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EP0918525A1 - Use of mifepristone for the treatment of psychoses and addictive behaviours - Google Patents

Use of mifepristone for the treatment of psychoses and addictive behaviours

Info

Publication number
EP0918525A1
EP0918525A1 EP97952079A EP97952079A EP0918525A1 EP 0918525 A1 EP0918525 A1 EP 0918525A1 EP 97952079 A EP97952079 A EP 97952079A EP 97952079 A EP97952079 A EP 97952079A EP 0918525 A1 EP0918525 A1 EP 0918525A1
Authority
EP
European Patent Office
Prior art keywords
mifepristone
psychoses
treatment
receptors
dopamine
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.)
Withdrawn
Application number
EP97952079A
Other languages
German (de)
French (fr)
Inventor
Claude Oberlander
Pier Vincenzo-Université de Bordeaux II PIAZZA
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.)
Institut National de la Sante et de la Recherche Medicale INSERM
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
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 Institut National de la Sante et de la Recherche Medicale INSERM filed Critical Institut National de la Sante et de la Recherche Medicale INSERM
Publication of EP0918525A1 publication Critical patent/EP0918525A1/en
Withdrawn legal-status Critical Current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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • the present invention relates to the application of mifepristone having an antiglucocorticoid activity for the preparation of medicaments intended for the prevention or
  • Products with anti-glucocorticoid activity are known as being able to be used as medicaments to fight mainly against the side effects of glucocorticoids; they also help fight
  • glucocorticoids It is very likely that glucocorticoid hormones modify the activity of these neurons by an action on these receptors.
  • 35 anti-dopaminergics In fact, they very significantly decrease the basal release of dopamine and the release of dopamine caused by depolarizing stimuli. The release of dopamine is considered to be one of the para- most reliable meters to assess dopamine activity.
  • the present invention therefore relates to the application of mifepristone corresponding to the formula:
  • the subject of the present invention is therefore the application of mifepristone having an antiglucocorticoid activity with the exception of mifepristone for the preparation of medicaments intended for the prevention or treatment on the one hand of schizophrenia and manic states , and on the other hand compulsive consumption behavior towards drugs such as opiates, psychostimulants, bartiturics and cannabis (or derivatives), nicotine or alcohol, disorders of eating behavior such as bulimia and compulsive behaviors like pathological gambling.
  • the invention extends to pharmaceutical compositions containing as active ingredient mifepristone.
  • the useful dosage varies depending on the type of psychosis or addiction to be prevented or treated and the route of administration. It can vary from 1 to 1000 mg per day in adults orally.
  • VTA ventral tegmental area
  • This behavioral response specifically depends on the activation of the dopaminergic neurons of the midbrain. Blockage of type II receptors also decreases the locomotor response to intra-ATV injection of morphine.
  • type II receptors we examined how type II receptors can exert their effects on the dopaminergic system. For this, we measured by intracerebral microdialysis the effect of blocking these receptors on the release of dopamine in the nucleus accumbens. A very significant decrease (more than 50%) of extracellular dopamine concentrations has been observed. the basal state and in response to morphine. It is important to note that the administration of type II receptor antagonists does not affect motor behavior. These substances have no effect either on the locomotor response to a new environment, or on the locomotor response to an injection of solvent (0.9% NaCl).
  • Dopamine release is estimated by direct measurement of its extracellular concentrations.
  • Spironolactone (1 ⁇ m) or 173-hydroxy 10 / 3- [(4-methylphenyl) methyl] 17 ⁇ - (prop-1-ynyl) estra 4, 9 (11) -dien-3 -one (200 nM) have have been used to block type I corticosteroid receptors or type II corticosteroid receptors, respectively.
  • the dopaminergic neurons are characterized by a basal release of TTX-sensitive dopamine and dependent Ca and by a release caused by K + , also, Ca 2+ dependent. In addition, these neurons express presynaptic receptors and functional reuptake sites.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention concerns the use of mifepristone with anti-glucocorticoid for preparing medicine for the prevention or treatment of psychoses or addictive behaviour, and compositions containing them.

