LU92975B1 - Use of Lisuride and Terguride and its 2-Halogen Derivatives for the Treatment as Antipsychotics - Google Patents

Use of Lisuride and Terguride and its 2-Halogen Derivatives for the Treatment as Antipsychotics Download PDF

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LU92975B1
LU92975B1 LU92975A LU92975A LU92975B1 LU 92975 B1 LU92975 B1 LU 92975B1 LU 92975 A LU92975 A LU 92975A LU 92975 A LU92975 A LU 92975A LU 92975 B1 LU92975 B1 LU 92975B1
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lisuride
terguride
bromerguride
treatment
combinations
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Reinhard Horowski
Werner Krause
Johannes Tack
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Vivotecc Gmbh
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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

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Abstract

This invention relates to the use of combinations of lisuride and/or 9,10-dihydrogenated lisuride (terguride) and/or their 2-halogen analogs, e.g. 2-bromo lisuride (bromerguride), either alone or in combination with a CYP2D6 inhibitor and pharmaceutical compositions thereof for the treatment of schizophrenia and all other forms of psychosis, agitation and dementia.

Description

Use of Lisuride and Terguride and its 2-Halogen Derivatives for the Treatment as Antipsychotics
Background
The invention comprises the use of combinations of lisuride and/or derivatives of lisuride, such as 9,10-dihydrogenated lisuride (terguride) and/or halogenated compounds (e.g. 2-bromo lisuride = bromerguride) for the treatment of psychiatric disorders such as schizophrenia, psychoses, dementia or others. The combinations of lisuride, terguride or their 2-halogen derivatives can be administered either alone or can additionally be combined with a CYP2D6 inhibitor such as quinidine, fluoxetine or other CYP2D6 inhibitors. Combination in the context of this patent application either means simultaneous administrations of individual formulations of the drugs or combination within one pharmaceutical formulation. This is based upon the more recent discovery that not only classical dopamine antagonists such as haloperidol and chlorpromazine with their known severe adverse events, e.g. extrapyramidal effects, but also newer, atypical neuroleptics such as clozapine, aripiprazol, olanzapine, and quetiapine exert their antipsychotic effects by blocking central 5-HT2A receptors and thus are derived of extrapyramidal effects.
Preferentially a dopamine agonist, e.g. lisuride, is combined with a dopamine antagonist, e.g. bromerguride. Both, lisuride and bromerguride are additionally serotonin (5-HT)2 antagonists, which is the effect that is needed for the treatment of the disorders as described. The combination of the dopamine-agonistic lisuride and the dopamine-antagonistic bromerguride therefore reduces or even eliminates all dopamine-related effects and side effects and, since both compounds are antagonists, increases the overall anti-serotonin activity. Moreover, since the different compounds bind to different serotonin subtype receptors, these combinations are able to address a much broader spectrum of psychiatric diseases and different forms of psychoses.
In order to further increase efficacy, a CYP2D6 inhibitor such as quinidine, fluoxetine, or paroxetine can added, which will result in an increased bioavailability and in much less variability of pharmacokinetic parameters. If melperone is selected as a CYP2D6 inhibitor, this will provide an additional neuroleptic efficacy component into the combination.
Fig. 1: Chemical structures of lisuride, terguride, and bromerguride (from left to right)
Lisuride is an iso-ergoline derivative, which acts as a dopamine agonist and a partial agonist for several serotonin receptors. It is an antagonist at the serotonin 5-HT2B receptor and has a high affinity for the dopamine D2, D3 and D4 receptors, as well as for serotonin 5-HT1A (as an agonist) and 5-HT2A/C receptors (as an antagonist).
Lisuride in its oral form has been approved for the prevention of migraine attacks since 1977, for the treatment of hyperprolactinemia since 1981, and Parkinson’s disease since 1985. It has been marketed in most European and some other countries under quite a number of different tradenames, such as Dopergin,
Dopergine, Dipergon, Dopagon, and Cuvalit (all Bayer, Leverkusen, Germany, formerly Schering AG, Berlin, Germany), Arolac (Lisapharm, Paris, France),
Prolacam and Revanil (Cambridge Laboratories, Cambridge, UK), and Lysenil (Spofa, Prague, Czech Republic).
Terguride, a 9,10-transdihydrogenated derivative of the ergot alkaloid lisuride, has been characterized as a potent serotonin receptor antagonist, in particular regarding the 5-HT2A and 5-HT2B but also the 5-HT1A receptors. Additionally, the drug is acting at the dopamine D2 receptor as a mixed agonist/antagonist depending on the location and state of the receptor and at the alpha2 receptor as an antagonist.
