[go: up one dir, main page]

WO1998043646A1 - New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders - Google Patents

New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders Download PDF

Info

Publication number
WO1998043646A1
WO1998043646A1 PCT/EP1998/001920 EP9801920W WO9843646A1 WO 1998043646 A1 WO1998043646 A1 WO 1998043646A1 EP 9801920 W EP9801920 W EP 9801920W WO 9843646 A1 WO9843646 A1 WO 9843646A1
Authority
WO
WIPO (PCT)
Prior art keywords
mirtazapine
antipsychotic agent
treatment
combination
prophylaxis
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/EP1998/001920
Other languages
French (fr)
Inventor
Christophorus Louis Eduard Broekkamp
Hermanus Henricus Gerardus Berendsen
Roger Martin Pinder
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.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
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
Priority to HU0002742A priority Critical patent/HUP0002742A3/en
Priority to US09/380,723 priority patent/US6150353A/en
Priority to EP98919209A priority patent/EP0969845B1/en
Priority to NZ337618A priority patent/NZ337618A/en
Priority to DE69833645T priority patent/DE69833645T2/en
Priority to KR1019997008745A priority patent/KR100577865B1/en
Priority to PL335890A priority patent/PL191449B1/en
Priority to HK00102643.7A priority patent/HK1023293B/en
Priority to CA002284551A priority patent/CA2284551C/en
Priority to BR9808077-6A priority patent/BR9808077A/en
Application filed by Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to JP54116898A priority patent/JP4377456B2/en
Priority to AU72139/98A priority patent/AU726194B2/en
Publication of WO1998043646A1 publication Critical patent/WO1998043646A1/en
Priority to NO19994673A priority patent/NO994673L/en
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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to therapeutic combinations of mirtazapine and an antipsychotic agent, to pharmaceutical compositions containing said combinations and to their use in the treatment or prophylaxis of psychotic disorders.
  • antipsychotic agent includes those classical antipsychotics which work via dopamine D 2 receptor blockade and which are often referred to as “typical” antipsychotics or neuroieptics, and those new antipsychotics which are referred to as “atypical” antipsychotic agents. This atypicality has been defined in a number of ways, but recently it has been defined as the property of providing equal efficacy to established antipsychotic agents while producing fewer extrapyramidal side effects (Meltzer H.Y. Br. J. Psychiatry, 1996, 168 Suppl. 129:23-31).
  • Examples of such typical and atypical antipsychotics include acepromazine, chlorproethazine, chlorpromazine, cyamemazine fluopromazine, methotrimeprazine, promazine, mesoridazine, pericyazine, piperacetazine, pipothiazine, sulfo dazine, thioridazine, acetophenazine, carphenazine, dixyrazine, fluphenazine, perazine, perphenazine, prochlorperazine thiopropazate, thioproperazine, trifluperazine, chlorprothixene, flupenthixol, thiothixene, zudopenthixol, benperidol, bromperidol, droperidol, fluanisone, haloperidol, melperone, moperone, pipamperone, spiperone, timiperone, tri
  • mirtazapine which is one of the newest antidepressant agents and has been disclosed in US patent No. 4,062,848, in combination with an antipsychotic agent is able to enhance the antipsychotic effect of said antipsychotic.
  • the present invention provides a combination comprising mirtazapine and an antipsychotic agent as herein before described.
  • the combination includes mirtazapine.
  • the present invention also includes derivatives of mirtazapine and the antipsychotic agents.
  • Such derivatives include the pharmaceutically acceptable salts thereof.
  • Suitable salts include acid addition salts, for example, hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation.
  • Combinations of mirtazapine and an antipsychotic agent may hereinafter be referred to as combinations according to the invention.
  • the compounds of the combination may be administered simultaneously, either in the same or different pharmaceutical formulation or sequentially. If there is sequential administration, the delay in administering the second active ingredient should not be such as to lose the benefit of the efficacious effect of the combination of the active ingredients.
  • the present invention further provides combinations according to the invention for use in therapy, more particularly in the treatment or prophylaxis of psychotic disorders such as schizophrenia, mania, hyperactivity, substance abuse, emesis and schizophreniaform disorders.
  • psychotic disorders such as schizophrenia, mania, hyperactivity, substance abuse, emesis and schizophreniaform disorders.
  • the present invention further includes a method for the treatment of an animal, for example, a mammal including a human, suffering from or liable to suffer from a psychotic disorder, including any of the aforementioned disorders, which comprises administering an effective amount of a combination according to the invention.
  • a further feature of the present invention is the method of reducing the amount of antipsychotic agent required to produce an antipsychotic effect in an animal which comprises treating said animal with a therapeutically effective amount of a combination according to the present invention.
