CZ20004199A3 - Use of cabergoline and/or pramipexole - Google Patents

Abstract

The solution relates to new uses and treatments using cabergoline, pramipexole and new combinations of cabergoline - pramipexole for the treatment of patients. The solution describes the use of cabergoline or pramipexole for the treatment of PSP and MSA. The use of cabergoline and pramipexole for the treatment of PSP and MSA is described. In addition, the solution describes the combined treatment of cabergoline and pramipexole, which are applied simultaneously to patients in need of treatment for various central nervous system diseases, and in particular Parkinson's disease (PN), but also for PSP and MSA.

Description

Technical field

The invention relates to the field of diseases and the treatment of central nervous system (CNS) disorders with a focus on treatment using cabergoline and / or pramipexole.

BACKGROUND OF THE INVENTION

M. Asanuma, H. Hirata, Y. Kondo, and N. Ogawa. A time of progressive supranuclear palsy showing marked improvements in frontal hypoperfusion, as well as parkinism with amitriptyline. Rinsho-Shinkeingaku 1993 March, Volume 33 (3) pp. 317-321.

Burn D.J., Sawle G.V., and Brooks D.J. Differential Diagnosis of Parkinson's Disease, Multiple System Atrophy, and Steele-Richardson-Olszewski Syndrome: Discriminant Analysis of Striatal 18F-Dopa PET Data. J. Neurol. Neurosurg. Psychiatry 1994 March, Volume 57 (3), pp. 278-284.

Brooks DJ, Ibanez V, Sawle GV et al. Striatal D2 receptor status in patients with Parkinsoris disease, striatonigral degeneration, and progressive supranculear palsy measured with [11 C] -raclopride and positron emission tomography. Ann Neurol 1992; 31: 184-192.

Collins SJ, Ahlskog JE, Parisi JE, and Maraganore DM. Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg and Psychiatry 1995; 58: 167-173.

Foster NL, Aldrich MS, Bluemlein L, et al. Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP through sleep effects. Neurology 1989; 39: 257-261.

Ghika J, Tennis M, Hoffman E, et al. Idzoxan treatment in progressive supranuclear palsy. Neurology 1991; 41: 986-991.

Guttman M, Seeman P. L-Dopa Reverses the Elevated Density of D2 Dopamine Receptors in Parkinsoris Diseased Striatum. J Neural Trans 1985; 64: 93-103.

Guttman M., Seeman P., Reynolds GP, R. Riederer, Jellinger K., Tourtellotte WW. Dopamine D2 Density Remains Receptor Constant in Treated Parkinson's Disease. Ann Neurol 1986; 19: 487-492.

Hauw JJ, Daniel SE, Dickson E, et al. Preliminary NINDS neuropathological criteria for

Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology

1994; 44: 2015-2019.

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Jackson JA, Jankovic J, Ford J. Progressive supranuclear palsy: Clinical features and response to treatment in 16 patients. AnnNeurol 1983; 13: 273-278.

Litvan I, Chase TN. Traditional and experimental therapeutic approaches. In: Progressive Supranuclear Palsy: Clinical and Research Approaches. Ed. Litvan I and Agid Y. Oxford, New York 1992, pp. 254-269.

Litvan I, Blesa R, Clark K, et al. Pharmacological evaluation of the cholinergic system in progressive supranuclear palsy. AnnNeurol 1994; 36: 55-61.

Maruyama T, Tamaru F, Yamagisawa N, A Time of Progressive Supranuclear Palsy Dramatically Improved with L-threo-3,4-dihydroxyphenylserine (L-DOPS). Rinso-Shinkeigaku 1992 June, Vol: 32 (6), pp. 606-611.

Mierau J, Schingnitz G. Biochemical and pharmacological studies on pramipexole and potent and selective dopamine D2 receptor agonist. Eur J Pharmacol 1992; 215: 161-170.

Neiforth KA, Golbe LI. Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharm 1993; 16: 338-346.

Neophytides A, Lieberman AN, Goldstein M, et al. The use of lisuride, a potent dopamine and a serotonin agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosurg Psych 1982; 45: 261-263.