Terguride has been approved in Japan (Teluron; Bayer, Osaka, Japan) and in the Czech Republic (Mysalfon; Zentiva, Prague, Czech Republic) for the treatment of all forms of hyperprolactinemia.
Beneficial effects have also been reported in the treatment of Parkinson’s disease, pulmonary arterial hypertension, chronic fibro-proliferative disease, secondary Raynaud’s Syndrome, and chronic pain of various origins, to name just a few and without excluding additional indications.
Bromerguride (2-bromo-lisuride) is a dopamine antagonist and its pharmacological effects are characterized by a central depressant neuroleptic-like symptomatology. In vitro, the compound also antagonizes the decrease of cAMP accumulation produced by 5-HT and the decrease of extracellular 5-HT produced by 5-HT1A agonists. In addition, it has strong 5-HT2A antagonistic effects. The neuroleptic efficacy of bromerguride in animal experiments such as spontaneous inhibition of locomotor activity in mice and rats was four times that of haloperidol, which also induces catalepsy in rodents.
Additional compounds in this chemical class include the 2-fluoro, 2-chloro, and 2-iodo derivatives of lisuride and the 2-fluoro, 2-chloro, 2-bromo, and 2-iodo derivatives of terguride. All lisuride or terguride analogs with a halogen substitution in the 2-position act as atypical neuroleptics with less extrapyramidal and endocrine side effects. They can be used for treating schizophrenia and other psychoses as well as psychomotor agitation.
It was now surprisingly found that combinations of these compounds such as lisuride + terguride, lisuride + bromerguride, and terguride + bromerguride are particularly useful for the treatment of psychotic disorders. Including all 2-halogen derivatives, more combinations are possible and can be used for the treatment of these disorders. By reducing or neutralizing the dopamine-related components of activity in these combinations, the doses of individual drugs can be increased significantly without observing the dopamine-related side effects such as nausea and vomiting, which limit dosing of the individual drugs administered alone and, additionally, extrapyramidal side effects are completely avoided.
Detailed Description of the Invention
The present invention relates to the use of combinations of lisuride and/or 9,10-dihydro lisuride (terguride) and 2-halogenated (fluoro, chloro, bromo, iodo) derivatives of lisuride and terguride for the treatment of psychotic disorders. For simplicity reasons, the description will use lisuride + terguride as an example without precluding analogy of the other possible combinations. The most effective combination would be lisuride + 2-bromoterguride.
Terguride has been reported to be effective in various indications and is approved and on the market in Japan and the Czech Republic for the treatment of hyperprolactinemia. It is known to be a very safe drug.
Lisuride has been shown to be an antagonist at the 5-HT2B and 5-HT2A/C receptors and has a high agonistic affinity at the 5-HT1A receptor. Terguride is a potent serotonin receptor antagonist, in particular regarding the 5-HT2A and 5-HT2B receptors. Bromerguride is strongly antagonizing serotonin, in particular, 5-HTA1 but also 5-HT2A- mediatated effects. The observed differences in concentrations necessary to affect serotonin receptors relative to other monoamine receptors such as dopamine apply to both lisuride and terguride and their 2-halogen derivatives.
It was now additionally and surprisingly found that the different ergot derivatives mentioned above can be combined in these indications, resulting in combinations such as lisuride + terguride, lisuride + a 2-halogen lisuride (such as bromerguride), lisuride + a 2-halogen terguride, terguride + a 2-halogen lisuride (such as bromerguride) or terguride + a 2-halogen terguride. This is in strong contrast to the currently used indications such as Parkinson’s disease where activity at the dopamine receptors is mandatory. In Parkinson’s disease, bromerguride, a dopamine receptor antagonist would block the activity of lisuride, a dopamine agonist. On the other hand, some of the major side effects of lisuride, in particular emesis and vomiting but also dopaminergic psychosis are linked to dopamine agonistic activity. A dopamine antagonist such as bromerguride would therefore block this activity and reduce or eliminate these side effects, whereas on the other hand it would increase the serotonin-related activity, since both compounds are serotonin antagonists and act in the same direction. Another benefit of these combinations would be that different ergot derivatives affect different serotonin receptors as already mentioned above. Lisuride preferentially acts as an antagonist on the 5-HT2B receptor, terguride on the 5-HT1A and 5-HT2A/C receptors, and bromerguride on 5-HT1A. Another advantage of these combinations is that these drugs all have similar terminal half-lives, which greatly facilitates their combination in the same pharmaceutical product.