  • the present invention also provides the use of mirtazapine in the manufacture of a medicament for administration simultaneously or sequentially with an antipsychotic agent for the treatment and/or prophylaxis of a psychotic disorder. It will be appreciated that an antipsychotic agent may be used in the manufacture of the above medicament for administration simultaneously or sequentially with mirtazapine.
  • an antipsychotic agent in combination with mirtazapine allows a lower dosing of the antipsychotic agent to achieve the same antipsychotic effect.
  • the dosage of the antipsychotic agent may be reduced by 25-90%, for example, 40-80% and typically 50-70%.
  • the reduction in the amount of antipsychotic agent required will be dependent on the amount of mirtazapine given. Typically the dose of mirtazapine used is that described infra.
  • the amount of a combination of mirtazapine and an antipsychotic agent required to produce the efficacious effect will, of course, vary and is ultimately at the discretion of the medical practitioner.
  • the factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.
  • a suitable dose of mirtazapine for administration to a human will be in the range of 0.01 to 30 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 5 mg per kilogram body weight per day and most preferably in the range of 0.3 to 1.0 mg per kilogram body weight per day.
  • a suitable dose of an antipsychotic agent will be in the range of 0.001 to 25 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day and most preferably in the range 0.25 to 5 mg per kilogram body weight per day.
  • the components of the combination which may be referred to as active ingredients may be administered for therapy to an animal e.g. a mammal including a human in a conventional manner.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
  • a combination of mirtazapine and an antipsychotic agent may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
  • a convenient unitary dosage formulation contains the active ingredients in amounts of from 0.1 mg to 1 g each for example, 5 mg to 100 mg.
  • unit dosages may, for example, contain 5 to 50 mg, preferably 10 mg of mirtazapine.
  • Suitable dosage units of mirtazapine are for instance, 5 to 50 mg and suitable dosage units containing an antipsychotic agent are 0.1 to 100 mg.
  • a patient pack comprising at least one active ingredient of the combination of the invention and an information insert containing directions on the use of the combination of the invention.
  • the invention provides a double pack comprising in association for separate administration either mirtazapine and an antipsychotic agent.
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and their Manufacture).
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents and wetting agents.
  • Formulations suitable for oral administration may be presented as discrete units such as pills, tablets or capsules each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or suspension.
  • the active ingredient may also be present as a bolus or paste, or may be contained within liposomes.
  • Formulations for rectal administration may be presented as a suppository or enema.
  • suitable formulations include aqueous and non- aqueous sterile injection.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
  • Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
  • the compounds of the combination of the present invention may be obtained in a conventional manner.
  • Mirtazapine may be prepared using the methods described in US 4,062,843.
  • antipsychotic agents may be prepared by methods known in the chemical literature.
  • Haloperidol may, for example, be synthesized using the methods described in US patent no. 3,438,991.
  • mirtazapine The interaction of mirtazapine with the neuroleptic compound haloperidol was evaluated in the apomorphine climbing test. It was found that the effect of haloperidol on apomorphine-induced climbing behaviour was enhanced by mirtazapine.
  • dopamine agonist apomorphine induces in mice a peculiar motor behaviour consisting mainly in rearing or climbing vertical up the walls of the cage. This behaviour is elicited by stimulation of dopamine receptors in the striatum because it is suppressed after coagulation of this structure and facilitated when the receptors in this area are made hypersensitive by pretreatments with 6- hydroxydopamine or haloperidol.
  • mice Male mice (Cr CD-l(lcR)BR from Charles River, Germany or MFI from Harlan OLAC UK) weighing 21-25 g were used. Groups of 10 mice each were subcutaneously (s.c.) injected with placebo or mirtazapine and a dose of haloperidol or risperidone at the same time. Thirty minutes later all mice were s.c. injected with apomorphine 1 mg/kg or 0.75 mg/kg.
  • the results for the haloperidol experiment are shown in Fig 1/2.
  • the mean score of the placebo group ⁇ standard error of the mean (S.E.M.) was 3.35 ⁇ 0.20.
  • the mean scores ⁇ S.E.M. after haloperidol 22 and 46 ⁇ g/kg were 3.2 ⁇ 0.33 and 2.6 ⁇ 0.37 respectively.
  • the inhibition of climbing behaviour by haloperidol was dose dependentiy enhanced if the mice were concomitantiy treated with mirtazapine (1 and 10 mg/kg). Results of an experiment with mirtazapine only demonstrated that mirtazapine up to 22 mg/kg had no effect on apomorphine climbing behaviour; see Figure 2/2
  • Table 1 The figures represent the % inhibition in apomorphine climbing.
  • Fig 1/2 Effect of mirtazapine on apomorphine ( 1 mg/kg)-induced climbing behaviour in mice. Mirtazapine was injected s.c 30 min before apomorphine. * P ⁇ 0.05 if compared to placebo treatment. Fig 2/2

