MXPA00011219A - Cabergoline and pramipexole:new uses and combinations - Google Patents

Abstract

This invention discloses new uses and treatments involving cabergoline, pramipexole and new combinations of cabergoline plus pramipexole used to treat patients. Here we disclose the use of cabergoline or pramipexole to treat PSP and MSA. Also disclosed is a combination treatment of cabergoline and pramipexole provided concurrently to a patient in need thereof for the treatment of various central nervous system diseases and in particular for the treatment of Parkinson's Disease (PD), but also for PSP and MSA.

Description

CABERGOLINA AND PRAMIPEXOL FOR THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM, ESPECIALLY PARKINSON'S DISEASE FIELD OF THE INVENTION This invention relates to the field of diseases and treatments for central nervous system (CNS) disorders, specifically to treatments comprising cabergolma and pramipexole.

DESCRIPTION OF THE INFORMATION M. Asanuma, H. Hirata, Y. Kondo and N. Oga a. A case of progressive supranuclear palsy showing marked improvements of frontal hypoperfusion, as well as parkmsonism with amitriptyline. Rmsho-Shinkeigaku 1993 March Vol. 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." Discpmmant Analysis of Stpatal 18F-dopa PET data. " J. Neurol. Neurosurg. Psychiatry 1994 March Vol. 57 (3), pp. 278-284. Brooks DJ, Ibanez V, Sawle GV et al. Stpatal D2 receptor status in patients with Parkinson's disease, stpatomgral degeneration, and progressive supranculear palsy measured with [11C] -raclopride and positron emission tomography. Ann Neurol 1992; 31: 184-192. Collins SJ, Ahlskog JE, Papsi JE, and Maraganore DM. Progressive supranuclear palsy: neuropathologically based diagnostic clinical entena. J Neurol Neurosurg and Psychiatry 1995; 58: 167-173. Foster NL, Aldrich MS, Bluemlem L, et al. Failure of cholinergic agonist RS-86 to improve cogmtion and movement in PSP despite effets on sleep. Neurology 1989; 39: 257-261. Ghika J, Tennis M, Hoffman E, et al. ldzoxan treatment ín progressive supranuclear palsy. Neurology 1991; 41: 986-991. Guttman M, Seeman P. L-Dopa Reverses the Elevated Density of D2 Dopamme Receptors in Parkmson's Diseased Stpatum. J Neural Trans 1985; 64: 93-103. Guttman M, Seeman P, Reynolds GP, Riederer P, Jellinger K, Tourtellotte WW. Dopamme D2 Receiver Density Remanís Constant ín Treated Parkinson's Disease. Ann Neurol 1986; 19: 487-492. Hauw JJ, Daniel SE, Dickson E, et al. Preliminary NINDS neuropathologic entena for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy).

Neurology 1994; 44 - 2015-2019. Jackson JA, Jankovic J, Ford J. Progressive supranuclear palsy. Clmical features and response to treatment in 16 patients. Ann Neurol 1983, 13: 273-278. Litvan 1, 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 1, Blesa R, Clark K, etal. Pharmacological evaluation of the cholmergie system in progressive supranuclear palsy. Ann Neurol 1994; 36: 55-61. Maruyama T, Tamaru F, Yamagisawa N, A Case of Progressive Supranuelear Palsy Dramatically Improved with L-threo-3, 4-d? Hydroxyphenylserme (L-DOPS). Rinso-Shmkeigaku 1992 June, Vol: 32 (6), pp. 606-611. Mierau J, Schingmtz G. Biochemical and pharmacological studies on pramipexole a potent and selective dopamine D2 receptor agonist. Eur J Pharmacol 1992; 215: 161-170. Neiforth KA, Golbe LI. Retrospective study of drug response m 87 patients with progressive supranuclear palsy. Clin Neuropharm 1993; 16: 338-346. Neophytides A, Lieberman AN, Goldstein M, etal. The use of lisupde, a potent dopamine and serotonm agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosur Psych 1982; 45: 261-263. Pascual J, Berciano J, Gpjalba B, et al Dopamine DI and D2 receptors in progressive supranuclear palsy: An autoradiographic study. Ann Neurol 1992, -332-703-707. Peirot L, Desnos C, Blin J, et al. DI 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 bromocpptine in the Shy-Drager and Steele-Richardson-Olszewski syndromes. In: K. Fuxe, D.B. Calne, eds.