Pascual J, Berciano J, Grijalba B, et al. Dopamine D1 and D2 receptors in progressive supranuclear palsy: An autoradiographic study. AnnNeurol 1992; 332-703-707.

Peirot L, Desnos C, Blin J, et al. D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy. J Neurol Sci 1988; 86: 291-306

Williams AC, Nutt J, Lake CR et al. Actions of bromocriptine in Shy-Drager and Steele-Richardson-Olszewski syndromes. In: K. Fuxe, D.B. Calne, publishers. Dopaminergic Ergot Derivatives and Motor Function. Oxford: Pergamon Press 1979, pp. 271-283.

SUMMARY OF THE INVENTION

The invention relates to new uses and treatments using cabergoline, pramipexole and new cabergoline-pramipexole combinations. The invention describes the use of cabergoline and pramipexole for the treatment of PSP and MSA. Furthermore, the invention describes a combination treatment of cabergoline and pramipexole, which are administered either simultaneously or alternately to patients in need of treatment for various diseases of the central nervous system and in particular Parkinson's disease (PN) but also progressive supranuclear palsy (PSP) and multisystem atrophy (MSA). .

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Cabergoline is the common name for the active ingredient of DOSTINEX® tablets marketed in the US for the treatment of hyperprolactinic diseases and CABASER® marketed in Europe for the treatment of Parkinson's disease. The synthesis and use of cabergoline is described and claimed in U.S. Pat. No. 4,526,892, which is hereby incorporated by reference. The chemical name of the compound is 1 [(6-allylergolin-8β-yl) carbonyl] -1- [3- (dimethylamino) propyl] -3-ethylurea. Cabergoline and its pharmaceutical salts are most preferred as part of the combination of drugs of the invention, but all of the compounds described in US 4,526,892 can also be considered useful drugs falling within other classes of drugs of the invention.

Cabergoline has the following structural formula:

Conventional pharmaceutical formulations of cabergoline, for example based on an inert pharmaceutical carrier and an effective dose of the active ingredient, can be used; for example, uncoated or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups and suppositories, etc. Tablets are preferred.

CABASER® is sold by Pharmacia & Upjohn Inc, a major pharmaceutical company. The attached instructions describing CABASER®, its pharmacokinetics, the indication group - Parkinson's disease patients, clinical studies, indications and uses, contraindications and warnings are provided by Pharmacia & Upjohn Inc. This annex for the package and its description are hereby incorporated into the description.

Dose response in both efficacy and side effects depends mainly on the individual sensitivity of the individual. Dose optimization was performed by slow baseline dose titration from baseline doses of 0.5 mg (de novo) to 1 mg (patients receiving other dopamine agonists). In patients already taking levodopa, the levodopa dose was gradually reduced while CABASER dose was increased until the optimal balance was established. In view of the long-lasting cabergoline kinetics, the daily dose was adjusted at weekly or biweekly intervals by increments of 0.5 to 1 mg until an optimal value was found.

The recommended therapeutic dose is 2 to 4 mg daily as monotherapy in newly diagnosed patients and 2 to 6 mg daily as adjunctive therapy in patients receiving levodopa / carbidopa. CABASER is given as a single daily dose. Maximum doses greater than 6 mg per day up to 20 mg per day were administered to a small proportion of patients who were exposed to the drug during studies prior to patent registration.

Under certain conditions and in suitable patients, the initial dose of cabergoline is administered to the patient at a dose of 0.5 to 1 mg per patient per day and is gradually increased at weekly intervals to a therapeutic dose of 2, 4, 6, 8 or 10 mg per patient. patient at day.

Safety and efficacy have not been studied in children.

The exact dosage depends on factors such as disease progression, weight and age of the patient, whether and to what extent they are taking other medicines such as L-Dopu or levodopa and other factors that are routinely investigated prior to determining a patient's central nervous system dose.