Landscapes

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

Abstract

The present invention relates to therapeutic combinations of mirtazapine and an antipsychotic agent, to pharmaceutical compositions containing said combinations and to their use in the treatment or prophylaxis of psychotic disorders.

Description

NEW THERAPEUΗC COMBINATIONS OF MIRTAZAPINE AND ANTIPSYCHOTIC AGENTS, FOR THE TREATMENT OR PROPHYLAXIS OF PSYCHOTIC DISORDERS
The present invention relates to therapeutic combinations of mirtazapine and an antipsychotic agent, to pharmaceutical compositions containing said combinations and to their use in the treatment or prophylaxis of psychotic disorders.
The term antipsychotic agent includes those classical antipsychotics which work via dopamine D2 receptor blockade and which are often referred to as "typical" antipsychotics or neuroieptics, and those new antipsychotics which are referred to as "atypical" antipsychotic agents. This atypicality has been defined in a number of ways, but recently it has been defined as the property of providing equal efficacy to established antipsychotic agents while producing fewer extrapyramidal side effects (Meltzer H.Y. Br. J. Psychiatry, 1996, 168 Suppl. 129:23-31). Examples of such typical and atypical antipsychotics include acepromazine, chlorproethazine, chlorpromazine, cyamemazine fluopromazine, methotrimeprazine, promazine, mesoridazine, pericyazine, piperacetazine, pipothiazine, sulfo dazine, thioridazine, acetophenazine, carphenazine, dixyrazine, fluphenazine, perazine, perphenazine, prochlorperazine thiopropazate, thioproperazine, trifluperazine, chlorprothixene, flupenthixol, thiothixene, zudopenthixol, benperidol, bromperidol, droperidol, fluanisone, haloperidol, melperone, moperone, pipamperone, spiperone, timiperone, trifluperidol, fluspirilene, penfluridol, pimozide, amisuipride, raclopride, remoxipride, sulpiride, sultopride, tiapride, molindone, oxypertine, clozapine, loxapine, risperidone, olanzapine, sertindole, quetiapine and ziprasidone.
It has now been found that the administration of mirtazapine, which is one of the newest antidepressant agents and has been disclosed in US patent No. 4,062,848, in combination with an antipsychotic agent is able to enhance the antipsychotic effect of said antipsychotic.
It is a feature of this invention that the use of such drug combinations will enhance the effect of the antipsychotic agent to be used and therefore allow reduced quantities of an antipsychotic agent to be used and furthermore, therefore allow better management of drug related toxicity and side effects.
Thus according to one aspect, the present invention provides a combination comprising mirtazapine and an antipsychotic agent as herein before described. Preferably the combination includes mirtazapine.
It will be understood that the present invention also includes derivatives of mirtazapine and the antipsychotic agents. Such derivatives include the pharmaceutically acceptable salts thereof. Suitable salts include acid addition salts, for example, hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation.
Combinations of mirtazapine and an antipsychotic agent may hereinafter be referred to as combinations according to the invention.
It will be appreciated that the compounds of the combination may be administered simultaneously, either in the same or different pharmaceutical formulation or sequentially. If there is sequential administration, the delay in administering the second active ingredient should not be such as to lose the benefit of the efficacious effect of the combination of the active ingredients.
The present invention further provides combinations according to the invention for use in therapy, more particularly in the treatment or prophylaxis of psychotic disorders such as schizophrenia, mania, hyperactivity, substance abuse, emesis and schizophreniaform disorders.
The present invention further includes a method for the treatment of an animal, for example, a mammal including a human, suffering from or liable to suffer from a psychotic disorder, including any of the aforementioned disorders, which comprises administering an effective amount of a combination according to the invention. A further feature of the present invention is the method of reducing the amount of antipsychotic agent required to produce an antipsychotic effect in an animal which comprises treating said animal with a therapeutically effective amount of a combination according to the present invention.
The present invention also provides the use of mirtazapine in the manufacture of a medicament for administration simultaneously or sequentially with an antipsychotic agent for the treatment and/or prophylaxis of a psychotic disorder. It will be appreciated that an antipsychotic agent may be used in the manufacture of the above medicament for administration simultaneously or sequentially with mirtazapine.
Administration of an antipsychotic agent in combination with mirtazapine allows a lower dosing of the antipsychotic agent to achieve the same antipsychotic effect. The dosage of the antipsychotic agent may be reduced by 25-90%, for example, 40-80% and typically 50-70%.
The reduction in the amount of antipsychotic agent required will be dependent on the amount of mirtazapine given. Typically the dose of mirtazapine used is that described infra.
The amount of a combination of mirtazapine and an antipsychotic agent required to produce the efficacious effect will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.
In general, a suitable dose of mirtazapine for administration to a human will be in the range of 0.01 to 30 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 5 mg per kilogram body weight per day and most preferably in the range of 0.3 to 1.0 mg per kilogram body weight per day. A suitable dose of an antipsychotic agent will be in the range of 0.001 to 25 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day and most preferably in the range 0.25 to 5 mg per kilogram body weight per day.
The components of the combination which may be referred to as active ingredients may be administered for therapy to an animal e.g. a mammal including a human in a conventional manner.