Dopaminergic Ergot Depvatives and Motor Function. Oxford: Pergamon Press 1979, pp. 271-283.

SUMMARY OF THE INVENTION This invention describes new uses and treatments comprising cabergolma, pramipexole and new combinations of cabergolma plus pramipexole. The use of cabergoline or pramipexole to treat PSP and MAS is also described A combination treatment of cabergolma and pramipexole provided concurrently or alternatively to a patient in need thereof for the treatment of various diseases of the central nervous system and in particular is described. for the treatment of Parkinson's disease (PD), but also for PSP and MAS.

ADDITIONAL DESCRIPTION OF THE INVENTION Cabergoline is the generic name for the active ingredient in the DOSTINEXR tablets, sold in the United States of America as a treatment for hyperprolactinemic disorders, and CABASERE, sold in Europe as a treatment for Parkinson's disease. The synthesis and use of cabergoline is described and claimed in U.S. Patent No. 4,526,892, which is incorporated herein by reference. The chemical name for the compound is 1 [(6-allylergolin-8β-yl) -carbonyl] -1- [3- (dimethylamino) propyl] -3-ethylurea. Cabergoline and its pharmaceutical salts are the most preferred of a part of the drug combination of this invention, but all of these compounds described in U.S. Patent No. 4,526,892, must also be considered useful drugs that are a part of the different classes of drugs comprising this invention.

Cabergoline has the following structural formula: Conventional cabergolymer pharmaceutical preparations can be used, for example, consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance; for example, flat or coated tablets, capsules, pills, powders, solutions, suspensions, emulsions, syrups, suppositories, etc. The tablets are preferred. CABASER®, is marketed by Pharmacia & Upjohn Inc., a leading pharmaceutical company. A package instruction sheet describing CABASER®, its pharmacokinetics, Parkinson's disease patients, clinical studies, indications and use, contraindications and warnings are provided by Pharmacia & Upjohn. This instruction sheet and its descriptions are incorporated as a reference in this application. The dose response for both efficacy and side effects seems to be primarily linked to individual sensitivity. Obtain the optimization of the dose through the slow titration of the initial dose, from the initial dose of 0.5 mg ("de novo" patients) to 1 mg (patients taking other dopamine agonists). In patients who already receive levodopa, gradually decrease the dose of levodopa while increasing the dose of CABASER, until the optimal balance is determined. In view of the lasting kinetics of the cabergolma, adjust the daily dose in weekly intervals (initial weeks) or biweekly intervals using increments of 0.5 to 1 mg, up to the optimal dose. The recommended therapeutic dose is 2 to 4 mg daily as monotherapy in newly diagnosed patients and 2 to 6 mg daily as adjuvant therapy to levodopa / carbidopa. Administer CABASER as an individual daily dose. Maximum doses greater than 6 mg daily and up to 20 mg daily have been administered in a small proportion of patients exposed to the drug during the pre-registration studies. Under some circumstances and with appropriate patients, the dose level of cabergolma is where the initial dose of cabergolm is administered to the patient at a dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 2, 4, 6, 8 or 10 mg / patient / day.