Description

UTILISATION DE MIFEPRISTONE POUR LE TRAITEMENT DES PSYCHOSES ET DES COMPORTEMENTS ADDIC- TTFSUSE OF MIFEPRISTONE FOR THE TREATMENT OF ADDIC- TTFS PSYCHOSES AND BEHAVIORS
La présente invention a pour objet l'application de la mifepristone ayant une activité antiglucocorticoide pour la préparation de médicaments destinés à la prévention ou auThe present invention relates to the application of mifepristone having an antiglucocorticoid activity for the preparation of medicaments intended for the prevention or
10 traitement des psychoses ou des comportements addictifs.10 treatment of psychoses or addictive behaviors.
Les produits présentant une activité antiglucocorticoide sont connus comme pouvant être utilisés comme médicaments pour lutter principalement contre les effets secondaires des glucocorticoides ; ils permettent de lutter également contreProducts with anti-glucocorticoid activity are known as being able to be used as medicaments to fight mainly against the side effects of glucocorticoids; they also help fight
15 les troubles dus à une hypersécrétion de glucocorticoides notamment contre le vieillissement en général et plus particulièrement contre l'hypertension, le glaucome, l'athérosclérose, 1 'ostéoporose, le diabète, l'obésité ainsi que la dépression de l'immunité et l'insomnie.15 disorders due to hypersecretion of glucocorticoids, in particular against aging in general and more particularly against hypertension, glaucoma, atherosclerosis, osteoporosis, diabetes, obesity, as well as depression of immunity and 'insomnia.
20 Ils sont également connus comme médicaments destinés à la prévention ou au traitement des manifestations liées au syndrome de sevrage spontané ou précipité des narcotiques (demande de brevet européen EP 0676203) .They are also known as medicaments intended for the prevention or treatment of manifestations linked to the spontaneous or precipitated withdrawal syndrome from narcotics (European patent application EP 0676203).
Ils ont également été décrits comme médicaments destinésThey have also been described as drugs intended
25 au traitement des désordres de l'anxiété (demande de brevet internationale WO 95104536) .25 in the treatment of anxiety disorders (international patent application WO 95104536).
La demanderesse a mis en évidence l'application nouvelle et inattendue de la mifepristone.The Applicant has highlighted the new and unexpected application of mifepristone.
Les neurones dopaminergiques expriment les récepteursDopaminergic neurons express receptors
30 aux glucocorticoides. Il est très probable que les hormones glucocorticoides modifient l'activité de ces neurones par une action sur ces récepteurs.30 with glucocorticoids. It is very likely that glucocorticoid hormones modify the activity of these neurons by an action on these receptors.
L'action inattendue des anti-glucocorticoides réside dans leur efficacité particulière à agir comme substancesThe unexpected action of anti-glucocorticoids lies in their particular effectiveness in acting as substances
35 anti-dopaminergiques. En effet, ils diminuent de façon très importante la libération basale de dopamine et la libération de dopamine provoquée par des stimuli dépolarisants. La libération de dopamine est considérée comme l'un des para- mètres les plus fiables pour évaluer l'activité dopaminer- gique .35 anti-dopaminergics. In fact, they very significantly decrease the basal release of dopamine and the release of dopamine caused by depolarizing stimuli. The release of dopamine is considered to be one of the para- most reliable meters to assess dopamine activity.
Les effets anti-dopaminergiques des antiglucocorticoïdes permettent d'envisager leur utilisation comme agents théra- peutiques des psychoses et des comportements addictifs. D'une part, une hyper-activité des neurones dopaminergiques est associée à plusieurs troubles du comportement dont certains états psychotiques comme la schizophrénie. D'autre part, les effets addictifs des drogues résulteraient d'une activation extra-physiologique des neurones dopaminergiques qui sont spontanément hyper-actifs chez les sujets vulnérables à développer des comportements addictifs.The anti-dopaminergic effects of antiglucocorticoids make it possible to envisage their use as therapeutic agents for psychoses and addictive behaviors. On the one hand, hyper-activity of dopaminergic neurons is associated with several behavioral disorders including certain psychotic states such as schizophrenia. On the other hand, the addictive effects of drugs appear to result from an extra-physiological activation of dopaminergic neurons which are spontaneously hyperactive in subjects vulnerable to developing addictive behaviors.