Pramipexole dihydrochloride monohydrate (pramipexole) is the common name for the active ingredient Mirapex®. This compound is also known by the chemical name 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate and (S) -2-amino-4,5,6,7-tetrahydro- 6-propylamino-2,6-benzothiazole dihydrochloride. The compound and its structurally related analogs are claimed in U.S. Pat. No. 4,886,812, which is incorporated herein by reference. Pramipexole, pharmaceutically acceptable acid addition salts, including dihydrochloride, are preferably included in the combination of drugs of the invention, but all of the compounds disclosed in U.S. Pat. No. 4,886,812 should also be considered useful drugs falling within the other classes of drugs of the invention.

Pramipexole has the following structural formula:

2HCl »HO 2

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Conventional pharmaceutical preparations of pramipexole consisting of an inert pharmaceutical carrier and an effective dose of the active ingredient can be used, for example uncoated or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups and suppositories, etc., preferably tablets.

Mirapex® (pramipexole) is marketed by Pharmacia & Upjohn Inc, a major pharmaceutical company. Mirapex® has been approved by U.S. Pat. The Food and Drug Administration (F.D.A.) and the package instructions describing Mirapex®, its pharmaceutical effects, the Parkinson's disease indication group, clinical trials, indications and uses, contraindications and warnings are provided by Pharmacia & Upjohn Inc. This package guide and description are incorporated herein by reference.

The preferred dosage of pramipexole when used in combination with or concomitantly with cabergoline according to the invention is the same as that described above in the package instructions. Dosage should be initiated at sub-therapeutic level to avoid adverse reactions of the organism and ortho-static hypotension. Mirapex® should be titrated sequentially in all patients with normal renal function starting from 0.375 mg / day in three doses per day and should not be increased more frequently than every 5 to 7 days. A description of the increasing dosage is given in the package instructions. Maintenance treatment may be effective over a wide dosage range, but a range of 1.5 to 4.5 mg / day given in equally divided doses three times a day is recommended. An effective dosage range may be from 0.1 to 10 mg / day / patient, preferably 2 to 8 mg / day / patient, and more preferably between 2 and 5 mg / day / patient.

In certain circumstances and in suitable patients, the patient is administered a dose of pramipexole of 0.5 to 1.0 or preferably 0.375 mg / day / patient and is increased every 5 to 7 days to a therapeutic dose of 3, 4, 5, 6 or 7 mg / day. /patient/.

The dosage should increase gradually. Provided patients do not experience side effects, dosing should be titrated to maximize therapeutic benefit.

The exact dosage is dependent on the evaluation of the patient's physical indicators, such as the stage of development of the disease, the weight and age of the patient, whether and to what extent he is taking other medicines such as L-Dopu or levodopa. system to the patient.

In one aspect, the invention relates to a combination of drugs useful for the treatment of various diseases of the central nervous system and partially suitable for the treatment of Parkinson's disease (PN). The two combination drugs are cabergoline and / or derivatives thereof and pramipexole and / or derivatives thereof.

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The concomitant or concomitant treatment of the invention requires that both cabergoline and pramipexole be administered to a patient suffering from CNS. The dosage should be about the same as previously reported for each drug and each drug should be administered separately. The medicaments may be administered in separate or combined form (individual tablet or capsule), may be administered by administering one of the two medicaments at intervals of 24 hours, or alternating the medicaments every 24 hours. The drugs may be administered concurrently with or without the administration of levodopa. Levodopa may be administered at doses of approximately 800 mg / day, but dose reductions of levodopa should be considered. The dosage described herein is not intended as a guide for use in practice, but rather merely as a description of the invention. Due care should be taken and no CNS medicinal product should be administered without the guidance and supervision of a physician.

Concomitant therapy is particularly effective in treating patients with advanced forms of PN, but is also effective in treating mild forms of the disease.

The treatment described herein provides particular benefits to patients. First, the system of treatment with these drugs affects the entire nervous system of a patient suffering from PN, including presynaptic and postsynaptic cells. Cabergoline is preferably a D2 agonist and pramipexole is preferably a D3 agonist. Administration of both drugs to the patient simultaneously provides the patient with a surprising and unexpected relief from the symptoms of Parkinson's disease. The pramipexole-induced relief herein is presynaptic effective protection, and concomitant cabergoline treatment provides a postsynaptic effect and acts as an agent that increases or replaces dopamine.