While it is possible for the active ingredients of the combination to be administered as the raw chemical it is preferable to present them as a pharmaceutical formulation. Pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof. When the individual components of the combination are administered separately they are generally each presented as a pharmaceutical formulation.
A combination of mirtazapine and an antipsychotic agent may conveniently be presented as a pharmaceutical formulation in a unitary dosage form. A convenient unitary dosage formulation contains the active ingredients in amounts of from 0.1 mg to 1 g each for example, 5 mg to 100 mg. Typically unit dosages may, for example, contain 5 to 50 mg, preferably 10 mg of mirtazapine.
More commonly these days pharmaceutical formulations are prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patients supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physicians instructions. It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, with a package insert directing the patient to the correct use of the invention is a desirable additional feature of this invention. Suitable dosage units of mirtazapine are for instance, 5 to 50 mg and suitable dosage units containing an antipsychotic agent are 0.1 to 100 mg.
According to a further aspect of the invention, there is provided a patient pack comprising at least one active ingredient of the combination of the invention and an information insert containing directions on the use of the combination of the invention.
According to another aspect the invention provides a double pack comprising in association for separate administration either mirtazapine and an antipsychotic agent.
Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and their Manufacture). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Such accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents and wetting agents.
Formulations suitable for oral administration may be presented as discrete units such as pills, tablets or capsules each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or suspension. The active ingredient may also be present as a bolus or paste, or may be contained within liposomes. Formulations for rectal administration may be presented as a suppository or enema.
For parenteral administration, suitable formulations include aqueous and non- aqueous sterile injection. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
The compounds of the combination of the present invention may be obtained in a conventional manner. Mirtazapine may be prepared using the methods described in US 4,062,843.
The antipsychotic agents may be prepared by methods known in the chemical literature. Haloperidol may, for example, be synthesized using the methods described in US patent no. 3,438,991.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
The interaction of mirtazapine with the neuroleptic compound haloperidol was evaluated in the apomorphine climbing test. It was found that the effect of haloperidol on apomorphine-induced climbing behaviour was enhanced by mirtazapine.
Administration of the dopamine agonist apomorphine induces in mice a peculiar motor behaviour consisting mainly in rearing or climbing vertical up the walls of the cage. This behaviour is elicited by stimulation of dopamine receptors in the striatum because it is suppressed after coagulation of this structure and facilitated when the receptors in this area are made hypersensitive by pretreatments with 6- hydroxydopamine or haloperidol. Lesions of the nucleus accumbens did not change the climbing behaviour This climbing behaviour induced by apomorphine is antagonised by antipsychotics including ciozapine and sulpiride (Protais et al 1976; Costentin et al, 1975, Von Voigtlander et al 1975; Puech et al, 1978; Costall et al 1978).
It is now reported how the inhibition of apomorphine-induced climbing behaviour by haloperidol is influenced by concomitant treatment with the new antidepressant mirtazapine.
Materials and methods
The test method used is described in Protais et al 1976, Climbing behaviour induced by apomorphine in mice : a simple test for the study of dopamine receptors in striatum. Psychopharmacology 50: 1-6. Male mice (Cr CD-l(lcR)BR from Charles River, Germany or MFI from Harlan OLAC UK) weighing 21-25 g were used. Groups of 10 mice each were subcutaneously (s.c.) injected with placebo or mirtazapine and a dose of haloperidol or risperidone at the same time. Thirty minutes later all mice were s.c. injected with apomorphine 1 mg/kg or 0.75 mg/kg. Immediately after the apomorphine injection they were placed individually in a wire mesh cylinder (diameter 12 cm, height 14 cm). At 10 and 20 min hereafter the climbing behaviour of the mice is scored as follows: 4 paws on the floor = 0; 1 or 2 paws holding the wail =1 ; 3 or 4 paws holding the wall = 2. For each mouse the total score of the observations at 10 and 20 min is calculated and the mean score for each treatment group is determined. The mean score of the control group should be at least 2.0 (maximum possible score is 4.0). An indication of significance is tested with the 2-tailed Yates test.
Results and discussion
The results for the haloperidol experiment are shown in Fig 1/2. The mean score of the placebo group ± standard error of the mean (S.E.M.) was 3.35 ± 0.20. The mean scores ± S.E.M. after haloperidol 22 and 46 μg/kg were 3.2 ± 0.33 and 2.6 ± 0.37 respectively. The inhibition of climbing behaviour by haloperidol was dose dependentiy enhanced if the mice were concomitantiy treated with mirtazapine (1 and 10 mg/kg). Results of an experiment with mirtazapine only demonstrated that mirtazapine up to 22 mg/kg had no effect on apomorphine climbing behaviour; see Figure 2/2
Results for experiments with risperidone and quetiapine are presented in Tables 1 and 2.
Table 1 The figures represent the % inhibition in apomorphine climbing.
Figure imgf000010_0001
Figure imgf000010_0002
LEGEND TO THE FIGURES
Fig 1/2 Effect of mirtazapine on apomorphine ( 1 mg/kg)-induced climbing behaviour in mice. Mirtazapine was injected s.c 30 min before apomorphine. *P <0.05 if compared to placebo treatment. Fig 2/2
Effect of haloperidol and of haloperidol + mirtazapine treatment on apomorphine (1 mg/kg)-induced climbing behaviour in mice.
*P<0.05; **P<0.01 ; ***P<0.001 if compared to placebo + placebo treated group. °P<0.05; °°P<0.01 if compared to placebo + haloperidol treated group.