Since ergot alkaloids and their chemical derivatives are primarily metabolized by CYP2D6 resulting in a very high variability of pharmacokinetic parameters, in particular of oral bioavailabilities ranging from nearly 0-100% (1 ), the combination with a CYP2D6 inhibitor such as quinidine, fluoxetine, paroxetine or melperone might be helpful. Melperone has the additional advantage of being itself a strong 5-HT2A antagonist.
Normally, the compounds are formulated as salts of organic or inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, methane sulfonic acid, succinic acid, tartaric acid, maleic acid, etc. The preferred salt for lisuride, terguride and their 2-halogen derivatives is hydrogenmaleate.
Examples
Example 1 - Treatment of Schizophrenia with a Combination of Lisuride and Terguride
Patients with florid hallucinatory schizophrenia are treated once daily with a slow-release oral formulation consisting of 0.6 mg lisuride hydrogen maleate and 6 mg terguride hydrogen maleate (or both compounds as free base) over a period of three months or until the acute symptomatology disappears.
Subsequently, these patients receive similar oral slow-release forms at half the dosages for one year or more in order to prevent relapses or new exacerbations. If these should occur despite the therapy, the full dosages as administered initially are resumed for another three months. Equivalent dosages can alternatively be administered by transdermal patches.
Example 2 - Treatment of Psychosis with a Combination of Lisuride and Bromerguride
Patients with psychosis and/or dementia of the Alzheimer type, Diffuse Lewy Body Dementia or with vascular dementia are treated with a daily oral dose of 0.3 mg lisuride hydrogen maleate and 3 mg of bromerguride in an oral slow-release form over an unlimited period of time in order to reduce or prevent paranoid ideation, aggressive or aberrant behavior, disturbances of the day-night rhythm or any related symptoms.
Example 3 - Treatment of Dementia with a Combination of Lisuride and Bromerguride or Bromoterguride
Patients with dementia of the Alzheimer type, with Diffuse Lewy Body Dementia or with vascular dementia are treated with an oral slow-release form of lisuride hydrogen maleate (total daily dose of 0.4 mg) combined with 20 mg of bromerguride or bromoterguride and an additional oral daily dose of 50 mg quinidine until the acute symptomatology, restlessness, disturbed day-night rhythms or aggressive and other aberrant behaviors subside. A maintenance therapy at half the dosages described above then follows for an unlimited period of time or until extrapyramidal signs appear, which would require a further dose reduction.
Example 4 - Preparation of Micronized Bromerguride and Lisuride
The preparation will be described in detail for bromerguride and can analogously be done for lisuride so that mixtures of both drugs can be obtained. In the same way, a CYP2D6 inhibitor can be added.
The particle size of, for example, bromerguride can be significantly reduced by using specific milling techniques like jet stream milling in a steel chamber under nitrogen pressure. The micronization occurs when the bromerguride powder is fed at a velocity of about 50 m/s into the milling chamber and the faster particles, accelerated by a series of jet nozzles to a speed of about 300 m/s collide with the incoming slower particles. The particle size distribution (by volume) of bromerguride, which can be achieved by the jet milling techniques described above, is about 2-3 pm (d50), 10-12 pm (d99) and <15 pm (d100) by using Laser diffractometry. A preferred dosage form is a multiparticulate system, consisting of multiparticulates of a size of 1-3 mm, which ensures rapid gastric emptying, low variability in gastric transit time, and optimized drug absorption.
Step 1. Preparation of uncoated pellets containing bromerguride.
Five grams (g) of micronized bromerguride is added to a mixture of 85 grams of microcrystalline cellulose (Avicel® PH-101) and 8 grams of hydroxypropyl methylcellulose (HPMC E6). After homogenization of the dry powders, the mixture is granulated by adding an aqueous PVP (25.000 MW) solution (5%, w/w) q.s. The wet granulate obtained is extruded at room temperature at 30 rpm using a CLS Extruder 20 (2 mm orifice diameter) followed by spheronization of the extrudates using a CLS MBS 120 spheronizer with friction plate. The resulting spherical pellets are dried to a humidity of 3-5 % containing about 5% (w/w) micronized bromerguride.
Step 2. Preparation of coated pellets for immediate release containing micronized bromerguride. A spray suspension of 90 ml containing 6.25 grams of amino methacrylate copolymer-NF (Eudragit® E 100), 0.625 grams of polyethylenglycol (PEG 6000) and 3.1 grams (g) of talcum, dissolved/suspended in acetone/isopropanol 1:1 is prepared by using a shear mixer. Then 10 ml of destilled water was added to the suspension. The resulting spray suspension is finally passed through a 0.5 mm sieve.