In another embodiment of the invention, pramipexole is administered to a patient prior to cabergoline administration. The patient starts taking pramipexole and later, if the effect so requires, the patient is also treated with cabergoline. Another variant is that the patient can start taking pramipexole and also a very low dose of cabergoline, which is less well accepted by the body than pramipexole. Cabergoline may be titrated to achieve optimal dosing once the beneficial effect of pramipexole has stabilized.

Preferably, the combination of drugs and dosage can be a combination of up to 18 mg cabergoline and up to 8 mg pramipexole. More preferred would be up to 12 mg cabergoline and up to 8 mg pramipexole. Depending on the patient and after titration from a low dose, it may be most advantageous to administer to the patient up to 8 mg cabergoline and up to 5 mg pramipexole with or without levodopa.

1-Dopa or levodopa may also be administered in conjunction with the combination of cabergoline and pramipexole.

It is believed that the invention has been sufficiently described herein. The following examples are given by way of illustration only and are not intended to limit the invention in any way.

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Four patients with developed Parkinson's disease received a combination of up to 12 mg cabergoline, up to 5 mg pramipexole, and a low dose of 300 mg 1-Dopa or levodopa. In all cases there was a significant improvement in symptoms.

A second aspect of the invention is the finding that either cabergoline or pramipexole, or combinations thereof, can be used to treat patients with symptoms of two diseases that are not usually treated with a D2 agonist. These diseases are progressive supranuclear palsy (PSP) and multisystem atrophy (MSA).

PSP is a neurodegenerative disease of unknown etiology first described in 1964 by Steele, Richardson and Olszewski J, Arch. Neurol. 1964; 10: 333-359. PSP is also known as Steele-Richardson-Olszewski Syndrome. See. Manyo Y., "Steele-Richardson-Olszewski Syndrome" Nippon-Rins November 1993, Volume 51 (11), pp. 2962-2967. The syndrome usually begins in the seventies and is described by postural instability, visual palsy, mental changes and signs of parkinsonism such as bradykinesia and rigidity. The syndrome has a rapid and severe course.

PSP is a very progressive neurodegenerative disease described by postural instability, stiffness, bradykinesia, bulbar dysfunction, and loss of control of free eye movements. It causes progressive disability and death, usually within six years of diagnosis. PSP has many features in common with Parkinson's disease, with which it is often confused. It is estimated that PSP progresses much faster than Parkinson's disease. The lifespan of patients with Parkinson's disease was estimated to be 15 to 20 years after diagnosis. The life expectancy of PSP patients was estimated to be less than six years. PSP patients have several systems damaged (dopamine, 5-HT, Ach) and the progression of neuronal degeneration is unknown. Patients with Parkinson's disease are mainly affected by the dopamine system, but the 5-HT and Ach systems are less damaged. Unlike Parkinson's disease, a good treatment method for PSP is currently lacking.

PSP is associated with neuropathological changes in the substance of the brain mass, caudate, putamen, pallida globus, subtalamic nucleus, as well as in many brainstem nuclei (Hauw et al. 1994). Post-mortem neurochemical analyzes showed some changes in PSP different from those found in the analysis of samples from patients affected by Parkinson's disease. (Kish et al. 1985). The depletion of striatal dopamine is severe and reaches similar levels as in patients with Parkinson's disease. This is probably the cause of Parkinson's disease symptoms that most patients report. However, patients with PSP do not show the regional changes in dopamine depletion observed in patients with Parkinson's disease. Patients with PSP experience severe depletion of dopamine in the caudate nucleus and putamen, while in PSP, dopamine depletion occurs in the caudate nucleus and putamen, while Patients with PN have a large decrease in PN. Serotonin is not reduced in the striatum corpus of PSP patients, but is reduced to approximately 50% in PN patients. Signs of striatal cholinergic neurons are reduced in patients with PSP due to loss of cholinergic cells, but this is not the case with patients with PS. This may explain changes in cognitivity in patients. Striatal noradrenaline levels are unchanged in PSP patients.