Le blocage pharmacologique de l'activité dopaminergique est classiquement opéré grâce aux antagonistes des récepteurs dopaminergiques. Les antiglucocorticoïdes présentent plusieurs avantages par rapport à ces antagonistes. Ils réduisent l'activité dopaminergique dans un délai plus court (quelques heures contre plusieurs jours) , ce qui devrait réduire la latence d'apparition des effets cliniques. D'autre part, les antiglucocorticoïdes devraient produire moins d'effets indésirables sur le comportement. En effet, aux doses efficaces sur l'activité dopaminergique, les antiglucocorticoïdes n'ont pas d'effets sédatifs et ne désorganisent pas le comportement moteur, effets caractéristiques des antagonistes dopaminergiques.The pharmacological blockage of dopaminergic activity is conventionally operated by dopamine receptor antagonists. Antiglucocorticoids have several advantages over these antagonists. They reduce dopaminergic activity in a shorter time (a few hours against several days), which should reduce the latency of onset of clinical effects. On the other hand, antiglucocorticoids should produce fewer unwanted behavioral effects. Indeed, at effective doses on dopaminergic activity, antiglucocorticoids have no sedative effects and do not disrupt motor behavior, characteristic effects of dopaminergic antagonists.
La présente invention a donc pour objet l'application de la mifepristone répondant à la formule :The present invention therefore relates to the application of mifepristone corresponding to the formula:
ayant une activité antiglucocorticoide pour la préparation de médicaments destinés à la prévention ou au traitement des psychoses et des comportements addictifs.having an anti-glucocorticoid activity for the preparation of drugs intended for the prevention or treatment of psychoses and addictive behaviors.
La mifepristone est décrite et préparée dans le brevet européen EP 0057115.Mifepristone is described and prepared in European patent EP 0057115.
Sous le terme psychose, on entend notamment la schizo- phrénie et les états maniaques tels qu'ils sont définis dans le DSM-IV. L'addiction définit toute conduite compulsive de consommation où il apparaît une dépendance physique ou biologique à l'objet consommé. Sont inclus dans les addictions, notamment les toxicomanies aux drogues telles que les opiacés, les psychostimulants, les barbituriques et le cannabis ou dérivés, le tabagisme ou l'alcoolisme, les désordres du comportement alimentaire comme la boulimie et les comportements compulsifs comme le jeu pathologique.Under the term psychosis, we mean in particular schizophrenia and manic states as defined in the DSM-IV. Addiction defines any compulsive consumption behavior where there appears a physical or biological dependence on the object consumed. Are included in addictions, in particular drug addiction such as opiates, psychostimulants, barbiturates and cannabis or derivatives, smoking or alcoholism, eating disorders such as bulimia and compulsive behaviors such as pathological gambling .
En particulier, la présente invention a donc pour objet l'application de la mifepristone ayant une activité antiglucocorticoide à l'exception de la mifepristone pour la préparation de médicaments destinés à la prévention ou au traitement d'une part de la schizophrénie et des états maniaques, et d'autre part des conduites compulsives de consommation vis-à-vis des drogues telles que les opiacés, les psychostimulants, les bartituriques et le cannabis (ou dérivés), de la nicotine ou de l'alcool, des désordres du comportement alimentaire tels que la boulimie et des comportements compulsifs comme le jeu pathologique. L'invention s'étend aux compositions pharmaceutiques renfermant comme principe actif la mifepristone.In particular, the subject of the present invention is therefore the application of mifepristone having an antiglucocorticoid activity with the exception of mifepristone for the preparation of medicaments intended for the prevention or treatment on the one hand of schizophrenia and manic states , and on the other hand compulsive consumption behavior towards drugs such as opiates, psychostimulants, bartiturics and cannabis (or derivatives), nicotine or alcohol, disorders of eating behavior such as bulimia and compulsive behaviors like pathological gambling. The invention extends to pharmaceutical compositions containing as active ingredient mifepristone.
Ce principe actif peut être utilisé par voie digestive, parentérale ou locale, par exemple par voie percutanée. Il peut être prescrit sous forme de comprimés simples ou dragéifiés, de gélules, de granulés, de suppositoires, d'ovules, de préparation injectable, de pommades, de crèmes, de gels, de microsphères, d'implants, de patchs, lesquels sont préparés selon les méthodes usuelles.This active principle can be used by the digestive, parenteral or local route, for example percutaneously. It can be prescribed in the form of simple or coated tablets, capsules, granules, suppositories, eggs, injectable preparation, ointments, creams, gels, microspheres, implants, patches, which are prepared according to the usual methods.