Claims

1. A combination comprising mirtazapine and an antipsychotic agent.
2. A combination according to claim 1 wherein the antipsychotic agent is a typical or atypical antipsychotic agent.
3. A combination according to claim 1 wherein the antipsychotic agent is selected from acepromazine, chlorproethazine, chlorpromazine, cyamemazine fluopromazine, methotrimeprazine, promazine, mesoridazine, pericyazine, piperacetazine, pipothiazine, sulforidazine, thioridazine, acetophenazine, carphenazine, dixyrazine, fluphenazine, perazine, perphenazine, prochlorperazine thiopropazate, thioproperazine, trifluperazine, chlorprothixene, flupenthixol, thiothixene, zudopenthixol, benperidol, bromperidol, droperidol, fluanisone, haloperidol, melperone, moperone, pipamperone, spiperone, timiperone, triflupe dol, fluspirilene, penfluridol, pimozide, amisulpride, raclopride, remoxipride, sulpiride, sultopride, tiapride, moiindone, oxypertine, clozapine, loxapine, risperidone, olanzapine, sertindole, quetiapine and ziprasidone.
4. A combination according to claim 1 wherein the antipsychotic agent is selected from acepromazine, chlorpromethazine, chlorpromazine, cyamemazine fluopromazine, methotrimeprazine, promazine, mesoridazine, pericyazine, piperacetazine, pipothiazine, sulforidazine, thioridazine, acetophenazine, carphenazine, dixyrazine, fluphenazine, perazine, perphenazine, prochlorperazine thiopropazate, thioproperazine, trifluperazine, chlorprothixene, flupenthixol, thiothixene, zudopenthixol, benperidol, bromperidol, droperidol, fluanisone, haloperidol, melperone, moperone, pipamperone, spiperone, timiperone, trifluperidol, fluspirilene, penfluridol, pimozide, amisulpride, raclopride, remoxipride, sulpiride, sultopride, tiapride, moiindone, oxypertine, clozapine, loxapine, risperidone and olanzapine.
5. A combination according to any of claims 1 to 4 for use in medical therapy.
6. A pharmaceutical formulation comprising a combination according to any of claims 1 to 4 in association with one or more pharmaceutically acceptable carriers therefor.
7. A method for the treatment of a psychotic disorder in an animal which comprises treating said animal with a therapeutically effective amount of a combination as defined in any of claims 1 to 4 or a formulation described in claim 6.
8. Use of mirtazapine in the manufacture of a medicament for administration either simultaneously or sequentially with an antipsychotic agent for the treatment and/or prophylaxis of a psychotic disorder.
9. Use of an antipsychotic agent in the manufacture of a medicament for administration either simultaneously or sequentially with mirtazapine for the treatment and/or prophylaxis of a psychotic disorder.
10. Use of mirtazapine and an antipsychotic agent in the manufacture of a medicament for the treatment and/or prophylaxis of a psychotic disorder.
11. A patient pack comprising at least one active ingredient selected from mirtazapine and an antipsychotic agent, and comprising an information insert containing directions on the use of the active ingredient, or the active ingredients, in a combination comprising mirtazapine and an antipsychotic agent.
PCT/EP1998/001920 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders Ceased WO1998043646A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
CA002284551A CA2284551C (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
EP98919209A EP0969845B1 (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
NZ337618A NZ337618A (en) 1997-03-27 1998-03-25 Enhanced effects of antipsychotic agents when combined with mirtazapine (anti-depressant)
DE69833645T DE69833645T2 (en) 1997-03-27 1998-03-25 NEW THERAPEUTIC COMBINATIONS OF MIRTAZAPINE AND ANTIPSYCHOTICS, FOR THE TREATMENT OR PROPHYLAXIS OF PSYCHOTIC DISORDER
KR1019997008745A KR100577865B1 (en) 1997-03-27 1998-03-25 Novel therapeutic combinations of mirtazapine and antipsychotics for the treatment or prevention of psychotic disorders
PL335890A PL191449B1 (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
HK00102643.7A HK1023293B (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
HU0002742A HUP0002742A3 (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
US09/380,723 US6150353A (en) 1997-03-27 1998-03-25 Therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
BR9808077-6A BR9808077A (en) 1997-03-27 1998-03-25 Combination, pharmaceutical formulation, process for treating a psychotic disorder in an animal, uses of mirtazapine and an antipsychotic agent, and, patient pack
JP54116898A JP4377456B2 (en) 1997-03-27 1998-03-25 Composition for treating and / or preventing psychiatric disorders
AU72139/98A AU726194B2 (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
NO19994673A NO994673L (en) 1997-03-27 1999-09-24 New therapeutic combinations of mirtazapine and antipsychotics and their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP97200881 1997-03-27
EP97200881.7 1997-03-27
EP97202785 1997-09-11
EP97202785.8 1997-09-11

Publications (1)

Publication Number Publication Date
WO1998043646A1 true WO1998043646A1 (en) 1998-10-08

Family

ID=26146283

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/001920 Ceased WO1998043646A1 (en) 1997-03-27 1998-03-25 New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders

Country Status (24)

