WO1998035670A1 - Product containing idazoxan and 1-dopa as combined pharmaceutical preparation useful for treating parkinson disease - Google Patents

Product containing idazoxan and 1-dopa as combined pharmaceutical preparation useful for treating parkinson disease Download PDF

Info

Publication number
WO1998035670A1
WO1998035670A1 PCT/FR1998/000261 FR9800261W WO9835670A1 WO 1998035670 A1 WO1998035670 A1 WO 1998035670A1 FR 9800261 W FR9800261 W FR 9800261W WO 9835670 A1 WO9835670 A1 WO 9835670A1
Authority
WO
WIPO (PCT)
Prior art keywords
dopa
idazoxan
disease
pharmaceutical preparation
product according
Prior art date
Application number
PCT/FR1998/000261
Other languages
French (fr)
Inventor
Francis Colpaert
Marc Marien
Thierry Imbert
Original Assignee
Pierre Fabre Medicament
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 Pierre Fabre Medicament filed Critical Pierre Fabre Medicament
Priority to AU66272/98A priority Critical patent/AU6627298A/en
Publication of WO1998035670A1 publication Critical patent/WO1998035670A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/415—1,2-Diazoles

Definitions

  • the present invention relates to products containing 1-Dopa of formula I and Idazoxan of formula 2 as a combined pharmaceutical preparation for simultaneous, separate or spread over time use to treat Parkmson's disease and associated pathologies .
  • Parkmson's disease is a degenerative disease which particularly affects the neurons of the substantia nigra - pars compacta - and its igro-stnated projections.
  • Symptomatic manifestations are motor disorders such as tremors, muscle stiffness, hypokinesia.
  • the diagnosis of the disease is delicate, only a histological analysis practiced post-mortem, by the demonstration of cellular degeneration at the level of the black substance, makes it possible to affirm without ambiguity the diagnosis. This degeneration gives rise to a dopaminergic deficit which is expressed by these three major disorders. In the absence of this histopathological evidence, the clinical characteristics determine membership in this disease.
  • Parkinson's disease is done, among other things, by the use of dopaminergic substances, in particular 1-Dopa possibly associated with a 1-Dopa decarboxylase inhibitor, such as carbidopa, to avoid peripheral side effects.
  • 1-Dopa decarboxylase inhibitor such as carbidopa
  • This therapy compensates for the too low endogenous brain dopamine levels and improves the symptomatology of the disease. It has major drawbacks such as dyskinesias, gastrointestinal and cardiovascular side effects. The reappearance of motor symptoms is observed immediately after cessation of treatment.
  • This 1-Dopa therapy has been known and used for several decades. Little progress has been made despite the contribution of dopamine agonists. There is a therapeutic need for improving the treatment of Parkinson's disease with 1-Dopa.
  • Idazoxan of formula 2 (2- [2- (1,4-benzodioxanyl)] -2-imidazoline) has antagonistic properties on noradrenergic ⁇ 2 receptors.
  • This compound is known and described in GB 2068376, by its chemical structure, its synthesis process, its pharmaceutical formulations and its application in therapy as an antidepressant drug.
  • Idazoxan has been studied in human clinics in the treatment of depression at doses varying from 5 to 40 mg, three times a day over four weeks and has shown a significant improvement on the scale of Hamilton versus placebo (Drug of the Future 1_0, # 9, 782 (1985)).
  • the products of the invention contain 1-Dopa and / or Idazoxan in the form of a salt with a pharmaceutically acceptable mineral or organic acid.