Dopamine receptors have been studied in postmortem brain samples of PN and PSP patients (Pierot et al. 1988) and in vivo using PET and SPECT. D-2 dopamine receptors are elevated in untreated PN patients according to homogenate radioreceptor assays (Guttman and Seeman, 1985). This hypersensitivity may be altered by treatment (Guttman et al. 1986). In vivo image studies have confirmed these findings (Brooks et al. 1992). However, in PSP patients there is a decrease in receptor binding compared to control. The magnitude of the reduction is variable - a change of 15 to 50% (Pasual et al. 1990). PE studies with raclopride (Brooks et al., 1992) confirmed decreased binding in the corpus striatum. These changes in image studies are not specific to PSP, while other forms of secondary Parkinsonism have similar findings, including multisystem atrophy. D-1 dopamine receptors are not reduced as found in post-mortem studies of PSP patient samples (Pascual et al. 1992). It has been suggested that lowering D-2 receptors may partially cause therapeutic failure of dopamine replacement therapy. Since the reduction observed in some studies is minimal, it is not clear what this effect is.

Although PSP is one of the most common forms of parkinsonism, it has been difficult to determine therapy using formalized trials under these conditions. Litvan and Chase reviewed all published PSP reports and summarized the results (Litvan and Chase, 1992). They stated that it is difficult to draw conclusions from the literature because it does not contain enough controlled clinical trials. Between 1965 and 1990, 381 patients were reported in the literature. Golbe retrospectively reviewed therapy records for 83 PSP patients and concluded that L-dopa therapy was the most effective treatment (Nieforth and Golbe, 1993). The dosage ranged from 750 to 1500 mg daily and the response rate was 54% of patients showing a slight improvement based on clinical effect and 44% of patients had no effect. The response to treatment was varied, and many authors report that if patients receive a response, the response is not pronounced and is usually transient. Most patients were taking combination drugs containing L-dopa, such as Sinemet or Prolopa, and titrated at higher doses compared to PN patients. Because the response to L-dopa is not convincing, some procedures for diagnostic classification of PSP use a lack of response to L-dopa as part of the diagnosis criterion (Collins et al., 1995). The most common side effects that have been reported are the development of hallucinations (Litvan and van t t van van van van van).

Chase 1992). It is interesting to note that L-dopa dyskinesia was not reported.

Dopamine agonists have been used to treat a small number of patients. (Litvan and Chase, 1992). Bromocriptine has been studied in a double-blind, placebo-controlled clinical group of nine patients (Williams et al., 1979). This study showed no significant increase in 6/9 subjects at doses up to 90 mg / day. The remaining 3 had a slight improvement in Parkinson's disease symptoms. In other studies, approximately 25% of subjects responded to ameliorating the symptoms of Parkinson's disease. In PN, bromocriptine monotherapy was not successful in most patients. Pergoline was also used in a small number of patients. In the study group, 2/3 of the subjects showed a slight improvement in Parkinson's disease (Jackson et al.). This may be because the drug has a higher effect compared to the effect of bromocriptine and its agonists at D-1 receptors. Lisuride treatment has been tested in a small number of patients with PSP. Neophytides found that in a control trial, 7 subjects showed no significant results and two patients showed slight improvement (Neophytides et al. 1982).

In an attempt to increase cholinergic neurotransmission, cholinergic agonists have been used to treat subjects with sPSP. Foster did not detect any associated motor and cognitive changes in a group of 10 patients in the double-blind, cross-over study of sRS-86, which is a relatively non-selective M1 and M2 agonist (Foster et al., 1989). Litvan applied physostigmine to a small number of PSP patients in a double blind crossover study. Patients showed no improvement in parkinsonian, extraocular, or pseudobulbar symptoms (Litvan et al., 1994). Idazoxsan is an experimental alphaadrenergic antagonist. It was used in a two-week open trial at 120 mg / day in two patients (Ghika et al., 1991). A marginal improvement ranging from 12% to 34% was observed in these subjects, but sympathetic side effects also commonly occurred.

