbiturates and derivatives thereof as used herein includes, but is not limited to phenobarbital, pentobarbital, mepobarbital and primidon.
  • benzodiazepines as used herein includes, but is not limited to clonazepam, diazepam and lorazepam.
  • carboxyamides as used herein includes, but is not limited to carbamazepine, oxcarbazepine, 10-hydroxy-10,11-dihydrocarbamazepine and the compounds of formula II
  • Ri' represents C C 3 alkyl carbonyl.
  • hydantoins as used herein includes, but is not limited to phenytoin.
  • succinimides as used herein includes, but is not limited to ethosuximide, phensuximide and mesuximide.
  • valproic acid and other fatty acid derivates as used herein includes, but is not limited to valproic acid sodium salt, tiagabine hydrochloride monohydrate and vigrabatrine.
  • other anti-epileptic drugs includes, but is not limited to levetiracetam, lamotrigine, gabapentin, sultiam, felbamate, the 1 ,2,3-1 H-triazoles disclosed in EP 114 347, esp. rufinamide [1-(2,6-difluoro- benzyl)-1H-[1,2,3]triazole-4-carboxylic acid amide] and the 2-aryl-8-oxodihydropurines disclosed in WO99/28320.
  • Lithium acetate can be administered, e.g., in the form as marketed, e.g. under the trademark QuilonormTM.
  • Lithium carbonate can be administered, e.g., in the form as marketed, e.g. under the trademark EskalithTM.
  • Lithium citrate can be administered, e.g., in the form as marketed, e.g. under the trademark LitarexTM.
  • Lithium sulfate can be administered, e.g., in the form as marketed, e.g. under the trademark Lithium-DurilesTM, or, e.g., by transdermal release (US 6,375,990).
  • Valproic acid sodium salt can be administered, e.g., in the form as marketed, e.g. under the trademark Divalproex SodiumTM.
  • Haloperidol can be administered, e.g., in the form as marketed, e.g. under the trademark Haloperidol STADATM.
  • Olanzapine can be administered, e.g., in the form as marketed, e.g. under the trademark ZyprexaTM.
  • Risperidone can be administered, e.g., in the form as marketed, e.g. under the trademark RisperdalTM.
  • Quetiapine can be administered, e.g., in the form as marketed, e.g. under the trademark SeroquelTM.
  • Fluphenazine can be administered, e.g., in the form of its dihydro- chloride as marketed, e.g. under the trademark ProlixinTM.
  • Lamotrigine can be administered, e.g., in the form as marketed, e.g. under the trademark LamictalTM.
  • Fluoxetine can be administered, e.g., in the form of its hydrochloride as marketed, e.g. under the trademark ProzacTM.
  • Paroxetine can be administered, e.g., in the form as marketed, e.g. under the trademark PaxilTM.
  • Methylphenidate can be administered, e.g., in the form as marketed, e.g. under the trademark RitalinTM.
  • Methylphenidate is the most commonly prescribed psychotropic medication for children in the United States, primarily for the treatment of children diagnosed with attention deficit disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD), and thus, is widely available. Methylphenidate is described in U.S. Patent Nos. 2,838,519 and 2,957,880. U.S. Patent Nos. 5,922,736; 5,908,850; 5,773,478; 6,113,879 describe administering d-threo methylphenidate to treat nervous system disorders. U.S. Patent Nos. 6,100,401; 6,121,453; and 6,162,919 describe processes for preparing substantially the single enantiomer d-threo methylphenidate. U.S. Patent Nos. 5,874,090 and 5,837,284 describe sustained release formulations of methylphenidate. All these citations are included herein by reference.
  • AMPA receptor antagonists as used herein includes, but is not limited to the quinoxaline-dione aminoalkylphosphonates of formula I wherein
  • Ri represents hydroxy or an aliphatic, aryl aliphatic or aromatic group
  • X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group
  • R 2 represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and
  • R 3 , R 4 and R 5 represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro, and wherein the radicals have the meanings as defined in WO 98/17672.
  • AMPA receptor antagonists include also, EGIS 8332 (7-acetyl-5-(4-aminophenyl)-8,9- dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 4- (7-chloro-2-methyI-4H-3,10,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BUR 561; N,N-dimethyl-2-[2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4- [[[[[(4-carboxyphenyI)-amino]carbonyl]oxy]methyl]-1H-imidazol-1-yl]-3,4-dihydro-3-oxo-6- (trifluoromethyl)-2-quinoxalinecarboxy
  • YM90K (6-imidazol-1- yl-7-nitro-1 ,4-dihydro-quinoxaline-2,3-dione), S-34730 (7-chIoro-6-sulfamoyl-2-(1 H)- quinolinone-3-phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-dioxo- 3,4-dihydro-2H-quinoxalin-1-yl)-acetic acid), GYKI-52466 (4-(8-methyl-9H-1 ,3-dioxa-6,7- diaza-cyclohepta[fjinden-5-yl)-phenylamine), ZK-200775 (MPQX, (7-morpholin-4-yl-2,3- dioxo-6-trifluoromethyl-3,4-dihydro-2H-quinoxalin-1 -ylmethyl)-phosphonic acid), CP
  • Topiramate can be administered, e.g., in the form as marketed, e.g. under the trademark TopamaxTM.
  • TopamaxTM e.g., the trademark of TopamaxTM.
  • the compounds of formula I as well as their production process and pharmaceutical compositions thereof are known e.g. from WO 98/17672.
  • the structure of the active ingredients identified by code nos., generic or trade names and their preparation may be taken from the actual edition of the standard compendium "The Merck Index” (e.g.M. J. O'Neil et al., ed., The Merck Index', 13 th ed., Merck Research Laboratories, 2001) or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active ingredients and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • 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 at least one AMPA receptor antagonist and at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate and antidepressants, 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.
  • Test 1 NMDA-antagonist induced locomotion:
  • AMPA receptor antagonist on locomotor activity 2) Solvent 1 , combination partner and solvent 3 to study the effects of the combination partner on locomotor activity.
  • Locomotion is recorded with a videotracking system. Animals are on a normal 12/12 h day- night cycle, with light on at 06:00 H. Experiments are performed in a dimly lit room between 07:00 H and 15:00 H. Animals are placed in a round arena (diameter 42 cm, height 32 cm) made of grey polyvinylchloride plastic.