Safety and effectiveness in children have not yet been investigated. The precise dose will be determined by the attending physician evaluating factors such as the progress of the disease status, the weight and age of the patient, if other drugs were administered and to what extent such as L-dopa or levodopa, and other such factors as they are typically evaluated by a physician before determining the dose and a CNS drug to be administered to a patient. Pramipexole dihydrochloride monohydrate (pramipexole) is the generic name for the active ingredient in Mirapex®. This compound is also known by the clinical names of 2-ammo-6-n-propyl-ammo-4, 5, 6, 7-tetrahydrobenzot-azol monohydrate dihydrochloride and (S) -2-ammo dihydrochloride -4, 5, 6, 7-tetrahydro-6-prop? Lammo-2,6-benzot? Azole monohydrate. The compound of the structurally related analogs are claimed in U.S. Patent No. 4,886,812, incorporated by reference. Pramipexole, the pharmaceutically acceptable acid addition salts, including the dihydrochloride, are most preferred from a part of the drug combination of this invention but all of these compounds described in U.S. Patent No. 4,886,812 should also be considered useful drugs that are a part of the different classes of drugs from this invention. Pramipexole has the following structural formula: Conventional pharmaceutical preparations of pramipexole, for example, consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance; for example, flat or coated tablets, capsules, pills, powders, solutions, suspensions, emulsions, syrups, suppositories, etc. The tablets are preferred. Mirapex® (pramipexole) is marketed by Pharmacia & Upjohn Inc., a leading pharmaceutical company. Mirapex® has been tested by the North American Food and Drug Administration (FDA) and the packaging instruction sheet describing Mirapex®, its pharmacokinetics, Parkmson's disease patients, clinical studies, indications and use, contraindication and warnings is provided by Pharmacia & Upjohn. This package instructions manual and its descriptions are incorporated as a reference in this application. Preferred doses of pramipexole when used as described in this invention, as a combination or concurrent drug administered with cabergolma are the same doses as described in the package instruction sheet mentioned above. The dose should be initiated at a sub-therapeutic level to avoid intolerable adverse effects and orthostatic hypotension. Mirapex® should be titrated gradually in all patients, starting from 0.375 mg / day in patients with normal renal function given in three divided doses and should not be increased more frequently than every 5 to 7 days. Upward dose programs can be found on the package instruction sheet. Maintenance treatment can be effective over a wide range and is recommended over a range of 1.5 to 4.5 mg / day, administered in equally divided doses three times a day. The effective dose range can be from 0.1 to 10 mg / day / patient, preferably 2-8 mg / day / patient and more preferably between 2 and 5 mg / day / patient. Under some circumstances and with appropriate patients, the initial dose of pramipexole is administered to the patient in a dose of 0.5 to 1.0 or preferably 0.375 mg / patient / day and is adjusted up every 5 to 7 days at a therapeutic dose of 3. , 4, 5, 6, or 7 mg / patient / day.

Doses should be increased gradually. The provision to patients who do not experience intolerable side effects, the dose should be titrated to achieve a maximum therapeutic effect. The precise dose will be determined by the doctor who evaluates factors such as the progress of the disease status, the weight and age of the patient, if other drugs were administered and to what extent such as L-Dopa or levodopa, and other factors such as as they are typically evaluated by a physician before determining the dose of a CNS drug to be administered to a patient.

PART I The first aspect of this invention describes a combination of drugs useful in the treatment of various diseases of the central nervous system and in particular for the treatment of Parkinson's disease (PD). The two drugs to be combined are cabergoline and / or its derivatives and pramipexole and / or its derivatives. The concomitant or concurrent treatment described herein requires that both cabergoline and pramipexole be administered to a patient suffering from a CNS disease. The doses will be approximately the same as indicated above for each drug and each drug will typically be administered separately.