Ce principe actif peut y être incorporé à des excipients habituellement employés dans ces compositions pharmaceutiques, tels que le talc, la gomme arabique, le lactose, l'amidon, le stéarate de magnésium, le beurre de cacao, les véhicules aqueux ou non, les corps gras d'origine animale ou végétale, les dérivés paraffiniques, les glycols, les divers agents mouillants, dispersants ou émulsifiants, les conservateurs .This active principle can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal origin or vegetable, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
La posologie utile varie en fonction du type de psychose ou d'addiction à prévenir ou à traiter et de la voie d'administration. Elle peut varier de 1 à 1000 mg par jour chez l'adulte par voie orale.The useful dosage varies depending on the type of psychosis or addiction to be prevented or treated and the route of administration. It can vary from 1 to 1000 mg per day in adults orally.
ETUDE PHARMACOLOGIQUEPHARMACOLOGICAL STUDY
Expérience in vivoIn vivo experiment
Dans une première série d'expériences, nous avons étudié l'effet du blocage de chacun des deux types de récepteurs aux corticostéroïdes sur les effets locomoteurs de la morphine. Cette réponse comportementale a été choisie puisqu'elle met en jeu les neurones dopaminergiques. Seul le blocage des récepteurs de type II par la mifepristone et le 17/3-hydroxy IOJS- t (4-méthylphényl) méthyl] 17α- (prop-1-ynyl) estra 4, 9 (11) -dièn-3-one réduit considérablement la réponse à la morphine tandis que la spironolactone, antagoniste des récepteurs de type I, ne modifie pas significativement cette réponse. Dans une deuxième série d'expériences, nous avons déterminé si l'influence des récepteurs de type II sur la réponse comportementale à la morphine dépendait véritablement de la dopamine. Pour ce faire, la morphine a été injectée directement dans l'aire tegmentale ventrale (ATV) , où se trouvent les corps cellulaires des neurones dopaminergiques. Cette réponse comportementale dépend spécifiquement de l'activation des neurones dopaminergiques du mésencéphale . Le blocage des récepteurs de type II diminue aussi la réponse locomotrice à l'injection intra-ATV de morphine. Dans une troisième série d'expériences, nous avons examiné comment les récepteurs de type II pouvaient exercer leurs effets sur le système dopaminergique. Pour cela, nous avons mesuré par microdialyse intracérêbrale l'effet du blocage de ces récepteurs sur la libération de dopamine dans le noyau accumbens. Il a pu être observé une diminution très importante (plus de 50 %) des concentrations extracellulaires de dopamine à l'état basai et en réponse à la morphine. Il est important de signaler que l'administration des antagonistes des récepteurs de type II ne modifie pas le comportement moteur. En effet, ces substances n'ont d'effet ni sur la réponse locomotrice à un environnement nouveau, ni sur la réponse locomotrice à une injection de solvant (0,9 % de NaCl) .In a first series of experiments, we studied the effect of blocking each of the two types of corticosteroid receptors on the locomotor effects of morphine. This behavioral response was chosen since it involves dopaminergic neurons. Only blocking of type II receptors by mifepristone and 17/3-hydroxy IOJS- t (4-methylphenyl) methyl] 17α- (prop-1-ynyl) estra 4, 9 (11) -dien-3-one considerably reduces the response to morphine, while spironolactone, a type I receptor antagonist, does not significantly modify this response. In a second series of experiments, we determined whether the influence of type II receptors on the behavioral response to morphine really depended on dopamine. To do this, morphine was injected directly into the ventral tegmental area (VTA), where the cell bodies of dopaminergic neurons are located. This behavioral response specifically depends on the activation of the dopaminergic neurons of the midbrain. Blockage of type II receptors also decreases the locomotor response to intra-ATV injection of morphine. In a third series of experiments, we examined how type II receptors can exert their effects on the dopaminergic system. For this, we measured by intracerebral microdialysis the effect of blocking these receptors on the release of dopamine in the nucleus accumbens. A very significant decrease (more than 50%) of extracellular dopamine concentrations has been observed. the basal state and in response to morphine. It is important to note that the administration of type II receptor antagonists does not affect motor behavior. These substances have no effect either on the locomotor response to a new environment, or on the locomotor response to an injection of solvent (0.9% NaCl).