Country Link
EP (1) EP0969845B1 (en)
JP (2) JP4377456B2 (en)
KR (1) KR100577865B1 (en)
CN (1) CN1226036C (en)
AR (1) AR012193A1 (en)
AT (1) ATE318604T1 (en)
AU (1) AU726194B2 (en)
BR (1) BR9808077A (en)
CA (1) CA2284551C (en)
CZ (1) CZ298105B6 (en)
DE (1) DE69833645T2 (en)
DK (1) DK0969845T3 (en)
ES (1) ES2259207T3 (en)
HU (1) HUP0002742A3 (en)
ID (1) ID22283A (en)
IL (1) IL123716A (en)
NO (1) NO994673L (en)
NZ (1) NZ337618A (en)
PL (1) PL191449B1 (en)
PT (1) PT969845E (en)
RU (1) RU2222330C2 (en)
TR (1) TR199902334T2 (en)
TW (1) TW587938B (en)
WO (1) WO1998043646A1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2797399A1 (en) * 1999-08-13 2001-02-16 Aventis Pharma Sa USE OF CYAMEMAZINE IN THE TREATMENT OF BENZODIAZEPINE WEANING
FR2802101A1 (en) * 1999-12-10 2001-06-15 Aventis Pharma Sa ASSOCIATION OF CYMEMAZINE AND AN ATYPICAL NEUROLEPTIC
US6280763B1 (en) 1999-05-10 2001-08-28 Pierce Management, Llc Apparatus and method for transdermal delivery of bupropion
WO2001052855A3 (en) * 2000-01-19 2002-01-10 Akzo Nobel Nv Drug combination for the treatment of depression and related disorders comprising mirtazapine and gepirone
US6350773B1 (en) 1999-12-10 2002-02-26 American Home Products Corporation Therapeutic combinations of (S)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro 7H-1,4-dioxino{2,3-e}indol-8-one and neuroleptics for the treatment or prevention of psychotic disorders
WO2002062346A1 (en) * 2001-02-06 2002-08-15 Astrazeneca Ab Method of treating substance abuse with quetiapine
WO2002041883A3 (en) * 2000-11-21 2003-12-18 Vivus Inc As-needed administration of tricyclic and other non-sri antidepressant drugs to treat premature ejaculation
EP1541197A1 (en) * 2003-12-02 2005-06-15 B&B Beheer NV Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
WO2005053796A1 (en) * 2003-12-02 2005-06-16 B & B Beheer Nv Use of d4 and 5-ht2a antagonists, inverse agonists or partial agonists
EP1547650A1 (en) * 2003-12-02 2005-06-29 B &amp; B Beheer NV Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
EP1795199A3 (en) * 2001-02-06 2007-07-25 AstraZeneca AB Quetiapine for the treatment of substance dependence or substance abuse
US7855195B2 (en) 2003-12-02 2010-12-21 Pharmaneuroboost N.V. Method of treating mental disorders using D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7884096B2 (en) 2003-12-02 2011-02-08 Pharmaneuroboost N.V. Method of treating mental disorders using of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7951405B2 (en) 2004-06-03 2011-05-31 OSI Pharmaceuticals, LLC Combined treatment with cisplatin and an epidermal growth factor receptor kinase inhibitor
US10292966B2 (en) 2003-10-29 2019-05-21 Wyeth Llc Sustained release pharmaceutical compositions

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL121076A (en) * 1996-06-19 2000-10-31 Akzo Nobel Nv Pharmaceutical combinations comprising mirtazapine and one or more selective serotonin reuptake inhibitors
RU2232574C2 (en) * 2002-04-05 2004-07-20 Новосибирский институт органической химии им. Н.Н.Ворожцова СО РАН "fluoglysine" medicinal preparation for treating different forms of depression
US8354121B2 (en) * 2006-06-09 2013-01-15 Dainippon Sumitomo Pharma Co., Ltd. Tape preparation
JOP20120083B1 (en) * 2011-04-05 2021-08-17 Otsuka Pharma Co Ltd Combinations comprising brexpiprazole or a salt thereof and a second drug for use in the treatment of a cns disorder
DE102012011839B4 (en) * 2012-06-14 2018-03-22 Norbert Müller Use of interferon-gamma in a method for the treatment of psychiatric disorders
RU2509560C1 (en) * 2013-03-22 2014-03-20 Общество С Ограниченной Ответственностью "Валента-Интеллект" New therapeutic combinations of mirtazapine applicable in pain conditions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2410821A1 (en) * 1974-03-07 1975-09-18 Hoechst Ag PHARMACEUTICAL COMBINATION PREPARATIONS WITH PSYCHOTROPIC EFFECT AND METHOD FOR THEIR PRODUCTION
WO1994002138A1 (en) * 1992-07-15 1994-02-03 Ivy, Mary, Elizabeth Pharmaceutical composition and method of treatment for serotonin depletion illness
JPH07242669A (en) * 1994-03-07 1995-09-19 Akikazu Ogawa Compound bonding tetracyclic system to butyrophenone derivative

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1327008C (en) * 1988-01-15 1994-02-15 Walter Merz Anti-psychotic imidazobenzodiazepine
EP0431663B1 (en) * 1989-12-06 1994-01-12 Akzo Nobel N.V. Stabilized solutions of psychotropic agents
NZ241481A (en) * 1991-02-04 1994-06-27 Hoechst Roussel Pharma Derivatives of 8-aza-bicyclo[3.2.1]octane and pharmaceutical compositions thereof
RU2062114C1 (en) * 1992-09-30 1996-06-20 Московский научно-исследовательский институт психиатрии МЗ РФ Method for treating the cases of endogenous psychoses
PT669128E (en) * 1992-11-17 2000-06-30 Yoshitomi Pharmaceutical A SUSTAINABLE LIBERTACARD SPHERE CONTAINING ANTI-PHYSICIANS AND A PROCESS FOR PRODUCING THE SAME