  • Test 2 NMDA-channel blocker induced head swaying and circling:
  • Video-recordings of the animals behavior over the period 0 - 30 min following PCP are scored by an observer who is unaware about the animals pretreatment. Head-swaying (rocking the head repeatedly by at least 2 cm left and right) and circling (turning around by using the forepaws, whereas the hindpaws remain more or less on the original position) are scored as present (1) or absent (0), every five minutes for the duration of 1 min.
  • the scores for individual animals is summed and group scores used for statistical analysis (t-test with Bonferroni correction).
  • PCP (10 mg/kg, s.c.) induces weak head-swaying and circling.
  • ADHD attention deficit hyperactivity disorders
  • other attention disorders e.g. autism
  • the pharmacological activity of a COMBINATION OF THE INVENTION may also be demonstrated in a clinical study.
  • Such clinical studies are preferably randomized, double- blind, clinical studies in patients with affective and attention disorders.
  • Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION.
  • the beneficial effects on affective and attention disorders can be determined directly through the results of these studies 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 monotherapy 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. 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 affective and attention disorders which is refractory to monotherapy.
  • the AMPA receptor antagonists used in the present invention are competitive AMPA receptor antagonists.
  • the COMBINATION OF THE INVENTION comprises an AMPA antagonist, which is a quinoxalinedione aminoalkylphosphonate, in particular a quinoxalinedione aminoalkylphosphonate of formula I, wherein
  • Ri represents hydroxy or an aliphatic, aryl aliphatic or aromatic group
  • X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group
  • R 2 represents hydrogen or an aliphatic or aryl aliphatic group
  • alk stands for C1-C7alkylene
  • R 3 , R4 and R 5 represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro.
  • the COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist which is a compound of formula I, wherein R-i represents hydroxyl, X represents methylene, R 2 represents hydrogen, alk stands for methylene, R 3 and R 5 represent hydrogen, and R 4 represents nitro or a salt thereof, i.e. is ⁇ [(7-Nitro-2,3-dioxo-1 ,2,3,4- tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl ⁇ -phosphonic acid or a salt thereof (cf. WO 97/08155, Example 57, 1st entry, and WO 98/17672, Example 12, 4th entry).
  • the AMPA receptor antagonists is selected from EGIS 8332 (7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1 ,3- dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 (4 ⁇ (7-chloro-2-methyl- 4H-3,10,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BUR 561 ; N,N- dimethyl-2-[2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4- [[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl]-1H-imidazol-1-yl]-3,4-dihydro-3-oxo- 6-(trifluoromethyl)-2
  • YM90K (6-imidazol-1-yl-7-nitro-1 ,4-dihydro-quinoxaline-2,3-dione), S-34730 (7-chloro-6-sulfamoyl-2-(1 H)-quinolinone-3-phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl)-acetic acid), GYKI- 52466 (4-(8-methyl-9H-1 ,3-dioxa-6,7-diaza-cyclohepta[f]inden-5-yl)-phenylamine), ZK- 200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H- quinoxalin-1-ylmethyl)-phosphonic acid), CP
  • a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against affective and attention disorders, comprises at least one AMPA receptor antagonist, at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate and antidepressants 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.
  • 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
  • parenteral administration to mammals (warm-blooded animals), including man
  • 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.
  • compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, 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.
  • the present invention relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of affective and attention disorders.
  • the present invention provides a method of treating a warm-blooded animal having affective and attention disorders comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against affective and attention 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 affective and attention disorders.
  • 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 affective and attention disorders 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.
  • administering also encompasses the use of a pro-drug of an active ingredient that convert in vivo to the active ingredient.
  • 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 COMBINATION OF THE INVENTION is used for the treatment of affective and attention disorders which is 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 condition 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.
  • Topiramate may be administered to an adult patient in a total daily dosage of between about 250 to about 500 mg.
  • Haloperidol may be administered to a patient in a total daily dosage of between about 2.5 to about 30 mg.
  • Lithium can be administered to a patient in a total daily dosage of between about 0.5 to about 2 g.
  • Olanzapine can be administered to a patient in a total daily dosage of between about 2.5 to about 20 mg.
  • Quetiapine can be administered to a patient in a total daily dosage of between about 500 to about 600 mg.
  • Risperidone may be administered to a patient in a total daily dosage of between about 2 to about 6 mg.
  • Valproic acid sodium salt may be administered to a patient in a total daily dosage of between about 2000 to about 3000 mg.
  • Amitriptyline may be administered to a patient in a total daily dosage of between about 30 to about 300 mg.
  • Clomipramine may be administered to a patient in a total daily dosage of between about 30 to about 150 mg. Desipramine may be administered to a patient in a total daily dosage of between about 25 to about 200 mg.
  • ⁇ [(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl ⁇ -phosphonic acid may be administered to a patient in a total daily dosage of about 60 to about 400 mg.