  • Idazoxan can be present both in its racemic form and in the form of a pure enantiomer.
  • the products of the invention contain 1-Dopa together with Idazoxan, that is to say that the invention also extends, and preferably to pharmaceutical compositions containing a synergistic mixture of 1- Dopa and Idazoxan intended to be used in the treatment of Parkinson's disease and associated pathologies such as dyskiesia.
  • compositions may optionally contain a 1-Dopa decarboxylase inhibitor at the peripheral level.
  • the products of the invention are in the form of unit dosages containing 50 mg to 4 g of 1-Dopa and 0.5 to 50 mg of Idazoxan, and can thus be adapted to each individual case by the practitioner. .
  • Parkinson's patients Twenty-one Parkinson's patients, presenting the disease in its idiopathic form, were the subject of a double-blind, randomized study, with a control group, on placebo. These patients have already been treated with 1-Dopa for three weeks before the study. From day 1 to day 21, patients receive 20 mg tid of Idazoxan or a placebo. Antiparkmsonian activity is evaluated using the UPDRS (Unified Parkmson's Rating Scale), on days 1 and 21. Neuropsychological tests are performed on days 1 and 21.
  • UPDRS Unified Parkmson's Rating Scale
  • Idazoxan can be expressed in the following table in which:.
  • the ON column represents the improvement of the symptomatology after three weeks of treatment, either by 1-Dopa, or by Idazoxan, or by the combination 1-Dopa and Idazoxan.
  • the score measurement is made after taking the product. This assessment is made on the UPDRS scale.
  • the OFF column represents the improvement in symptomatology after treatment either with 1- Dopa, or with Idazoxan, or with the combination 1- Dopa and Idazoxan. After the treatment, means that the measurement is made 12 hours after the last intake of the product, and thus shows the patient's basic condition.
  • dyskinesias which inevitably occur in a very large majority of cases (80%), are observed in parkinsonian patients treated with conventional dopamine replacement drugs such as 1-Dopa. .
  • dopamine replacement drugs such as 1-Dopa.
  • the results of the study show that there is a very significant decrease in the average intensity and also, in the duration of tardive dyskinesias. This activity is judged by video recording, and the results are shown in the following table, showing the percentage of decrease in mean intensity and duration of dyskinesias.
  • This improvement brought by the combined action of 1-Dopa and Idazoxan is used in human therapy to treat Parkinson's disease and the diseases conventionally treated with 1-Dopa, such as, for example, dyskinesias.
  • Another characteristic of the present invention resides in the fact that the co-administration of the two compounds can be carried out either by separate pharmaceutical compositions, the clinician having the choice of dosage and of the mode of administration according to the condition and characteristics of the patient. , or in a single pharmaceutical composition containing an excipient suitable for oral administration, in capsules or tablets, parenteral, transdermal, these pharmaceutical compositions being prepared according to conventional methods, at the dosages as described below.
  • 1-Dopa can be administered orally in daily doses between approximately 50 mg and 4 g at the same time as Idazoxan in doses between 0.5 and 50 mg, and this once or several times a day.
  • the two compounds can be incorporated into pharmaceutical compositions in the form of mineral or organic salts and that Idazoxan can also be in the form of a pure enantiomer.