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2410821A1 (en) * 1974-03-07 1975-09-18 Hoechst Ag PHARMACEUTICAL COMBINATION PREPARATIONS WITH PSYCHOTROPIC EFFECT AND METHOD FOR THEIR PRODUCTION
WO1994002138A1 (en) * 1992-07-15 1994-02-03 Ivy, Mary, Elizabeth Pharmaceutical composition and method of treatment for serotonin depletion illness
JPH07242669A (en) * 1994-03-07 1995-09-19 Akikazu Ogawa Compound bonding tetracyclic system to butyrophenone derivative

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BALANT-GORGIA ET AL: "THERAPEUTIC DRUG MONITORING AND DRUG-DRUG INTERACTIONS: A PHARMACOEPIDEMIOLOGICAL PERSPECTIVE", THÉRAPIE, vol. 51, no. 4, 1996, pages 399 - 402, XP002034773 *
BARBHAIYA ET AL: "INVESTIGATION OF PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTIONS AFTER COADMINISATRATION OF NEFAZODONE AND HALOPERIDOL", JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, vol. 16, no. 1, February 1996 (1996-02-01), pages 26 - 34, XP002034771 *
BERENDSEN ET AL: "Mirtazapine Enhances the Effect of Haloperidol on Apomorphine-Induced Climbing Behavior in Mice and Attenuates Haloperidol-Induced Catalepsy in Rats", PSYCHOPHARMACOLOGY, vol. 135, no. 3, 1998, pages 284 - 289, XP002073590 *
BIOLOGICAL ABSTRACTS, vol. 84, Philadelphia, PA, US; abstract no. 101722, XP002034774 *
GOWER ET AL: "Pharmacological Evaluation of in vivo tests for alpha-2 Adrenoceptor Blockade in the CNS and the Effects of the Enantiomers of Mianserin and its Aza-Analog ORG3770", ARCH .INT. PHARMACODYN. THER., vol. 291, 1988, pages 185 - 201, XP002073591 *
NEAL-BELIVEAU ET AL: "SEROTONERGIC INVOLVEMENT IN HALOPERIDOL-INDUCED CATALEPSY", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 265, no. 1, 1993, pages 204 - 217, XP002034772 *
OHSUKA ET AL: "5-HT2 receptorsensitivity in chronic schizophrenics during the combination therapy of pimozide and mianserin", NEUROSCIENCES, vol. 13, no. 2, 1987, KOBE, pages 223 - 225 *
PATENT ABSTRACTS OF JAPAN vol. 096, no. 001 31 January 1996 (1996-01-31) *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6280763B1 (en) 1999-05-10 2001-08-28 Pierce Management, Llc Apparatus and method for transdermal delivery of bupropion
WO2001012265A1 (en) * 1999-08-13 2001-02-22 Aventis Pharma S.A. Use of cyamemazine for cold turkey benzodiazepine treatment
FR2797399A1 (en) * 1999-08-13 2001-02-16 Aventis Pharma Sa USE OF CYAMEMAZINE IN THE TREATMENT OF BENZODIAZEPINE WEANING
WO2001041769A3 (en) * 1999-12-10 2002-02-28 Aventis Pharma Sa Combination of cyamemazine and an atypical neuroleptic
US6350773B1 (en) 1999-12-10 2002-02-26 American Home Products Corporation Therapeutic combinations of (S)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro 7H-1,4-dioxino{2,3-e}indol-8-one and neuroleptics for the treatment or prevention of psychotic disorders
FR2802101A1 (en) * 1999-12-10 2001-06-15 Aventis Pharma Sa ASSOCIATION OF CYMEMAZINE AND AN ATYPICAL NEUROLEPTIC
US6720318B2 (en) 1999-12-10 2004-04-13 Aventis Pharma S. A. Combination of cyamemazine and an atypical neuroleptic
US6982262B2 (en) 1999-12-10 2006-01-03 Aventis Pharma S. A. Combination of cyamemazine and an atypical neuroleptic
WO2001052855A3 (en) * 2000-01-19 2002-01-10 Akzo Nobel Nv Drug combination for the treatment of depression and related disorders comprising mirtazapine and gepirone
US6835728B2 (en) 2000-01-19 2004-12-28 Akzo Nobel N.V. Drug combination for the treatment of depression and related disorders comprising mirtazapine
RU2268725C2 (en) * 2000-01-19 2006-01-27 Акцо Нобель Н.В. Combination of medicinal agents comprising mirtazapine for treatment of depression and associated disorders
US6946141B2 (en) 2000-11-21 2005-09-20 Vivus, Inc. As-needed administration of tricyclic and other non-SRI antidepressant drugs to treat premature ejaculation
WO2002041883A3 (en) * 2000-11-21 2003-12-18 Vivus Inc As-needed administration of tricyclic and other non-sri antidepressant drugs to treat premature ejaculation
US7304047B2 (en) 2001-02-06 2007-12-04 Astrazeneca Ab Method of treating substance abuse with quetiapine
EP1795199A3 (en) * 2001-02-06 2007-07-25 AstraZeneca AB Quetiapine for the treatment of substance dependence or substance abuse
WO2002062346A1 (en) * 2001-02-06 2002-08-15 Astrazeneca Ab Method of treating substance abuse with quetiapine
US10292966B2 (en) 2003-10-29 2019-05-21 Wyeth Llc Sustained release pharmaceutical compositions
US10463648B2 (en) 2003-10-29 2019-11-05 Wyeth, Llc Sustained release pharmaceutical compositions
US11179369B2 (en) 2003-10-29 2021-11-23 Wyeth Llc Sustained release pharmaceutical compositions
EP1547650A1 (en) * 2003-12-02 2005-06-29 B &amp; B Beheer NV Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
WO2005053796A1 (en) * 2003-12-02 2005-06-16 B & B Beheer Nv Use of d4 and 5-ht2a antagonists, inverse agonists or partial agonists
EP1541197A1 (en) * 2003-12-02 2005-06-15 B&B Beheer NV Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7855195B2 (en) 2003-12-02 2010-12-21 Pharmaneuroboost N.V. Method of treating mental disorders using D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7884096B2 (en) 2003-12-02 2011-02-08 Pharmaneuroboost N.V. Method of treating mental disorders using of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US8304431B2 (en) 2003-12-02 2012-11-06 Pharmaneuroboost N.V. Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7951405B2 (en) 2004-06-03 2011-05-31 OSI Pharmaceuticals, LLC Combined treatment with cisplatin and an epidermal growth factor receptor kinase inhibitor