En conclusion, ces résultats montrent que les glucocorticoides modifient l'activité dopaminergique via les récepteurs de type II et que les antagonistes de ces récepteurs peuvent être utilisés pour bloquer l'activité dopaminergique. Expériences in vitroIn conclusion, these results show that glucocorticoids modify dopaminergic activity via type II receptors and that antagonists of these receptors can be used to block dopaminergic activity. In vitro experiments
Les effets des antiglucocorticoïdes ont été testés sur la libération de dopamine de neurones dopaminergiques du mésencéphale en culture. Ce modèle in vitro permet de mesurer avec précision toute modification de l'activité de ces neurones .The effects of antiglucocorticoids have been tested on the release of dopamine from dopaminergic neurons of the midbrain in culture. This in vitro model enables precise measurement of any modification in the activity of these neurons.
La libération de dopamine est estimée par mesure directe de ses concentrations extracellulaires. La spironolactone (1 μm) ou le 173-hydroxy 10/3- [ (4-méthylphényl) méthyl] 17α- (prop-1-ynyl) estra 4, 9 (11) -dièn-3 -one (200 nM) ont été utilisés afin de bloquer respectivement les récepteurs aux corticostéroïdes de type I ou les récepteurs aux cortico- stêroïdes de type II. Dans la condition de culture qui a été utilisée, les neurones dopaminergiques se caractérisent par une libération basale de dopamine TTX-sensible et Ca dépendante et par une libération provoquée par le K+, elle aussi, Ca2+ dépendante. De plus, ces neurones expriment des récepteurs présynaptiques et des sites de recapture fonctionnels. En effet, les niveaux extracellulaires de dopamine sont diminués par un agoniste (le quinpirole, 10 μM) et augmentés par un antagoniste (le sulpiride 1 μM) des récepteurs dopaminergiques D2 ainsi que par des inhibiteurs de la recapture telles que la cocaïne (100 μM) et l'amphétamine (100 μM) . Les antagonistes des récepteurs aux corticostéroïdes ont, sur ce modèle in vitro, des effets similaires à ceux observés in vivo. L'antagoniste des récepteurs de type II diminue de façon importante (50 %) la libération basale de dopamine et la libération de dopamine provoquée par le K+. En revanche, l'antagoniste des récepteurs de type I n'a pas d'effet significatif. De plus, les effets de l'application combinée des deux antagonistes sont identiques à ceux de l'antagoniste de type II seul. En conclusion, ces résultats indiquent de façon claire que les glucocorticoides contrôlent l'activité dopaminergique via les récepteurs de type II, et que les antagonistes sélectifs de ces récepteurs de la mifepristone peuvent être utilisés pour diminuer l'activité dopaminergique. De plus, les effets des antiglucocorticoïdes en culture suggèrent que ces agents agissent de façon directe sur les neurones dopaminergiques. Ce résultat est très important puisqu'il conforte l'hypothèse d'une spécificité des effets observés. Dopamine release is estimated by direct measurement of its extracellular concentrations. Spironolactone (1 μm) or 173-hydroxy 10 / 3- [(4-methylphenyl) methyl] 17α- (prop-1-ynyl) estra 4, 9 (11) -dien-3 -one (200 nM) have have been used to block type I corticosteroid receptors or type II corticosteroid receptors, respectively. In the culture condition which was used, the dopaminergic neurons are characterized by a basal release of TTX-sensitive dopamine and dependent Ca and by a release caused by K + , also, Ca 2+ dependent. In addition, these neurons express presynaptic receptors and functional reuptake sites. Indeed, the extracellular dopamine levels are decreased by an agonist (quinpirole, 10 μM) and increased by an antagonist (sulpiride 1 μM) of dopamine D2 receptors as well as by reuptake inhibitors such as cocaine (100 μM ) and amphetamine (100 μM). Corticosteroid receptor antagonists, in this in vitro model, have effects similar to those observed in vivo. The type II receptor antagonist significantly decreases (50%) the basal release of dopamine and the release of dopamine caused by K + . On the other hand, the type I receptor antagonist has no significant effect. In addition, the effects of the combined application of the two antagonists are identical to those of the type II antagonist alone. In conclusion, these results clearly indicate that glucocorticoids control dopaminergic activity via type II receptors, and that the selective antagonists of these mifepristone receptors can be used to decrease dopaminergic activity. In addition, the effects of antiglucocorticoids in culture suggest that these agents act directly on dopaminergic neurons. This result is very important since it supports the hypothesis of a specificity of the observed effects.