Landscapes

  • 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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention concerns a product containing 1-Dopa and Idazoxan as combined pharmaceutical preparation to be used simultaneously, separately or at different times in antiparkisonian therapy.

Description

« PRODUIT CONTENANT DE L'IDAZOXAN ET DE LA 1-DOPA COMME PREPARATION PHARMACEUTIQUE COMBINEE UTILISE POUR LA MALADIE DE PARKINSON »"PRODUCT CONTAINING IDAZOXAN AND 1-DOPA AS A COMBINED PHARMACEUTICAL PREPARATION FOR PARKINSON'S DISEASE"
La présente invention est relative à des produits contenant de la 1-Dopa de formule 1_ et de 1 ' Idazoxan de formule 2 comme préparation pharmaceutique combinée pour une utilisation simultanée, séparée ou étalée dans le temps pour traiter la maladie de Parkmson et les pathologies associées.The present invention relates to products containing 1-Dopa of formula I and Idazoxan of formula 2 as a combined pharmaceutical preparation for simultaneous, separate or spread over time use to treat Parkmson's disease and associated pathologies .
Figure imgf000003_0001
Figure imgf000003_0001
La maladie de Parkmson est une maladie dégénérative affectant particulièrement les neurones de la substance noire - pars compacta - et ses projections igro-stnées . Les manifestations symptom tiques sont des troubles moteurs tels que tremblements, rigidité musculaire, hypokinésie. Le diagnostic de la maladie est délicat, seule une analyse histologique pratiquée post- mortem, par la mise en évidence de dégénérescence cellulaire au niveau de la substance noire, permet d'affirmer sans ambiguïté le diagnostic. Cette dégénérescence donne lieu à un déficit dopaminergique qui s'exprime par ces trois troubles majeurs. Dans l'absence de cette évidence histopathologique, les caractéristiques cliniques déterminent l'appartenance à cette maladie. Actuellement, le traitement de la maladie de Parkinson se fait entre autres par l'utilisation de substances dopaminergiques , en particulier de la 1-Dopa associée éventuellement à un inhibiteur de la 1-Dopa décarboxylase, comme la carbidopa, pour éviter les effets secondaires périphériques de la 1-Dopa sur le système cardiovasculaire et optimiser ses effets centraux.Parkmson's disease is a degenerative disease which particularly affects the neurons of the substantia nigra - pars compacta - and its igro-stnated projections. Symptomatic manifestations are motor disorders such as tremors, muscle stiffness, hypokinesia. The diagnosis of the disease is delicate, only a histological analysis practiced post-mortem, by the demonstration of cellular degeneration at the level of the black substance, makes it possible to affirm without ambiguity the diagnosis. This degeneration gives rise to a dopaminergic deficit which is expressed by these three major disorders. In the absence of this histopathological evidence, the clinical characteristics determine membership in this disease. Currently, the treatment of Parkinson's disease is done, among other things, by the use of dopaminergic substances, in particular 1-Dopa possibly associated with a 1-Dopa decarboxylase inhibitor, such as carbidopa, to avoid peripheral side effects. of 1-Dopa on the cardiovascular system and optimize its central effects.
Cette thérapeutique compense les trop faibles taux cérébraux endogènes de dopamine et améliore la symptomatologie de la maladie. Elle possède des inconvénients majeurs tels que les dyskinésies, des effets indésirables d'ordre gastro-intestinal et cardiovasculaire. On observe immédiatement après arrêt de traitement, la réapparition des symptômes moteurs. Cette thérapeutique à la 1-Dopa est connue et utilisée depuis plusieurs décennies. Peu de progrès ont été réalisés malgré l'apport des agonistes dopaminergiques. Il existe un besoin thérapeutique pour l'amélioration du traitement de la maladie de Parkinson par la 1-Dopa.This therapy compensates for the too low endogenous brain dopamine levels and improves the symptomatology of the disease. It has major drawbacks such as dyskinesias, gastrointestinal and cardiovascular side effects. The reappearance of motor symptoms is observed immediately after cessation of treatment. This 1-Dopa therapy has been known and used for several decades. Little progress has been made despite the contribution of dopamine agonists. There is a therapeutic need for improving the treatment of Parkinson's disease with 1-Dopa.
L' Idazoxan de formule 2 (2- [2- (1,4- benzodioxanyl) ] -2-imidazoline) possède des propriétés antagonistes sur les récepteurs α2 noradrénergiques . Ce composé est connu et décrit dans le brevet GB 2068376, par sa structure chimique, son procédé de synthèse, ses formulations pharmaceutiques et son application en thérapeutique comme médicament antidépresseur.Idazoxan of formula 2 (2- [2- (1,4-benzodioxanyl)] -2-imidazoline) has antagonistic properties on noradrenergic α 2 receptors. This compound is known and described in GB 2068376, by its chemical structure, its synthesis process, its pharmaceutical formulations and its application in therapy as an antidepressant drug.