The drugs can be administered in separate or combined forms (tablet or single capsule), can be administered so that some of both drugs are in the patient during any period of 24 hours or the administration of the drugs can be staggered with each drug that It is given every 24 hours, alternating with the other drug. The drugs can be administered with or without the administration of levodopa. Levodopa can be given at a dose of approximately 800 mg / day but the dose reduction of levodopa should be considered. The doses provided herein are not intended to guide a practitioner but rather are only intended to describe the invention. Appropriate precautions should be taken and a CNS drug should not be given unless it is under the direction and supervision of a physician. Concurrent treatment is especially effective in the treatment of patients with advanced forms of PD, but it is also effective in treating moderate forms of the disease. The treatment described herein provides special benefits to the patient. For the first time, a drug treatment system is provided that aids in the control of the entire system of a patient with PD, including pre- and post-synaptic cells. Cabergolma is a preferred D2 agonist and pramipexole isa preferred D3 agonist. Providing the two drugs to a patient concurrently gives patients surprising and unexpected relief from the symptoms of Parkinson's disease. Pramipexole provides self-protection, which is the protection of the pre-synaptic effect and therapy at the same time that cabergoline provides postsynaptic effects and acts as an enhancer or dopamine replacement agent. In another embodiment of this invention, pramipexole is provided to a patient prior to the administration of cabergoline. The patient starts with pramipexole, later when efficacy becomes necessary, the patient is also treated with cabergoline. Alternatively, a patient can be started with pramipexole and also a very low dose of cabergoline, which is less well tolerated than pramipexole. The cabergoline can then be titrated in order to reach the optimal dose as the beneficial effects of pramipexole tend to reach the plateau or constant point. A preferred combination of drugs and dosage will be with a combination of up to 18 mg of cabergoline and up to 8 mg of pramipexole. More preferred will be up to 12 mg of cabergoline and up to 5 mg of pramipexole. Depending on the patients, and after titration from a low dose, it should be more preferred to provide a patient with up to 8 mg of cabergolma and up to 5 mg of pramipexole, with or without levodopa. It is noted that 1-Dopa or levodopa can also be provided in conjunction with the combination of cabergolma and pramipexole. Without further description it is believed that the invention is fully described above. The following example, below, is provided to illustrate the invention without restricting it in any way. Four patients with advanced Parkmson disease were provided with a combination of up to 12 mg of cabergoline, up to 5 mg of pramipexole and a low dose of 300 mg of 1-Dopa or levodopa. In all cases in the opinion of the researcher, the symptoms showed significant improvement.