Claims

REVENDICATIONS
1) Application de la mifepristone répondant à la formule1) Application of mifepristone corresponding to the formula
ayant une activité antiglucocorticoïde pour la préparation de médicaments destinés à la prévention ou au traitement des psychoses et des comportements addictifs.having an anti-glucocorticoid activity for the preparation of drugs intended for the prevention or treatment of psychoses and addictive behaviors.
2) Application selon la revendication 1, caractérisée en ce que les psychoses sont choisies parmi la schizophrénie et les états maniaques .2) Application according to claim 1, characterized in that the psychoses are chosen from schizophrenia and manic states.
3) Application selon la revendication 1, caractérisée en ce que les comportements addictifs sont choisis parmi les conduites compulsives de consommation vis-à-vis des drogues telles que les opiacés, les psychostimulants, les barbituriques et le cannabis ou dérivés, de la nicotine ou de l'alcool, les désordres du comportement alimentaire tel que la boulimie et les comportements compulsifs comme le jeu pathologique. 3) Application according to claim 1, characterized in that the addictive behaviors are chosen from compulsive consumption behaviors with respect to drugs such as opiates, psychostimulants, barbiturates and cannabis or derivatives, nicotine or alcohol, eating disorders such as bulimia and compulsive behaviors such as pathological gambling.
EP97952079A 1996-12-19 1997-12-17 Use of mifepristone for the treatment of psychoses and addictive behaviours Withdrawn EP0918525A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9615649A FR2757400B1 (en) 1996-12-19 1996-12-19 APPLICATION OF ANTIGLUCOCORTICOIDAL COMPOUNDS IN THE TREATMENT OF PSYCHOSIS OR ADDICTIVE BEHAVIORS
FR9615649 1996-12-19
PCT/FR1997/002321 WO1998026785A1 (en) 1996-12-19 1997-12-17 Use of mifepristone for the treatment of psychoses and addictive behaviours

Publications (1)

Publication Number Publication Date
EP0918525A1 true EP0918525A1 (en) 1999-06-02

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EP97952079A Withdrawn EP0918525A1 (en) 1996-12-19 1997-12-17 Use of mifepristone for the treatment of psychoses and addictive behaviours
EP97952078A Withdrawn EP0892641A1 (en) 1996-12-19 1997-12-17 Uses of anti-glucocorticoid compounds for the treatment of psychoses or addictive behaviours

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP97952078A Withdrawn EP0892641A1 (en) 1996-12-19 1997-12-17 Uses of anti-glucocorticoid compounds for the treatment of psychoses or addictive behaviours

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EP (2) EP0918525A1 (en)
AU (2) AU5563298A (en)
FR (1) FR2757400B1 (en)
WO (2) WO1998026783A1 (en)

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Publication number Priority date Publication date Assignee Title
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