L' Idazoxan a été étudié en clinique humaine dans le traitement de la dépression à des doses variant de 5 à 40 mg, trois fois par jour sur quatre semaines et a montré une amélioration significative sur l'échelle de Hamilton contre placebo (Drug of the Future 1_0, n° 9, 782 (1985)) .Idazoxan has been studied in human clinics in the treatment of depression at doses varying from 5 to 40 mg, three times a day over four weeks and has shown a significant improvement on the scale of Hamilton versus placebo (Drug of the Future 1_0, # 9, 782 (1985)).
Différentes études ont également été menées sur des singes ou des rats pour évaluer l'action de différents composés sur des symptômes analogues à ceux de la maladie de Parkinson, tels que les "symptômes" induits par la réserpine chez le rat (F.C. COLPAERT, Neuropharmacology, 2_6, 1431, 1987) ou par la neurotoxine MPTP (F.C. COLPAERT et al., Brain Res . Bull, 26, 627, 1991), ou encore les symptômes associés chez l'homme avec une autre maladie extrapyramidale : la paralysie supranucléaire progressive (J. GHIKA et al., Neurology, 4_1, 986, 1991) .Different studies have also been carried out on monkeys or rats to evaluate the action of different compounds on symptoms similar to those of Parkinson's disease, such as "symptoms" induced by reserpine in rats (FC COLPAERT, Neuropharmacology , 2_6, 1431, 1987) or by the neurotoxin MPTP (FC COLPAERT et al., Brain Res. Bull, 26, 627, 1991), or the symptoms associated in humans with another extrapyramidal disease: progressive supranuclear palsy (J. GHIKA et al., Neurology, 41, 986, 1991).
Une étude clinique a été entreprise visant à observer l'influence, sur le comportement moteur chez les patients parkinsoniens , d'un traitement par 1' Idazoxan seul, par la 1-Dopa seule, et la combinaison des deux composés en traitements associés :' 1-Dopa et Idazoxan . II a été trouvé de manière inattendue que le traitement par administration séparée ou non de la 1- Dopa et de l' Idazoxan provoquait une amélioration durable de la symptomatologie motrice de la maladie de Parkinson, et de ses pathologies associées dues à son traitement classique par la 1-Dopa, par exemple les dyskinésies .A clinical study has been undertaken to observe the influence, on motor behavior in Parkinson's patients, of treatment with Idazoxan alone, with 1-Dopa alone, and the combination of the two compounds in associated treatments: 1-Dopa and Idazoxan. It has been unexpectedly found that treatment by separate administration or not of 1- Dopa and Idazoxan causes a lasting improvement in the motor symptomatology of Parkinson's disease, and its associated pathologies due to its conventional treatment with 1-Dopa, for example dyskinesias.
Ainsi l'administration conjointe, séparée, ou étalée dans le temps de la 1-Dopa et de l' Idazoxan provoquait une amélioration significative de l'activité antiparkmsonienne par cette association, par rapport à l'activité de chacun des composés après administration seule. Cette amélioration est tout à fait particulière puisqu'elle dure dans le temps après l'arrêt du traitement.Thus the joint, separate, or spread over time administration of 1-Dopa and Idazoxan caused a significant improvement in the antiparkmsonian activity by this combination, compared to the activity of each of the compounds after administration alone. This improvement is very special since it lasts over time after stopping treatment.
Selon une autre caractéristique de l'invention, les produits de l' invention renferment la 1-Dopa et/ou l' Idazoxan sous la forme d'un sel avec un acide minéral ou organique pharmaceutiquement acceptable.According to another characteristic of the invention, the products of the invention contain 1-Dopa and / or Idazoxan in the form of a salt with a pharmaceutically acceptable mineral or organic acid.
L' Idazoxan peut être présent aussi bien sous sa forme racémique que sous la forme d'un énantiomère pur .Idazoxan can be present both in its racemic form and in the form of a pure enantiomer.
Selon une autre caractéristique, les produits de l'invention contiennent la 1-Dopa conjointement avec 1' Idazoxan, c'est-à-dire que l'invention s'étend également, et de façon préférentielle aux compositions pharmaceutiques renfermant un mélange synergique de 1- Dopa et d' Idazoxan destiné à être utilisé dans le traitement de la maladie de Parkinson et des pathologies associées comme les dysk ésies .According to another characteristic, the products of the invention contain 1-Dopa together with Idazoxan, that is to say that the invention also extends, and preferably to pharmaceutical compositions containing a synergistic mixture of 1- Dopa and Idazoxan intended to be used in the treatment of Parkinson's disease and associated pathologies such as dyskiesia.