PART II In a second aspect of this invention, it is described that either the cabergolma or the pramipexole or the combination, can be used to treat patients having symptoms of the two diseases that are not typically treated with a D2 agonist. These diseases are progressive supranuclear palsy (PSP) and multisystem atrophy or MSA. PSP is a neurodegenerative disease of unknown etiology, described for the first time in 1964 by Steele, Richardson and Olszewski J. Arch. Neurol. 1964 10: 333-359. PSP is also known as the Steel-Richardson-Olszewski syndrome. See, Manyo Y., "Steele-Richardson-Olszewski syndrome" Nippon-Rinsho 1993, Nov. Vol. 51 (11), pp. 2962-2967. The syndrome usually started in the 1970s and is characterized by postural instability, gaze paralysis, mental changes, and parkinsonian signs such as bradykinesia and rigidity. Has a fast and severe course of affection. PSP is an inexorably progressive neurodegenerative disease characterized by postural instability, rigidity, bradydemicity, bulbar dysfunction and loss of control of the voluntary movements of the eye. It causes progressive disability and death, usually the space of six years of diagnosis. PSP has many characteristics in common with Parkinson's disease, a disorder with which it is frequently confused. It has been estimated that PSP progresses more rapidly than Parkinson's disease. The life span of patients with Parkinson's disease has been estimated to be between 15-20 years after the diagnosis is made. The life span for patients with PSP has been estimated to be less than 6 years. Patients with PSP have several affected systems (dopamine, 5-HT and Ach) and the progress of neuronal decay. Patients with Parkinson's disease have mainly affected the dopaminergic system, however, 5-HT and Ach are affected to a lesser degree. However, different from Parkinson's disease, good treatment strategies are currently lacking for PSP. PSP is associated with neuropathological changes in the substances nigra, caudate, putamen, pale globus, subthalamic nucleus as well as several nuclei of the brain stem (Hauw et al., 1994). The post-mortem neurochemical analysis has shown specific changes in PSP different from those found in Parkinson's Disease (PD) (Kish et al., 1985). The striatal dopamine depletion is severe and is similar in magnitude when compared to patients with Parkinson's disease. It is very likely that this is responsible for the parkinsonian symptoms that most patients report. Patients with PSP, however, do not show the regional variation in dopamine depletion seen in PD. In the PSP, both the caudate nucleus and the putamen have a severe depletion of dopamine, while the PD the putamen has a greater reduction. Serotonin is not decreased in the striatum of patients with PSP but is reduced by approximately 50% in PD. The markers of cholinergic striatal neurons in the PSP due to the colmérgica cell loss but this is not the case in PD. This may account for the cognitive changes in these patients. Nopapine levels are not changed in the PSP. Dopamine receptors have been studied in brains with PD and post-mortem PSP (Pierot et al., 1998) and in vivo with PET and SPECT. Dopamma D-2 receptors are elevated in patients with untreated PD using the homogenized radioreceptor assay (Guttman and Seeman, 1985). This supersensitivity is reversed with treatment (Guttman et al., 1986). In vivo imaging studies have shaped these findings (Brooks et al., 1992). However, PSP, there is a reduction in receptor binding compared to controls. The magnitude of the reduction is variable with reports of a 15-50% change (Pascual et al., 1990). Studies of PE with raclopride (Brooks et al., 1992) have confirmed reduced union in the stpatum. These changes in imaging studies are not specific to PSP, since other forms of secondary parkinsonism have similar findings including multisystem atrophy. The dopamma DI receptors are not reduced as measured by post-mortem studies in PSP (Pascual et al., 1992). There has been speculation that the reduction of D-2 receptors can possibly being responsible for the therapeutic failure of dopaminergic 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 secondary forms of parkinsonism, there have been few formalized trials to assess therapy in this condition. Litvan and Chase have reviewed all published reports regarding the PSP and have summarized the results (Litvan and Chase 1992). They comment that the literature is difficult to interpret due to the lack of controlled chemical tests. Three hundred and eighty-one patients have been reported between 1965-1990. Golbe has retrospectively reviewed his therapeutic experience in 83 patients with PSP and concluded that L-Dopa therapy was the most effective treatment (Nieforth and Golbe, 1993). The dose varied from 750-1500 mg per day and the response rate was 54%, showing a mild improvement to a moderate average based on clinical impressions with 44% showing no effect. The response to treatment has been variable and most authors suggest that if patients respond, then that response is not strong and is usually momentary. Most of the patients are offered a combination drug with L-dopa such as Sinemet or Prolopa and is titrated at higher doses in comparison to patients with PD. Since the response to L-dopa is not impressive, some diagnostic classification algorithms of PSP use the lack of dose to L-dopa as part of the criteria for making the diagnosis (Collins et al., 1995). The most common side effects that have been reported are the development of hallucinations (Litvan and Chase, 1992). It is interesting to note that the dyskinesias induced by L-dopa have not been reported. Dopamine agonists have been used to treat a small number of patients with PSP (Litvan and Chase, 1992). Bromocriptine was prospectively examined in a double-blind placebo controlled clinical trial in 9 subjects (Williams et al., 1979). This study could not show any significant improvement in 6/9 subjects at doses up to 90 mg / day. The remaining 3 had a modest improvement in their parkinsonian symptoms. In other studies, approximately 25% of the subjects responded with improvement to their parkinsonian characteristics. It should be noted that in PD, bromocriptine monotherapy has not been successful in the treatment of most patients. Pergoline has also been used in a small number of patients. In a controlled trial, 2/3 of the subjects have mild anti-parkinsonian effects (Jackson et al., 1983). This may be due to the greater potency of this drug in comparison to bromocriptine and its agonist effects in DI receptors. Treatment with lisuride has been studied in a small number of patients with PSP. Neophytides found that in a controlled trial of 7 subjects there was no significant result and two patients had a moderate improvement (Neophytides et al., 1982). In an attempt to improve cholinergic neurotransmission, cholinergic agonists have been used to treat subjects with PSP. Foster did not report consistent motor or cognitive changes in 10 patients in a double-blind crossover study with RS-86 which is a relatively non-selective MI and M2 agonist (Foster et al., 1989). Litvan used physostigmine in a small number of patients with PSP in a double-blind, cross-sectional study. They did not show any improvement in parkinsonian, estraocular or pseudobulbar symptoms (Litvan et al., 1994). Idazoxan is an experimental alpha-adrenergic antagonist. It has been used in a 2 week open label study at a dose of 120 mg / day in two patients (Ghika et al., 1991). There was a marginal improvement that varied from 12-34% in these subjects but sympathetic side effects were common. The dose level of cabergoline to treat any of these PSP or MSA diseases is the same dose given above for the treatment of Parkinson's disease. Multisystemic atrophy or MSA. A description of the MSA appears in Burn D.J., Sawle G.V., and Brooks D.J. "Differential Diagnosis of Parkinson 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, incorporated herein by reference.