Landscapes

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

Abstract

L'invention concerne des combinaisons appropriées pour traiter des troubles neurologiques/psychiatriques, en particulier des troubles affectifs et des troubles de l'attention. La combinaison comprend au moins un antagoniste du récepteur AMPA et au moins un composé sélectionné dans le groupe comprenant lithium, acide valproïque, sels de sodium, antipsychotiques classiques, antipsychotiques atypiques, lamotrigine, méthylphénidate, antidépresseurs et anti-épileptiques.
PCT/EP2004/012145 2003-10-28 2004-10-27 Combinaisons comprenant des antagonistes de recepteurs ampa, utilisees dans le traitement de troubles affectifs et de troubles deficitaires de l'attention Ceased WO2005049039A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0325172.5A GB0325172D0 (en) 2003-10-28 2003-10-28 Organic compounds
GB0325172.5 2003-10-28

Publications (1)

Publication Number Publication Date
WO2005049039A1 true WO2005049039A1 (fr) 2005-06-02

Family

ID=29725526

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/012145 Ceased WO2005049039A1 (fr) 2003-10-28 2004-10-27 Combinaisons comprenant des antagonistes de recepteurs ampa, utilisees dans le traitement de troubles affectifs et de troubles deficitaires de l'attention

Country Status (2)

Country Link
GB (1) GB0325172D0 (fr)
WO (1) WO2005049039A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017672A1 (fr) * 1996-10-24 1998-04-30 Novartis Ag Acides aminoalcanophosphoniques substitues
WO2003092701A2 (fr) * 2002-04-30 2003-11-13 Novartis Ag Utilisation d'acides amino-alcane-phosphoniques substitués

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017672A1 (fr) * 1996-10-24 1998-04-30 Novartis Ag Acides aminoalcanophosphoniques substitues
WO2003092701A2 (fr) * 2002-04-30 2003-11-13 Novartis Ag Utilisation d'acides amino-alcane-phosphoniques substitués