Ces compositions pharmaceutiques peuvent éventuellement contenir un inhibiteur de 1-Dopa décarboxylase au niveau périphérique.These pharmaceutical compositions may optionally contain a 1-Dopa decarboxylase inhibitor at the peripheral level.
Avantageusement, les produits de l'invention se présentent sous la forme de dosages unitaires contenant 50 mg à 4 g de 1-Dopa et de 0,5 à 50 mg d' Idazoxan, et peuvent ainsi être adaptés à chaque cas individuel par le praticien.Advantageously, the products of the invention are in the form of unit dosages containing 50 mg to 4 g of 1-Dopa and 0.5 to 50 mg of Idazoxan, and can thus be adapted to each individual case by the practitioner. .
Etude clinique :Clinical study :
Vingt et un patients parkinsoniens , présentant la maladie sous sa forme idiopathique, ont fait l'objet d'une étude en double aveugle, randomisée, avec un groupe contrôle, sous placebo. Ces patients ont été déjà traités par la 1-Dopa pendant trois semaines avant l'étude. Du jour 1 au jour 21, les patients reçoivent 20 mg t.i.d. d' Idazoxan ou un placebo. L'activité antiparkmsonienne est évaluée en utilisant l'échelle UPDRS (Unified Parkmson' s Rating Scale), aux jours 1 et 21. Des tests neuropsychologiques sont pratiqués aux jours 1 et 21.Twenty-one Parkinson's patients, presenting the disease in its idiopathic form, were the subject of a double-blind, randomized study, with a control group, on placebo. These patients have already been treated with 1-Dopa for three weeks before the study. From day 1 to day 21, patients receive 20 mg tid of Idazoxan or a placebo. Antiparkmsonian activity is evaluated using the UPDRS (Unified Parkmson's Rating Scale), on days 1 and 21. Neuropsychological tests are performed on days 1 and 21.
Il ressort de cette étude que l'amélioration symptomatique des manifestations motrices, évaluées sur l'échelle UPDRS classiquement utilisée pour mesurer la gravité des symptômes de la maladie de Parkinson, par l'administration conjointe de la 1-Dopa et deIt emerges from this study that the symptomatic improvement of motor manifestations, evaluated on the UPDRS scale conventionally used to measure the severity of the symptoms of Parkinson's disease, by the joint administration of 1-Dopa and
1' Idazoxan, peut être exprimée dans le tableau suivant dans lequel : . La colonne ON représente l'amélioration de la symptomatologie après trois semâmes de traitement, soit par la 1-Dopa, soit par l' Idazoxan, soit par l'association 1-Dopa et Idazoxan. La mesure du score est faite après la prise du produit. Cette évaluation est faite sur l'échelle UPDRS.1 Idazoxan, can be expressed in the following table in which:. The ON column represents the improvement of the symptomatology after three weeks of treatment, either by 1-Dopa, or by Idazoxan, or by the combination 1-Dopa and Idazoxan. The score measurement is made after taking the product. This assessment is made on the UPDRS scale.
. La colonne OFF représente l'amélioration de la symptomatologie après le traitement soit par la 1- Dopa, soit par l' Idazoxan, soit par l'association 1- Dopa et Idazoxan. Après le traitement, signifie que la mesure est faite 12 heures après la dernière prise de produit, et fait ainsi apparaître l'état de base du patient. . The OFF column represents the improvement in symptomatology after treatment either with 1- Dopa, or with Idazoxan, or with the combination 1- Dopa and Idazoxan. After the treatment, means that the measurement is made 12 hours after the last intake of the product, and thus shows the patient's basic condition.
Figure imgf000008_0001
Figure imgf000008_0001
On observe, chez les patients parkinsoniens traités par les médications classiques substituts de la dopamine, comme la 1-Dopa, des troubles secondaires particulièrement invalidants tels que les dyskinésies, et qui surviennent de façon inéluctable dans une très grosse majorité des cas (80 %) . L'amélioration apportée chez ces patients avec le traitement, association 1-Dopa et Idazoxan et l'amélioration des effets secondaires, en particulier ces dyskinésies, sont particulièrement intéressantes. Les résultats de l'étude montrent qu'il y a une diminution très significative de l'intensité moyenne et également, de la durée des dyskinésies tardives. Cette activité est jugée au moyen d'enregistrement vidéo, et les résultats sont indiqués dans le tableau suivant, montrant le pourcentage de la diminution de l'intensité moyenne et de la durée des dyskinésies . Particularly disabling secondary disorders such as dyskinesias, which inevitably occur in a very large majority of cases (80%), are observed in parkinsonian patients treated with conventional dopamine replacement drugs such as 1-Dopa. . The improvement brought in these patients with the treatment, combination 1-Dopa and Idazoxan and the improvement of the side effects, in particular these dyskinesias, are particularly interesting. The results of the study show that there is a very significant decrease in the average intensity and also, in the duration of tardive dyskinesias. This activity is judged by video recording, and the results are shown in the following table, showing the percentage of decrease in mean intensity and duration of dyskinesias.