Claims (24)

1. CLAIMS; 1. The concomitant administration of cabergoline and pramipexole or its pharmacologically acceptable salts to a patient in need thereof.
2. 2. The concomitant administration of cabergolma and pramipexole according to claim 1 to a patient suffering from a disease of the central nervous system.
3. 3. The concomitant administration of cabergolma and pramipexole according to claim 2 to a patient suffering from Parkinson's disease.
4. 4. A method for treating patients suffering from central nervous system disease, comprising administering to the patient both cabergoline and pramipexole or their pharmacologically acceptable salts.
5. 5. A method according to claim 4 for the treatment of patients suffering from Parkinson's disease.
6. 6. A method according to claim 5, wherein the initial dose of cabergolma that is administered to the patient is a dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 2, 4, 6 , 8 or 10 mg / patient / day and where the initial dose of pramipexole starts at 0.375 mg / patient / day and adjusts up every 5 or 7 days at a therapeutic dose of 3, 4, 5, 6 or 7 mg / patient / day.
7. 7. The method according to claim 6, wherein the cabergoline is administered to the patient at a dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 4 to 6 mg / patient / day and the pramipexole is adjusts weekly in a dose of 5 to 6 mg / patient / day
8. 8. The method according to claim 7, wherein the therapeutic dose of cabergolm is 6 mg / patient / day and the therapeutic dose of pramipexole is 5 mg / patient /day.
9. 9. A method for treating patients suffering from progressive supranuclear palsy (PSP) comprising the administration of a therapeutic amount of cabergoline or a pharmacologically acceptable salt thereof.
10. The method according to claim 8, wherein the cabergoline is administered to the patient at a dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 2, 4, or 6 mg / patient /day .
11. The method according to claim 7, wherein the therapeutic dose of cabergoline is 6 mg / patient / day.
12. 12. A method for treating patients suffering from multisystemic atrophy or MSA comprising the administration of a therapeutic amount of cabergoline or a pharmacologically acceptable salt thereof.
13. The method according to claim 12, wherein the cabergolymer is administered to a patient in an initial dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 2, 4, 6 or 8 mg / patient / day.
14. The method according to claim 13, wherein the dose of cabergoline is 4-6 mg per day.
15. 15. A method for treating patients suffering from progressive supranuclear palsy (PSP) comprising the administration of a therapeutic amount of pramipexole or a pharmacologically acceptable salt thereof.
16. The method according to claim 15, wherein the pramipexole is administered to a patient in an initial dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 3, 4, 5 or 6 mg / patient / day.
17. 17. The method according to claim 16, wherein the initial dose of pramipexole is 0.375 mg / patient / day and the therapeutic dose is 5 mg / patient / day.
18. 18. A method for treating patients suffering from multisystem atrophy or MSA comprising the administration of a therapeutic amount of pramipexole or a pharmacologically acceptable salt thereof.
19. 19. The method according to claim 18, wherein the pramipexole is administered to the patient at a dose of 0.5 to 1 mg / patient / day and is adjusted upwardly at weekly intervals to a therapeutic dose of 3, 4, 5 or 6 mg / patient / day.
20. The method according to claim 19, wherein the dose is 5 mg per day.
21. 21. The use of cabergolma by itself and / or cabergoline in combination with pramipexole or the use of pramipexole by itself or its pharmacologically acceptable salts for the manufacture of a medicament for use in the treatment of Parkinson's disease (PD) .
22. 22. The use of cabergolma by itself and / or cabergolma in combination with pramipexole or the use of pramipexole by itself or its pharmacologically acceptable salts for the manufacture of a medicament for use in the treatment of mulsystemic atrophy or MSA.
23. 23. The use of cabergolma by itself and / or cabergolma in combination with pramipexole or the use of pramipexole by itself or its pharmacologically acceptable salts for the manufacture of a medicament for use in the treatment of progressive supranuclear palsy (PSP) .
24. 24. A pharmaceutical composition for use as a treatment of Parkmson's Disease (PD) and / or multisystemic atrophy (MSA), and / or progressive supranuclear palsy (PSP), comprising cabergoline by itself and / or cabergoline in combination with pramipexole or the use of pramipexole itself or its pharmacologically acceptable salts.