The dosage level of cabergoline for the treatment of either PSP or MSA is the same as the dosage level previously reported for the treatment of Parkinson's disease.

Multisystemic atrophy or MSA. A description of MSA is given in Burn D.J., Sawle G.V. and Brooks D.J. "Differential Diagnosis of Parkinson's Disease, Multiple System Atrophy and Steele-Richardson-Olszewski Syndrome: Discriminant Analysis of Striatal 18F-dopa PET Data." J. Neurol. Neurosurg. Psychiatry 1994 March Vol. 57 (3), pp. 278-284, which are hereby incorporated by reference.

Claims (21)

PATENT CLAIMS Use of cabergoline and / or pramipexole or pharmaceutical salts thereof for the manufacture of a medicament for the treatment of central nervous system disorders. Use of cabergoline and / or pramipexole or pharmaceutical salts thereof according to claim 1 for the treatment of Parkinson's disease. Use according to claim 2, wherein the initial dose of cabergoline is 0.5 to 1 mg / patient / day, increasing at weekly intervals to a therapeutic dose of 2, 4, 6, 8 or 10 mg / patient / day and wherein the initial dose pramipexole is 0.375 mg / patient / day, increasing every 5 to 7 days to a therapeutic dose of 3, 4, 5, 6 or 7 mg / patient / day. Use according to claim 3, wherein the initial dose of cabergoline is 0.5 to 1 mg / patient / day, increasing to a therapeutic dose of 4 or 6 mg / patient / day at weekly intervals and pramipexole is increased weekly to a therapeutic dose of 5 or 6 mg / patient / day. Use according to claim 4, wherein the therapeutic dose of cabergoline is 6 mg / patient / day and the therapeutic dose of pramipexole is 5 mg / patient / day. Use of cabergoline or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of progressive supranuclear palsy. Use according to claim 6, wherein the initial dose of cabergoline is 0.5 to 1 mg / patient / day, increasing to a therapeutic dose of 2, 4, or 6 mg / patient / day at weekly intervals. Use according to claim 6, wherein the therapeutic dose of cabergoline is 6 mg / patient / day. Use of cabergoline or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of multisystem atrophy. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ·· Use according to claim 9, wherein the initial dose of cabergoline is 0.5 to 1 mg / patient / day, increasing to a therapeutic dose of 2, 4.6 or 8 mg / patient / day at weekly intervals. The use of claim 10, wherein the therapeutic dose of cabergoline is 4 to 6 mg / day. Use of pramipexole or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of progressive subnuclear palsy. Use according to claim 12, wherein the initial dose of pramipexole is 0.5 to 1 mg / patient / day, increasing at weekly intervals to a therapeutic dose of 3, 4, 5 or 6 mg / patient / day. The use of claim 13, wherein the initial dose of pramipexole is 0.375 mg / patient / day and the therapeutic dose is 5 mg / patient / day. Use of pramipexole or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of multisystem atrophy. Use according to claim 15, wherein the initial dose of pramipexole is 0.5 to 1 mg / patient / day, increasing at weekly intervals to a therapeutic dose of 3, 4, 5 or 6 mg / patient / day. The use of claim 16, wherein the therapeutic dose is 5 mg / day. Use of cabergoline alone and / or cabergoline in combination with pramipexole or the use of pramipexole alone or pharmacologically acceptable salts thereof for the manufacture of a medicament for use in the treatment of Parkinson's disease. Use of cabergoline alone and / or cabergoline in combination with pramipexole or use of pramipexole alone or pharmacologically acceptable salts thereof for the manufacture of a medicament for use in the treatment of multisystem atrophy. Use of cabergoline alone and / or cabergoline in combination with pramipexole or the use of pramipexole alone or pharmacologically acceptable salts thereof for the manufacture of a medicament for use in the treatment of progressive supranuclear palsy. A pharmaceutical composition comprising cabergoline alone and / or cabergoline in combination with pramipexole or pramipexole alone or a pharmacologically acceptable salt thereof for use in the treatment of Parkinson's disease and / or multisystem atrophy and / or progressive supranuclear polio.