The suspension obtained is sprayed onto 50 grams of pellets according to Step 1 using a Caleva lab coater MCD 2. The process conditions are set to: spray rate 0.25 - 0.35 g/min, inlet temperature 42°-45° C, flow rate 60 L/min at 2 bar, air temperature 30°- 35° C. The spraying is maintained up to a 5% increase by weight due to the coating applied. The pellets are finally cured for about one hour at the air temperature of 30°- 35° C.
Example 6 - Preparation of Layered Pellets for Delayed Release (of Micronized Bromerguride and Lisuride) A spray suspension containing 5.25 grams of ammonio methacrylate copolymer (Eudragit® RL PO Type A), 17.25 grams of ammonio methacrylate copolymer (Eudragit® RS PO Typ B), 3.5 grams triethylcitrate (TEC) and 5.25 grams talcum, dissolved/suspended in 300 grams acetone/isopropanol 1:1 is prepared by using a shear mixer. The spray suspension is finally passed through a 0.5 mm sieve.
The suspension obtained is sprayed onto 50 grams (g) of a 1:1 mixture (by weight) of bromerguride and lisuride pellets obtained according to Step 2 (Example 5) using a Caleva lab coater MCD 2. The process conditions are set to: spray rate 0.2 - 0.3 g/min, inlet temperature 40°-45° C, flow rate 50 L/min at 2 bar, air temperature 30°-35° C. The spraying is maintained up to a 7% increase by weight due to the coating applied. The pellets are finally cured for about one hour at the air temperature of 30°- 35° C.
In order to achieve an appropriate osmotic pressure within the coated multiparticulate, osmogens of acceptable pharmaceutical grade of hydrophilic nature will be applied. These are preferably low molecular weight sugars like fructose, sucrose, mannitol, inorganic salts like sodium phosphates, or organic acids such as citric acid or tartaric acid. Upon penetration of the gastrointestinal fluid through the membrane of the coated dosage after oral administration the dissolution of the osmogen creates an osmotic pressure, which finally leads to a rupture of the polymeric membrane and releases the drug spontaneously and completely.
The compromise of the coating is influenced by the penetration rate of the gastrointestinal fluid that can be modulated by the adding hydrophilic low or large molecular weight compounds to the coating. Such modulators may be physiologically inert, water-soluble polymers, e.g., low molecular weight methylcellulose or hydroxypropyl-methylcellulose (HPMC), sugars, e.g., monosaccharides such as fructose and glucose, disaccharides such as lactose, sucrose, or polysaccharides such as cellulose, amylose and dextran.
In order to achieve appropriate timing of the release pulse, the modulator may be at least 10 percent, at least about 20 weight percent of the multiparticulate, and usually not more than about 50 weight percent, preferably not more than about 40 weight percent. The polymer coating may comprise at least about 5 and not more than 50 weight percent of the multiparticulate.
The exact proportion of modulator and active agent will be determined by formulation design experiments producing different types of multiparticulates for different amounts of modulator. A USP-approved method for dissolution or release test will be used to measure the rate of release (<711 >, USP 32 NF 27,2009, Vol. 1, Apparatus 1 with varying nominal capacities from 1 L to 4 L). In order to better mimic the conditions present in the digestive system and, if necessary to test under infinite sink conditions, a flow-through-cell apparatus according to the USP (Apparatus 4) can be used alternatively to determine the dissolution rate. The detection of the dissolved drug as a function of time may be followed by various state of the art methods, such as spectrophotometrically, HPLC, mass spectroscopy, etc. until the absorbance becomes constant or until greater than 90% of the drug has been released.
Example 7 - Preparation of Pellets for Extended Release (of Micronized Bromerguride and Lisuride) A spray suspension containing 22.25 grams of anionic copolymers based on methacrylic acid and methyl methacrylate (Eudragit® S 100 ), 3.5 grams triethylcitrate (TEC) and 5.25 grams talcum, dissolved/suspended in 300 grams acetone/isopropanol 1:1 is prepared by using a shear mixer. Then 10 ml of destilled water is added to the suspension. The resulting spray suspension is finally passed through a 0.5 mm sieve.
The suspension obtained is sprayed onto 50 grams (g) of a 1:1 mixture (by weight) of bromerguride and lisuride pellets obtained according to Step 2 (Example 5) using a Caleva lab coater MCD 2. The process conditions are set to: spray rate 0.25 - 0.35 g/min, inlet temperature 40°- 45° C, flow rate 50 L/min at 2 bar, air temperature 30°-35° C. The spraying is maintained up to an 8% increase by weight due to the coating applied. The pellets are finally cured for about one hour at the air temperature of 30°-35° C.
References 1. Krause, W, Dorow R, Nieuweboer B, Hasan SH; Pharmacokinetics and pharmacodynamics of the ergot alkaloid, transdihydrolisuride, in man. Eur J Clin Pharmacol 27: 335-339 (1984).