Figure imgf000009_0001
Figure imgf000009_0001
De cette étude, nous tirons trois conclusions montrant l'avantage de l'association 1-Dopa et Idazoxan:From this study, we draw three conclusions showing the advantage of the 1-Dopa and Idazoxan combination:
1) L'amélioration de 60 % du score (UPDRS) dans le cas du traitement d'association est importante et montre bien l'avantage obtenu par rapport au score obtenu par le traitement à la 1-Dopa seule.1) The 60% improvement in the score (UPDRS) in the case of combination therapy is significant and clearly shows the advantage obtained compared to the score obtained by treatment with 1-Dopa alone.
2) Par ailleurs, il est exceptionnel de montrer l'amélioration persistante du score de 30 % chez les sujets n'ayant plus reçu aucune médication depuis 12 heures .2) In addition, it is exceptional to show the persistent improvement in the score of 30% in subjects who have not received any medication for 12 hours.
3) Il est également montré l'intérêt exceptionnel du traitement par l' Idazoxan des patients Parkinsoniens recevant déjà la 1-Dopa, par diminution en intensité3) The exceptional benefit of Idazoxan treatment of Parkinson's patients already receiving 1-Dopa is also shown, by reduction in intensity
(46 %) et en durée (15 %) , des dyskinésies induites par la 1-Dopa. Cette amélioration permet d'envisager un traitement à plus long terme, sans subir l'inconvénient d'un arrêt de traitement dû à des troubles neurologiques néfastes.(46%) and in duration (15%), dyskinesias induced by 1-Dopa. This improvement makes it possible to envisage a longer-term treatment, without suffering the inconvenience of stopping treatment due to harmful neurological disorders.
Cette amélioration apportée par l'action combinée de la 1-Dopa et de l' Idazoxan est mise à profit en thérapeutique humaine pour soigner la maladie de Parkinson et les maladies traitées de façon classique par la 1-Dopa, comme par exemple les dyskinésies.This improvement brought by the combined action of 1-Dopa and Idazoxan is used in human therapy to treat Parkinson's disease and the diseases conventionally treated with 1-Dopa, such as, for example, dyskinesias.
Une autre caractéristique de la présente invention réside dans le fait que la coadministration des deux composés peut se faire, soit par des compositions pharmaceutiques séparées, le clinicien ayant le choix du dosage et du mode d'administration selon l'état et les caractéristiques du patient, soit dans une seule composition pharmaceutique contenant un excipient adapté pour une administration orale, en gélules ou en comprimés, parentérale, transdermique, ces compositions pharmaceutiques étant préparées selon les méthodes conventionnelles, aux posologies telles qu'elles sont décrites ci-après.Another characteristic of the present invention resides in the fact that the co-administration of the two compounds can be carried out either by separate pharmaceutical compositions, the clinician having the choice of dosage and of the mode of administration according to the condition and characteristics of the patient. , or in a single pharmaceutical composition containing an excipient suitable for oral administration, in capsules or tablets, parenteral, transdermal, these pharmaceutical compositions being prepared according to conventional methods, at the dosages as described below.
La 1-Dopa peut être administrée par voie orale à des doses journalières comprises entre environ 50 mg et 4 g en même temps que l' Idazoxan à des doses comprises entre 0,5 et 50 mg, et ceci une ou plusieurs fois par jour.1-Dopa can be administered orally in daily doses between approximately 50 mg and 4 g at the same time as Idazoxan in doses between 0.5 and 50 mg, and this once or several times a day.
Il est entendu également que les deux composés peuvent être incorporés dans des compositions pharmaceutiques sous forme de sels minéraux ou organiques et que l' Idazoxan peut se présenter également sous forme d' énantiomère pur. It is also understood that the two compounds can be incorporated into pharmaceutical compositions in the form of mineral or organic salts and that Idazoxan can also be in the form of a pure enantiomer.