Also Published As

Publication number Publication date
JP2009280596A (en) 2009-12-03
HK1023293A1 (en) 2000-09-08
CA2284551C (en) 2007-06-12
AR012193A1 (en) 2000-09-27
TW587938B (en) 2004-05-21
NO994673D0 (en) 1999-09-24
JP2001521497A (en) 2001-11-06
DK0969845T3 (en) 2006-06-19
DE69833645T2 (en) 2006-08-24
AU7213998A (en) 1998-10-22
IL123716A0 (en) 1998-12-06
PL335890A1 (en) 2000-05-22
ID22283A (en) 1999-09-30
ES2259207T3 (en) 2006-09-16
CN1226036C (en) 2005-11-09
HUP0002742A2 (en) 2001-05-28
EP0969845B1 (en) 2006-03-01
JP5023315B2 (en) 2012-09-12
HUP0002742A3 (en) 2003-03-28
CA2284551A1 (en) 1998-10-08
PT969845E (en) 2006-05-31
BR9808077A (en) 2000-03-08
TR199902334T2 (en) 2000-01-21
NO994673L (en) 1999-11-17
CZ298105B6 (en) 2007-06-27
KR20010005677A (en) 2001-01-15
ATE318604T1 (en) 2006-03-15
DE69833645D1 (en) 2006-04-27
RU2222330C2 (en) 2004-01-27
CN1251526A (en) 2000-04-26
KR100577865B1 (en) 2006-05-10
PL191449B1 (en) 2006-05-31
AU726194B2 (en) 2000-11-02
CZ343199A3 (en) 2000-04-12
NZ337618A (en) 2000-06-23
JP4377456B2 (en) 2009-12-02
EP0969845A1 (en) 2000-01-12
IL123716A (en) 2001-03-19

Similar Documents

Publication Publication Date Title
US6150353A (en) Therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
EP0969845B1 (en) New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
US20210038594A1 (en) Methods for Treating Antipsychotic-Induced Weight Gain
EP0659421A1 (en) 2-Phenyl-3-azoylbenzothiophenes for treating menstrual symptoms
WO1996005823A1 (en) Methods of inhibiting demyelinating and dysmyelinating diseases
US20150366852A1 (en) Prevention of Obesity in Antipsychotic, Antidepressant and Antiepileptic Medication
EP2012785A1 (en) Mono and combination therapy with a m1/m4 muscarinic agonist (sabcomeline) for treatment of cognitive disorders in schizophrenia
NO319421B1 (en) Therapeutic use of melatonin
HK1023293B (en) New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
KR890014109A (en) Medication
MXPA99008791A (en) New therapeutic combinations of mirtazapine and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders
US3497596A (en) Method of treating parkinsonism with morphanthridine derivatives
KR20030016207A (en) Combinations of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one and neuroleptics
CN101247796A (en) Composition for treating psychosis
JPS61280430A (en) Antilactic medicinal composition
RU98109932A (en) APPLICATION OF 1- (2-NAFT-2-YLETHYL) -4- (3-TRIFLUOROMETHYLPHENYL) -1,2,3,6-TETHRHYDROPYRIDINE FOR THE PRODUCTION OF MEDICINES FOR THE TREATMENT OF LATERAL AMYOTRAFRAZIC
JPS6040409B2 (en) Antiarteriosclerotic agent containing ethyl piperidyl acetylaminobenzoate

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 98803770.X

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU BB BG BR CA CN CZ EE GE HU ID IS JP KG KP KR LK LR LT LV MD MG MN MX NO NZ PL RO RU SG SI SK TR TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

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
WWE Wipo information: entry into national phase

Ref document number: 1998919209

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 337618

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 09380723

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2284551

Country of ref document: CA

Ref document number: 2284551

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 1998 541168

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1019997008745

Country of ref document: KR

Ref document number: 1999/02334

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/008791

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: PV1999-3431

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 72139/98

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 1998919209

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1999-3431

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019997008745

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 72139/98

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: 1019997008745

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 1998919209

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: PV1999-3431

Country of ref document: CZ