Claims (5)

1. Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid zur Behandlung von neuroleptischen Erkrankungen.1. Use of combinations of lisuride, terguride and / or 2-halogenated derivatives of lisuride or terguride for the treatment of neuroleptic disorders. 2. Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid und einem CYP2D6-lnhibitor zur Behandlung von neuroleptischen Erkrankungen.2. Use of combinations of lisuride, terguride and / or 2-halogenated derivatives of lisuride or terguride and a CYP2D6 inhibitor for the treatment of neuroleptic disorders. 3. Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid entsprechend den Ansprüchen 1 und 2 mit Chinidin, Fluoxetin, Paroxetin oder Melperon.3. Use of combinations of lisuride, terguride and / or 2-halogenated derivatives of lisuride or terguride according to claims 1 and 2 with quinidine, fluoxetine, paroxetine or melperone. 4. Langsam freisetzende Formulierungen zur oralen Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid mit einem CYP2D6-lnhibitor wie Chinidin, Fluoxetin, Paroxetin oder Melperon entsprechend den Ansprüchen 2 und 4.4. Slow-release formulations for the oral use of combinations of lisuride, terguride and / or 2-halogenated derivatives of lisuride or terguride with a CYP2D6 inhibitor such as quinidine, fluoxetine, paroxetine or melperone according to claims 2 and 4. 5. Verwendung von Formulierungen zur transdermalen Verabreichung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid entsprechend den vorigen Ansprüchen.5. Use of formulations for the transdermal administration of combinations of lisuride, terguride and / or 2-halogenated derivatives of lisuride or terguride according to the preceding claims.
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EP0207882A2 (en) * 1985-06-24 1987-01-07 Schering Aktiengesellschaft Use of terguride for the manufacture of a medicament for the treatment of geriatric infirmities
DE102005041613A1 (en) * 2005-09-01 2007-03-08 Ergonex Pharma Gmbh Use of octahydro-indolo-quinoline compound in the preparation of pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome
WO2009006194A1 (en) * 2007-06-28 2009-01-08 Avanir Pharmaceuticals Pharmaceutical compositions for the treatment of involuntary emotional expression disorder

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