Claims

REVENDICATIONS
1. Produit contenant de la 1-Dopa et de 1' Idazoxan comme préparation pharmaceutique combinée pour une utilisation simultanée, séparée ou étalée dans le temps pour traiter la maladie de Parkinson et les pathologies associées comme les dyskinésies induites par la 1-Dopa.1. Product containing 1-Dopa and Idazoxan as a combined pharmaceutical preparation for simultaneous, separate or spread over time use to treat Parkinson's disease and associated pathologies such as dyskinesias induced by 1-Dopa.
2. Produit selon la revendication 1 , caractérisé en ce qu'il renferme de la 1-Dopa et/ou de2. Product according to claim 1, characterized in that it contains 1-Dopa and / or
1' Idazoxan sous la forme d'un sel avec un acide minéral ou organique pharmaceutiquement acceptable .1 Idazoxan in the form of a salt with a pharmaceutically acceptable mineral or organic acid.
3. Produit selon l'une des revendications 1 et 2, caractérisé en ce qu'il renferme de l' Idazoxan sous la forme d'un énantiomère pur.3. Product according to one of claims 1 and 2, characterized in that it contains Idazoxan in the form of a pure enantiomer.
4. Produit selon les revendications 1 à 3, caractérisé en ce qu'il contient de la 1-Dopa conjointement avec l' Idazoxan.4. Product according to claims 1 to 3, characterized in that it contains 1-Dopa together with Idazoxan.
5. Produit selon l'une des revendications 1 à 4, caractérisé en ce qu'il se présente sous forme de dosages unitaires contenant de 0,5 à 50 mg d' Idazoxan.5. Product according to one of claims 1 to 4, characterized in that it is in the form of unit dosages containing from 0.5 to 50 mg of Idazoxan.
6. Produit selon l'une des revendications 1 à 5, caractérisé en ce qu'il se présente sous forme de compositions pharmaceutiques contenant éventuellement un inhibiteur de 1-Dopa décarboxylase. 6. Product according to one of claims 1 to 5, characterized in that it is in the form of pharmaceutical compositions optionally containing an inhibitor of 1-Dopa decarboxylase.
PCT/FR1998/000261 1997-02-13 1998-02-11 Product containing idazoxan and 1-dopa as combined pharmaceutical preparation useful for treating parkinson disease WO1998035670A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66272/98A AU6627298A (en) 1997-02-13 1998-02-11 Product containing idazoxan and 1-dopa as combined pharmaceutical preparation useful for treating parkinson disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR97/01670 1997-02-13
FR9701670A FR2759291A1 (en) 1997-02-13 1997-02-13 PRODUCT CONTAINING IDAZOXAN AND 1-DOPA AS A COMBINED PHARMACEUTICAL PREPARATION FOR PARKINSON'S DISEASE

Publications (1)

Publication Number Publication Date
WO1998035670A1 true WO1998035670A1 (en) 1998-08-20

Family

ID=9503662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1998/000261 WO1998035670A1 (en) 1997-02-13 1998-02-11 Product containing idazoxan and 1-dopa as combined pharmaceutical preparation useful for treating parkinson disease

Country Status (3)

Country Link
AU (1) AU6627298A (en)
FR (1) FR2759291A1 (en)
WO (1) WO1998035670A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051734A1 (en) * 2001-12-18 2003-06-26 Alto Plastics Limited Sipper cap with reciprocally movable nozzle
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6281207B1 (en) * 1999-09-15 2001-08-28 Reed Richter Treatment of movement disorders by administration of mirtazapine
EP1333828B1 (en) * 2000-11-14 2008-07-02 Orion Corporation Prevention of development of dyskinesias