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
COGHILL D: "Current issues in child and adolescent psychopharmacology. Part 1: Attention-deficit hyperactivity and affective disorders", ADVANCES IN PSYCHIATRIC TREATMENT 2003 UNITED KINGDOM, vol. 9, no. 2, 2003, pages 86 - 94, XP002316036, ISSN: 1355-5146 *
COWEN M S ET AL: "Neurobehavioral effects of alcohol in AMPA receptor subunit (GluR1) deficient mice.", NEUROPHARMACOLOGY, vol. 45, no. 3, September 2003 (2003-09-01), pages 325 - 333, XP002316034, ISSN: 0028-3908 *
GLICK I D ET AL: "PSYCHOPHARMACOLOGIC TREATMENT STRATEGIES FOR DEPRESSION, BIPOLAR DISORDER, AND SCHIZOPHRENIA", ANNALS OF INTERNAL MEDICINE, NEW YORK, NY, US, vol. 134, no. 1, 2 January 2001 (2001-01-02), pages 47 - 60, XP009000276, ISSN: 0003-4819 *
QUIRK JENNIFER C ET AL: "LY404187: a novel positive allosteric modulator of AMPA receptors.", CNS DRUG REVIEWS. FALL 2002, vol. 8, no. 3, October 2002 (2002-10-01), pages 255 - 282, XP009043432, ISSN: 1080-563X *
SAJATOVIC M: "Treatment of bipolar disorder in older adults", INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY 01 SEP 2002 UNITED KINGDOM, vol. 17, no. 9, 1 September 2002 (2002-09-01), pages 865 - 873, XP002316037, ISSN: 0885-6230 *
SVENSSON T H ET AL: "Atypical antipsychotic-like effect of AMPA receptor antagonists in the rat", AMINO ACIDS (VIENNA), vol. 19, no. 1, 2000, pages 221 - 226, XP002316035, ISSN: 0939-4451 *

Also Published As

Publication number Publication date
GB0325172D0 (en) 2003-12-03

Similar Documents

Publication Publication Date Title
AU2005206139B2 (en) Compositions of an anticonvulsant and an antipsychotic drug for affecting weight loss
US20080214592A1 (en) Methods of treating anxiety disorders
US20100179129A1 (en) Compositions of an anticonvulsant and mirtazapine to prevent weight gain
KR20060011873A (ko) 비정형 항정신약과 ｇａｂａ 조절제, 항경련성 약물 또는 벤조다이아제핀의 치료 혼합물
EP1503755A1 (fr) Utilisation de zonisamide dans le traitement de l'obesite et des troubles alimentaires
JP2012255039A (ja) ニコチン性アセチルコリンα７受容体アゴニストの組合せ剤
US20060160750A1 (en) Compositions of an anticonvulsant and an antipsychotic drug and methods of using the same for affecting weight loss
KR20090020703A (ko) 정신과 질환을 치료하기 위한 ｐ38 키나아제 억제제의 용도
AU2004290890B2 (en) Combinations comprising AMPA receptor antagonists for the treatment of schizophrenia
AU2004226825B2 (en) Combinations comprising anti-epileptic drugs for the treatment of neurological disorders
AU2003267557B2 (en) Treatment of dyskinesia
WO2016027259A1 (fr) Compositions pharmaceutiques pour le système nerveux central et procédés d'utilisation
WO2005049039A1 (fr) Combinaisons comprenant des antagonistes de recepteurs ampa, utilisees dans le traitement de troubles affectifs et de troubles deficitaires de l'attention
EP1545546B1 (fr) Traitement de la dyskinésie avec des 2,3-benzodiazépines
WO2005049041A1 (fr) Combinaisons comportant des antagonistes de recepteur ampa pour le traitement de troubles d'anxiete
WO2005097138A2 (fr) Combinaisons comprenant de l'oxcarbazepine pour le traitement de troubles affectifs
WO2005094797A2 (fr) Nouveaux antagonistes de recepteur ampa
WO2005049042A1 (fr) Combinaisons comprenant des antagonistes du recepteur ampa, utilisees dans le traitement du tinnitus
MXPA06007770A (en) Compositions of an anticonvulsant and an antipsychotic drug for affecting weight loss
CA2617420A1 (fr) Combinaisons therapeutiques d'antipsychotiques atypiques avec des modulateurs de l'acide 4-aminobutanoique et/ou des medicaments anticonvulsivants
TW201103546A (en) New use of 5H-dibenz/b,f/azepine-5-carboxamide derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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: A1

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
122 Ep: pct application non-entry in european phase