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989001774A1 (en) * 1987-09-02 1989-03-09 Saad Al Damluji Pharmaceutical compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989001774A1 (en) * 1987-09-02 1989-03-09 Saad Al Damluji Pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PEYRO-SAINT-PAUL H ET AL: "Short term oral administration of idazoxan in mild stable Parkinsonian patients treated with L-DOPA", THERAPIE (PARIS), 0 (SUPPL.). 1995. 172., XP002045789 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051734A1 (en) * 2001-12-18 2003-06-26 Alto Plastics Limited Sipper cap with reciprocally movable nozzle
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors

Also Published As

Publication number Publication date
AU6627298A (en) 1998-09-08
FR2759291A1 (en) 1998-08-14

Similar Documents

Publication Publication Date Title
EP1601349B1 (en) Use of the enantiomer (1s, 2r) of milnacipran for the preparation of a medicament
EP1071422B1 (en) Association of Riluzole and levodopa for the treatment of Parkinson disease
EP2305225A1 (en) Use of (1S, 2R) enantiomer of milnacipran for the preparation of a medicine
EP1773450A2 (en) Therapeutically combinations
BE897355A (en) ANALGESTIC AND ANTI-INFLAMMATORY COMPOSITIONS COMPRISING IBUPROFEN
KR20010041110A (en) Pharmaceutical combinations containing tramadol
WO1998035670A1 (en) Product containing idazoxan and 1-dopa as combined pharmaceutical preparation useful for treating parkinson disease
EP3429611A1 (en) Polycomplexes of poly-lysine compounds for preventing and/or combatting amyotrophic lateral sclerosis
US5948806A (en) Treatment of Parkinson's disease with (+)2-(ethyl-2,3-dihydrobenzofuranyl)-2-Imidazoline (dexefaroxan or (+) efaroxan)
CA2151039A1 (en) Idazoxan and derivatives thereof used for preparing a drug intended for the treatment of parkinsons's desease
FR2569109A1 (en) NEW PHARMACEUTICAL PREPARATIONS
EP0413694A1 (en) Cardio-protective drug preparations comprising amiodarone, a nitrate derivate, in particular isosorbide dinitrate and optionally a beta-blocker.
WO2008009798A1 (en) Composition based on d-glucosamine, on lactoferrin and on chondroitin sulphate for preventing and/or treating degenerative joint diseases
BE1003959A5 (en) Therapeutic agent for treatment of disorders associated with cerebral ischemia.
EP2229943B1 (en) Compounds for use in the treatment of peripheral neuropathy
FR2976807A1 (en) PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF DEPENDENCE IN HUMAN BEINGS
WO2004037256A1 (en) Pharmaceutical composition combining tenatoprazole and a histamine h2-receptor antagonist
BE1000087A3 (en) PHARMACEUTICAL COMPOSITION CONTAINING vinburnine AND METHOD OF PREPARATION.
BE475500A (en)
EP0287469B1 (en) Mixture containing as the active principles a central analgesic and forskolin
AU2023222362A1 (en) Pharmaceutical composition and medicament comprising l-tryptophan, l-5-hydroxytryptophan and a peripheral degradation inhibitor
FR2733911A1 (en) Compsn. contg. delapril and manidipine to prevent or treat cardiovascular and renal diseases
FR2802813A1 (en) Associations of deoxyfructosazine and a biguanide antidiabetic agent have a synergistic activity in the treatment of type 2 diabetes
BE858198A (en) PHARMACEUTICAL COMPOSITIONS BASED ON ANXIOLYTIC MEDICINAL PRODUCTS AND INHIBITORS OF THE ADRENERGIC SYSTEM
FR2526317A1 (en) Theophylline and cinnamamide association for asthma - gives prolonged activity, up to 24 hours, and uses some novel cpds. e.g. 3-cinnamoyl 2,2-di:methyl oxazolidine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN JP KR MX NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998535416

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase