HK1094538B - Use of rotigotine for the treatment or prevention of dopaminergic neurone loss - Google Patents

Description

Parkinson's disease is the result of a chronic progressive degeneration of neurons, the cause of which is not yet fully understood. It manifests itself clinically in the form of cardinal symptoms of restlessness, rigor, bradycinesia and postural instability.

The main medicinal products used to relieve motor symptoms are levodopa, dopamine agonists such as rotigotine, pramipexole, bromocriptine, ropinirole, cabergoline, pergolide, apomorphine and lisurid, anticholinergics, NMDA antagonists, β-blockers, and the MAO-B inhibitor selegelin and the COMT inhibitor encaptaone, most of which interfere with the dopamine and/ or cholinergic signalling cascade and thus symptomatically affect Parkinson' s typical movement disorders.

The current treatment of Parkinson's disease starts at the onset of cardinal symptoms. A clinically proven Parkinson's disease is generally considered to occur when at least two of the four cardinal symptoms (bradycynesia, restlessness, rigor, and postural instability) are present and respond to L-dopa (Hughes, J. Neurol Neurosurg Psychiatry 55,1992,181). Unfortunately, motor disorders in Parkinson's patients do not occur until about 70-80% of the dopaminergic neurons in the substance nigra (SN) are irreversibly damaged (Becker et al., 2002, J. Neurol 249, Suppl 3:III, 40; Hornykiewicz, Encyclopedia of Life Science 2001, 1).

Recent clinical observations, as well as anatomical and genetic studies, now show that it is possible to diagnose Parkinson's disease patients in the early stages and to identify those at risk.

For example, the following may be used as diagnostic markers: The following are the biochemical markers, such as neuromelanin (Gerlach, Neurotox Res 5,2003, 35; WO 02/31499), S-100 beta (Muramatsu, Glia 42, 2003, 307), alpha-synuclein (WO 03/069332; WO 00/02053) or parkin protein (Sharma, Neurol Clin N Am 20, 2002, 759) and semaphorin (Wo 03/007803) Genetic markers, such as Park genes 1-8 (Guttleinman, CMAJ 4, 2003, 168; WO 03/76658); CYP2D6-B (WO 03/012137), chromosome 2q 36-37 (Pratz, Jank, Humankind Gen 72, 2003, e-pub), a-synuclein (Polymer Science, 1997, 276, 2045) or mutations in GSB2 and CYP2D6-D12 (Amol, J12-D07, including the combination of other methods, including the ultrasound method, SN-B12), and, where appropriate, the amol (Amol, J12-07).The following are the most common types of neurological disorders: (i) neurological disorders, such as: (i) neurological disorders, such as: (i) neurological disorders, such as: (i) neurological disorders, such as: (ii) neurological disorders, such as: (iii) neurological disorders, such as: (iii) neurological disorders, such as: (iii) neurological disorders, such as: (iv) neurological disorders, such as: (v) neurological disorders, such as: (v) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as: (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as (vi) neurological disorders, such as)

This opens up the opportunity to influence the disease process at a time when there are even more neurons than at the time of the onset of several motor cardinal symptoms of Parkinson's disease and thus to protect a quantitatively higher number of neurons.

There is therefore a need for drugs that not only can influence dopamine transmission and alleviate the symptoms of advanced Parkinson's disease, but that can reverse, prevent or at least significantly slow the progressive decline of dopaminergic neurons in early, motor largely asymptomatic Parkinson's (Dawson, Nature Neuroscience Supplement 5, 2002, 1058).

Rotigotine [(-) -5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl) ethyl]amino]-1-naphthol] is known from the state of the art as a dopaminagonist and purely symptomatic Parkinson's disease therapeutic. For example, WO 02/089777 describes the transdermal administration of rotigotine to Parkinson's disease patients and the associated improvement in the UPD (Unified Parkinson's Disease Rating-Scale) scores. The UPDRS score is only an important tool for diagnosing and monitoring the progression or treatment of Parkinson's disease patients (Fahn S, Elton RL, Members of the UPD Development Committee (1987)), although recent information on this is not allowed on the Parkinson's Disease Symptomatic Scale, but on the Unicore's RMSS. In the case of RMSS, we use a drug called Florentine, a drug that is similar to Marsden, a drug that is used in Parkinson's Disease (CDN, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD, MD

Metman et al (Clin Neuropharmacol 24,2001, 163) also describe the effect of rotigotine on Parkinson' s disease-associated movement disorders.

From a technical point of view, rotigotine is therefore known to be a dopamine agonist for the symptomatic treatment of Parkinson' s disease, but purely symptomatic Parkinson' s medicinal products do not offer any benefit in the preventive treatment of Parkinson' s disease because they do not affect dopaminergic cell death and the progression or course of the disease.

However, experimental studies have now shown surprisingly that rotigotine, which has so far been used only for the symptomatic treatment of Parkinson's disease, has neuroprotective properties and promotes the regenerative capacity of neuronal elements, so that rotigotine can be used as a drug to prevent dopaminergic cell loss, also and especially in very early stages of Parkinson's disease or in candidates at risk.

The following

Figure 1 shows representative examples of the neuroprotective effect of rotigotine measured by the density of dopamine transporters as an indicator of the density of the remaining nerve endings in the striatum.

Groups 1 to 7 were treated as follows: group 1: untreated control; group 2: control treated with a mild solution of rotigotine and MPTP; group 3: MPTP treatment; group 4: MPTP treatment plus rotigotine 0.3 mg/ kg; group 5: MPTP treatment plus rotigotine 1.0 mg/ kg; group 6: MPTP treatment plus rotigotine 3.0 mg/ kg; group 7: treatment with rotigotine only (3.0 mg/ kg)

Figure 2 shows dopamine transporter (DAT) binding in the dorsal and ventral striatum in different groups by quantifying DAT density after an experiment as illustrated in Figure 1.The bar diagrams 1-7 correspond to the groups 1-7 shown in Figure 1.The groups marked with * showed a significant decrease in DAT binding compared to the control group 2.The groups marked with # showed a significant maintenance of DAT binding compared to the MPTP-treated group 3.

Description of the invention

Apoptotic processes are thought to play an important role in the destruction of dopaminergic neurons in Parkinson's disease (Barzilai, Cell Mol Neurobiol 21, 2001, 215). Neuroprotective substances are therefore desired that can stop or even reverse dopaminergic cell death.

Rotigotin surprisingly shows the desired pharmacological profile in both an acute and a subacute MPTP model.

For example, Rotigotin shows neuroprotective effects in a Parkinson model of the mouse: following acute administration of MPTP, which produces Parkinson' s syndrome in humans as in monkeys, the number of neurons degenerating in the acute phase was measured (Table 1) and the functional integrity of the striatum was recorded in the subacute phase by determining the density of the dopamine transporter in the terminal nerve endings (Figures 1 and 2). Other Tabelle 1: Anzahl degenerierender Neurone bei der Maus, dargestellt mit FluoroJade Färbung

Gruppe	Anzahl degen. Neurone	Stndrtabw
1: Vehikel-behandelte Kontrolle	2.0	2.4
2: MPTP Intoxikation	73.5	34.0
3: MPTP Intoxikation + Rotigotin 0.3 mg/kg	66.7	30.5
4: MPTP Intoxikation + Rotigotin 1.0 mg/kg	76.8	41.6
5: MPTP Intoxikation + Rotigotin 3.0 mg/kg	34.9	31.9
5: MPTP -Vehikel + Rotigotin 3.0 mg/kg	3.8	4.3

A pilot study also investigated the neuroprotective effects of rotigotine in monkeys.

In the model used, which reflects the progressive course of Parkinson' s disease in primates, monkeys (macaques) were injected with subcutaneously toxic doses of MPTP over several days. Parkinson' s symptoms developed in the model over a period of about 2 weeks. Once a certain degree of damage was reached, daily injections of rotigotine were made in a formulation that produced a continuous plasma level over 24 h. The injections of MPTP were stopped as soon as motor activity was reduced to a certain degree (about 5 days later). The animals' behaviour was assessed daily. Six weeks after the start of MPTP, the injections of rotigotine were stopped and the animals were observed for a further two weeks without treatment.

At the end of rotigotine administration and at the end of the wash-out phase, one group of animals was killed and the basal ganglia were histologically and biochemically examined. The density of nerve endings in the striatum was significantly increased compared to untreated animals. The levels of pre-pro-encephalin, an indicator of intact networking in the basal ganglia indirect pathway, showed a tendency to normalize after treatment and after the wash-out phase.

The results show that the neuroprotective potential of rotigotine can also be demonstrated in a primate model of Parkinson's disease, suggesting a neuroprotective effect in humans.

Rotigotine has thus provided an active substance for therapy, which is ideally suited to the production of a drug to prevent dopaminergic neuronal loss in neurodegenerative diseases.

Therefore, the present application concerns rotigotine for use in the treatment of dopaminergic neuronal loss in patients suffering from a neurodegenerative disease associated with increased dopaminergic cell death.

Increased dopaminergic neuronal loss is common in Parkinson' s disease patients, but is also common in other neurodegenerative diseases, such as alpha-synucleopathies or Huntington' s disease, and in REM sleep and olfactory disorders.

Compared to the previous use of rotigotine, which was limited to the purely symptomatic treatment of Parkinson's disease patients with movement disorders, the new application area will be in particular the prophylactic treatment of individuals in the early stages of Parkinson's disease or who are predisposed to Parkinson's disease due to genetic or other risks.

The invention therefore concerns the use of rotigotine or its salts and prodrugs as a medicinal product for the preventive treatment of dopaminergic cell loss in subjects who do not yet have at least three of the four cardinal symptoms of Parkinson's disease, which are bradycinesia, rigor, resting tremor and postural instability, before the onset of preventive treatment.

The individuals may also be healthy-looking individuals whose genetic or epidemic predisposition does not indicate an increased risk of Parkinson's disease.

However, rotigotine treatment is particularly suitable for individuals at increased risk of Parkinson' s disease or patients who have clinical, clinical chemical or clinical physical evidence of early Parkinson' s disease but do not already have two or more of the cardinal symptoms of Parkinson' s disease.

Finally, rotigotine may be used as a neuroprotective even when the diagnosis is not clear but the development of symptoms towards Parkinson' s-like neurodegeneration is expected.

The prevention of neuronal dopaminergic cell loss requires in particular: (a) Individuals at increased risk of Parkinson's disease or (b) Individuals with early symptoms of Parkinson's disease

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Such risk factors may include genetic mutations (Nut tree NEJM 348,2003, 25). For example, the Parkin gene on chromosome 6q25.2-27 (PARK2) is associated with juvenile Parkinsonism and is more common in families with autosomal recessive Parkinson's inheritance (Matsumine, Am. J. Hum. Genet., 60, 1997, 588; Kitada, Nature 392, 1998, 605; Abbas, Hum. Mol. Genet. 8, 1999, 567; Tassin, Am. J. Hum. Genet., 63, 1998, 88 and Lucking, N. J. Med., 2000, 15-760). Other gene loci, e.g., PARK6 and PARK7 have also been found to be more prevalent in families with juvenile, recessive Parkinson's disease (PARK60, J. Hum. Genet., 60, 1997, 588; Kitada, Nature 392, 1998, 605; Abbas, Hum. Mol. Genet., 8, 1999, 567; Tassin, Am. J. Hum. Genet., 63, 1998, 88 and Lucking, N. J. Med., 2000, 15-760). Other gene loci, e. PARK6 and PARK7 have also been found to be more prevalent in families with juvenile, recessive Parkinson's disease (PARK60, J. Hum. Genet., 2001, Am. Morbus, Am. Morb., J. Morb., 68, 68, 68, 68, 68, 2085; J. Morbus, J. Morb., 69, 208, 69, 208, 208, 208, 208, 269; and 278, 269, 278, 269, 279, 279, 279, 279, 269).

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Clinical physical early symptoms may be structural or functional changes in the brain, which can be identified, for example, physically by PET and SPECT studies or transcranial sonography (Becker, J Neurol 249, Suppl 3, 2002,111/40; Prunier C, et al., Neuroimage, 2003 Jul; 19(3):810-6).

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As discussed above, at the time of the first onset of at least two of the four cardinal symptoms, approximately 70-80% of the dopaminergic neurons of the substantia nigra have already been lost. To make effective use of the surprising neuroprotective potential of rotigotine, prophylactic treatment of patients should therefore preferably begin at a stage when patients have a lower loss of substantia nigra (SN) dopaminergic cells. Therefore, according to the invention, individuals who present one or no of the cardinal symptoms of Parkinson's disease in a pronounced form are first treated with routin.

Preference is given to individuals with a dopaminergic cell loss in the CN of less than 70%, 60%, 50% and, preferably, less than 40%, 30%, 20% or 10%.

Two scores can be used to aid in the diagnosis and control of therapy in patients with already marked motor impairments: the UPDRS score and the Hoehn and Yahr score.

In a preferred aspect of the invention, the patient population treated prophylactically with rotigotine has a modified Hoehn and Yahr score of 0 to 2, particularly preferred 0 to 1 and very preferred 0 to 1. Other

Tabelle 2: Modifizierte Stadienbestimmung nach Hoehn, The natural history of Parkinson's disease in the pre-levodopa and post-levodopa eras. Neurologic Clinics 10, 1992, 331

Stadium 0 = Keine Anzeichen der Erkrankung.

Stadium 1 = Einseitige Erkrankung.

Stadium 1.5 = Einseitige und axiale Beteiligung.

Stadium 2 = Beidseitige Erkrankung ohne Gleichgewichtsstörung.

Stadium 2.5 = Leichte beidseitige Erkrankung mit Ausgleich beim Zugtest.

Stadium 3 = Leichte bis mäßige beidseitige Erkrankung:

leichte Haltungsinstabilität; körperlich unabhängig.

Stadium 4 = Starke Behinderung; kann noch ohne Hilfe laufen oder stehen.

Stadium 5 = Ohne Hilfe an den Rollstuhl gefesselt oder bettlägerig.

Patients with a UPDRS score, Part III, of at least 10 (see example 5) are usually considered eligible for dopaminergic therapy, but the population of patients suitable for the neuroprotective effect of rotigotine is preferred to have a very low or undetectable motor UPDRS score (Part III). Therefore, for the purpose of the present invention, rotigotine should be preferred for preventive treatment in patients with a UPDRS score of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 and, in particular, in patients who do not yet have any motor disorders.

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Roottig has the formula Other

Prodrug is therefore a derivative of the phenolic hydroxy group, selected from the ester group, e.g. arylcarbon ester, alkylcarbon ester or cycloalkylcarbon ester, in particular alkylcarbon ester and cycloalkylcarbon ester with up to 6 carbon atoms; carbamate; acetals; ketals; phosphates; phosphates; sulphates; sulfonates; and silylethers.

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In the above definitions of prodrugs, R, R1 R2 are independently selected from hydrogen, alkyl, cycloalkyl or aryl, and preferably from group C1-6 alkyl, C3-10 cycloalkyl, and phenyl.

R3 is an alkyl, specifically C1-6 alkyl.

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The production of prodrugs by reaction of rotigotine with corresponding reactive precursors such as acid chlorides, acid anhydrides, carbamyl chlorides, sulfonyl chlorides, etc. is known to the clinical chemist and can be found in the relevant literature.

The use of the product is not recommended for the treatment of any of the following conditions:

The basic suitability of a rotigotine derivative as a prodrug can be determined by incubating the compound under defined conditions with an enzyme cocktail, cell homogenization or enzyme-containing cell fraction and measuring the resulting rotigotine.

Alternatively, incubation with fresh blood or plasma or a subcutaneous homogenate may be performed to demonstrate liver-independent metabolism of the prodrug to the active ingredient. For transdermal application, in vitro examination of the permeation to excised skin is necessary. Final demonstration of suitability and potential efficacy in disease models is by determination of the 2-N-propylamino-5-hydroxytetralin formed from the prodrug in plasma.

In vivo, a prodrug should release enough rotigotine to achieve a therapeutically/ prophylactically effective steady-state plasma rotigotine concentration, where effective concentrations are generally considered to be rotigotine concentrations between 0.01 and 50 ng/mL, preferably between 0.05 ng/mL and 20 ng/mL, and particularly between 0.1 and 10 ng/mL plasma.

Routin is the S ((-) enantiomer of 5,6,7,8-tetrahydro-6-[propyl[2-(thienyl) ethyl] amino]-1-naphthal. This means that the proportion of the inactive (R) enantiomer in Parkinson's models is low by design. The (R) enantiomer is preferably < 10 mol%, particularly preferably < 2 mol%, and most particularly preferably < 1 mol% in relation to the total amount of routin in the active substance.

Rotigotine and its prodrugs may be present in the medicinal product as free bases or as the physiologically acceptable salts, e.g. in the form of hydrochloride.

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There are several routes of administration for rotigotine and its prodrugs, which the practitioner can select and adjust according to the needs, condition and age of the patient, the required dose and the desired application interval.

A preferred route of administration of rotigotine is transdermal administration, which may be e. g. ointment, paste, spray, film, patch or an ionophoresis device.

Examples of suitable transdermal formulations are given in WO 99/49852, WO 02/89777, WO 02/89778, WO 2004/058247 and WO 2004/012721 and in Example 1. Such a dosage form allows for a largely constant plasma level setting and thus a constant dopamine stimulation over the entire application interval (WO 02/89778; Metman, Clinical Neuropharmacol. 24, 2001, 163).

However, if a subcutaneous or intramuscular depot is desired, rotigotine may be suspended and injected, for example, as a salt crystal, e.g. crystalline hydrochloride, in a hydrophobic, anhydrous medium, as described in WO 02/15903 and Example 2.

Rotigotine can also be administered in principle in the form of microcapsules, microparticles or implants based on biodegradable polymers, as described in WO 02/38646.

Other possible forms of administration of rotigotine and its prodrugs are transmukous forms, e. g. sublingual sprays, rectal forms or aerosols for pulmonary administration.

Appropriate doses of rotigotine are between 0.05 and approximately 50 mg/ day, with daily doses between 0.1 and 40 mg and in particular between 0.2 and 20 mg/ day being preferred, and may be administered in a single dose, i. e. treatment may be started at low doses and then increased to the maintenance dose if necessary.

The specialist will be aware that the dosage interval may vary depending on the amount applied, the type of application and the daily requirements of the patient, for example, a transdermal application may be designed to be administered once a day, three days or seven days, while a subcutaneous or intramuscular depot may allow injections, for example, at a one, two or four weekly rate.

The neuroprotective formulation may contain other active substances in addition to rotigotine that prevent the progression of dopaminergic cell loss.

Examples of these include anti-apoptotic agents (minocyclines, FK-506, cyclosporin A, zVAD) and neurotrophins such as glial cell-derived neurotrophic factor (GDNF).

In a combination preparation, sequential administration may be achieved, for example, by a dosage form, e.g. an oral tablet, having two different layers with differing release profiles for the different pharmaceutically active ingredients.

Examples of implementations: The test chemical is used to determine the concentration of the active substance in the test chemical.

1.8 g of rotigotine (free base) is dissolved in 2.4 g of ethanol and given to 0.4 g of collidon 90F (dissolved in 1 g of ethanol). This mixture is given to a 74% solution of silicon polymers (8.9 g BioPSA 7-4201 + 8.9 g BIO-PSA 7-4301 [Dow Corning]) in heptane. After adding 2.65 g of petrolether, the mixture is stirred for 1 hour at 700 UpM to obtain a homogeneous dispersion. After lamination on polyester, it was dried at 50 °C. The final P-weight was 50 g/cm2.

Example 2: Rotigotine deposit suspensions

(a) 1411,2 g of Miglyol 812 were weighed in a Duran bottle. 14,4 g of Imwitor 312 were added to the miglyol and then heated to 80°C for 30 minutes by stirring. The clear solution was cooled to room temperature and filtered. (b) 1188 g of the solution prepared under (a) were transferred to a glass laboratory reactor, 12 g of routin were added and homogenised for 10 minutes with an ultrasound at UpM under 10,000 nitrogen. The suspension was filled in brown glass bottles at running ultrasound (2,000 UpM).

The following is the list of the types of devices that can be used:

For intoxication, mice are given 80 mg/kg of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (in 20 mg/kg doses given every two hours, group 3-6 in Figures 1 and 2) which causes approximately 50-60% of Substantia nigra neurons to degenerate (maximum degeneration in group 3 in Figures 1 and 2). Rotigotine is given daily in doses of 0.3, 1 or 3 mg/kg for 7 days as a so-called 'slow-release formulation' (see Examples 2) (Group 4-6 in Figure 1 and 2), and MPTP-treated animals (Group 3) receive Rotigotine-L without a vehicle (Examples 2) and Rotigotine HCl 1 as a reference control.On day 8, the animals are killed, the brains removed and frozen. Freeze-cutting is performed with 100 pm [125I] PE21 ([125I]-(E) -N(3-iodoprop-2-enyl) -2-β-carboxymethyl-3β-(4'-methylphenyl) -norane) incubated in phosphate buffer, pH 7.4, to mark the amount of dopamine transporters still present in the nerve stream, which is an indication of the amount of functioning neurotransmitters. Routin serves to improve neuronal survival and their dose-dependent properties.

Example 4: Acute MPTP model (including apoptosis)

For intoxication, mice are given 80 mg/kg of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (in 20 mg/kg doses given every two hours) which causes approximately 50-60% of the neurons of the Substantia nigra to degenerate. About 16 hours before, rotigotine is given in doses of 0.3, 1 or 3 mg/kg in a so-called 'slow-release formulation'. Diffusion and absorption latency results in optimal rotigotine availability when MPTP is given. After 24 hours, the animals are killed and the brain is fixed. The brain sections are treated with fluorocarbons to identify the number of neuronal degeneration.

The test shall be performed on the vehicle in accordance with the requirements of paragraph 5.2.3.1.

The motor UPDRS score (Part III of the UPDRS score) is determined by examining patients using the criteria 18-31 as shown in Table 2 below, with the score values from each criterion added up.

The Commission has not yet decided on the application of the new rules. 18th language:

□	0 -	Normal.
□	1 -	Leichte Abnahme von Ausdruck, Diktion und/oder Volumen.
□	2 -	Monoton, verwaschen, aber verständlich; mäßig behindert.
□	3 -	Deutliche Beeinträchtigung, schwer zu verstehen.
□	4 -	Unverständlich.

19th facial expression:

□	0 -	Normal.
□	1 -	Minimal veränderte Mimik, könnte ein normales " Pokergesicht" sein.
□	2 -	Leichte, aber eindeutig abnorme Verminderung des Gesichtsausdruckes.
□	3 -	Mäßig verminderte Mimik; Lippen zeitweise geöffnet.
□	4 -	Maskenhaftes oder erstarrtes Gesicht mit stark oder völlig fehlendem Ausdruck; Lippen stehen um 7 mm auseinander.

Resting tremor: (G = face, RH = right hand, LH = left hand, RF = right foot, LF = left foot)

G	RH	LH	RF	LF
□	□	□	□	□	0 -	Keine.
□	□	□	□	□	1 -	Leicht und selten vorhanden.
□	□	□	□	□	2 -	Geringe Amplitude persistierend; oder mäßige Amplitude, aber nur intermittierend auftretend.
□	□	□	□	□	3 -	Mäßige Amplitude, die meiste Zeit vorhanden.
□	□	□	□	□	4 -	Ausgeprägte Amplitude, die meiste Zeit vorhanden.

Hand movement or posture tremor: (R = right, L = left)

R	L
□	□	0 -	Fehlt.
□	□	1 -	Leicht; bei Bewegung vorhanden.
□	□	2 -	Mäßige Amplitude, bei Bewegung vorhanden.
□	□	3 -	Mäßige Amplitude, bei Beibehalten der Haltung und bei Bewegung vorhanden.
□	□	4 -	Ausgeprägte Amplitude; beim Essen störend.

Rigidity: (tested with passive movement of the large joints on the patient sitting. Wheel phenomena can be ignored). (N = neck, ROE = right upper extremity, LOE = left upper extremity, RUE = right lower extremity, LUE = left lower extremity)

N	ROE	LOE	RUE	LUE
□	□	□	□	□	0 -	Fehlt.
□	□	□	□	□	1 -	Leicht oder nur erkennbar bei Aktivierung durch spiegelbildliche oder andere Bewegungen.
□	□	□	□	□	2 -	Leicht bis mäßig.
□	□	□	□	□	3 -	Ausgeprägt, jedoch voller Bewegungsumfang bleibt erreicht.
□	□	□	□	□	4 -	Stark; Schwierigkeit beim Ausführen aller Bewegungen.

23. Finger clapping: (Patient touches in rapid order and at the greatest possible amplitude, with each hand separating the thumb with the index finger).

R	L
□	□	0 -	Normal.
□	□	1 -	Leichte Verlangsamung und/oder-Verringerung der Amplitude.
□	□	2 -	Mäßig eingeschränkt. Eindeutige und frühzeitige Ermüdung. Bewegung kann gelegentlich unterbrochen werden.
□	□	3 -	Stark eingeschränkt. Verzögerter Start der Bewegungen oder Unterbrechung fortlaufender Bewegungen.
□	□	4 -	Kann die Aufgabe kaum ausführen.

Hand movements: (Patient opens and closes hands in rapid order at the widest possible amplitude and with each hand separately) (R = right, L = left)

R	L
□	□	0 -	Normal.
□	□	1 -	Leichte Verlangsamung und/oder Verringerung der Amplitude.
□	□	2 -	Mäßig eingeschränkt. Eindeutige und frühzeitige Ermüdung. Bewegung kann gelegentlich unterbrochen werden.
□	□	3 -	Stark eingeschränkt. Verzögerter Start der Bewegungen oder Unterbrechung fortlaufender Bewegungen.
□	□	4 -	Kann die Aufgabe kaum ausführen.

25. Rapidly changing hand movements: (pronational-supinational movements of the hands, vertical or horizontal, with the greatest possible amplitude, both hands at the same time).

R	L
□	□	0 -	Normal.
□	□	1 -	Leichte Verlangsamung und/oder Verringerung der Amplitude.
□	□	2 -	Mäßig eingeschränkt. Eindeutige und frühzeitige Ermüdung. Bewegung kann gelegentlich unterbrochen werden.
□	□	3 -	Stark eingeschränkt. Verzögerter Start der Bewegungen oder Unterbrechung fortlaufender Bewegungen.
□	□	4 -	Kann die Aufgabe kaum ausführen.

Leg agility: (The patient taps the floor in rapid succession with the heel, lifting the entire leg, and the amplitude should be at least 7.5 cm.

R	L
□	□	0 -	Normal.
□	□	1 -	Leichte Verlangsamung und/oder Verringerung der Amplitude.
□	□	2 -	Mäßig eingeschränkt. Eindeutige und frühzeitige Ermüdung. Bewegung kann gelegentlich unterbrochen werden.
□	□	3 -	Stark eingeschränkt. Verzögerter Start der Bewegungen oder Unterbrechung fortlaufender Bewegungen.
□	□	4 -	Kann die Aufgabe kaum ausführen.

27. Rising from the chair: (Patient tries to get up from a straight wooden or metal chair with arms crossed in front of the chest).

□	0 -	Normal.
□	1 -	Langsam; kann mehr als einen Versuch benötigen.
□	2 -	Stößt sich an den Armlehnen hoch.
□	3 -	Neigt zum Zurückfallen und muß es eventuell mehrmals versuchen, kann jedoch ohne Hilfe aufstehen.
□	4 -	Kann ohne Hilfe nicht aufstehen.

The 28th attitude:

□	0 -	Normal aufrecht.
□	1 -	Nicht ganz aufrecht, leicht vorgebeugte Haltung; könnte bei einem älteren Menschen normal sein.
□	2 -	Mäßig vorgebeugte Haltung; eindeutig abnorm, kann leicht zu einer Seite geneigt sein.
□	3 -	Stark vorgebeugte Haltung mit Kyphose; kann mäßig zu einer Seite geneigt sein.
□	4 -	Ausgeprägte Beugung mit extrem abnormer Haltung.

The 29th .

□	0 -	Normal.
□	1 -	Geht langsam, kann einige kurze Schritte schlurfen, jedoch keine Festination oder Propulsion.
□	2 -	Gehen schwierig, benötigt aber wenig oder keine Hilfe; eventuell leichtes Trippeln, kurze Schritte oder Propulsion.
□	3 -	Starke Gehstörung, benötigt Hilfe.
□	4 -	Kann überhaupt nicht gehen, auch nicht mit Hilfe.

30. Postural stability: (response to sudden backward movement by pulling on the patient's shoulders; standing upright with eyes open and feet slightly apart; patient is prepared for this).

□	0 -	Normal.
□	1 -	Retropulsion, gleicht aber ohne Hilfe aus.
□	2 -	Fehlen einer Haltungsreaktion; würde fallen, wenn er nicht vom Untersucher aufgefangen würde.
□	3 -	Sehr instabil; neigt dazu, spontan das Gleichgewicht zu verlieren.
□	4 -	Kann nicht ohne Unterstützung stehen.

Bradycynesia and hypokynesia of the body: (combination of slowness, hesitation, reduced arm movements, low range of motion and general poor mobility)

□	0 -	Keine.
□	1 -	Minimale Verlangsamung, Bewegung wirkt beabsichtigt; könnte bei manchen Menschen normal sein. Möglicherweise herabgesetzte Amplitude.
□	2 -	Leichte Verlangsamung und Bewegungsarmut, die eindeutig abnorm sind. Alternativ auch herabgesetzte Amplitude.
□	3 -	Mäßige Verlangsamung und Bewegungsarmut oder Herabsetzung der Amplitude.
□	4 -	Ausgeprägte Verlangsamung, Bewegungsarmut oder Herabsetzung der Amplitude.

Example 6: In vitro conversion of a prodrug into the active substance

The microsome fraction containing the essential metabolizing enzymes is obtained by differential centrifugation from human, monkey, dog, rat or mouse hepatocellular homogenous products; alternatively, the cytoplasmic fraction can be obtained. The subcellular fraction is suspended with a buffer to obtain a solution with a defined protein content. After 1 μM of prodrug to be tested, incubation is carried out at 37 °C for 60 min. Rotigotine is then quantified by HPLC/UV or also by HPLC/MS and related to the amount used. Concentration or time series are examined for more detailed analysis.

Claims (10)

1. Rotigotine, its salts or prodrugs thereof for use in the treatment of diseases which are associated with increased dopaminergic cellular decay, wherein the treatment is effected on individuals who are selected from the group

   (a) of individuals without symptoms of Parkinson's disease, but having an increased risk of Parkinson's disease, wherein the individuals have a mutation in a PARK gene and/or

   (b) of individuals in which at least three of the four cardinal symptoms of Parkinson's disease (rigidity, passive tremor, bradykinesia, postural instability) are not yet present,

   wherein the prodrug is selected from the group of esters, carbamates, acetals, petals, phosphates, phosphonates, sulphates, sulphonates and silyl ethers.
2. Rotigotine, its salts or prodrugs thereof for use according to claim 1, wherein the disease which is associated with increased dopaminergic cellular decay is selected from alpha-synucleopathies, REM sleep disturbances and disturbances of the sense of smell.
3. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein one or more of the following early clinical symptoms may be assigned to the individuals: olfactory disturbances, depression, sleep disturbances of the type REM Sleep Behaviour Disorders', constipation and short-term motor anomalies.
4. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein the individuals have a mutation in a PARK gene and/or changes in the alpha-synuclein or neuromelanine pattern.
5. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein before the start of medicament administration the individuals have a loss of dopaminergic cells in the substantia nigra of less than 60%.
6. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein before the start of medicament admmistration the individuals have a motor UPDRS score of less than 9.
7. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein the individuals have a Höhn-Yahr score of 0.
8. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein the medicament is intended for parenteral, transdermal or mucosal administration.
9. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein the rotigotine is administered in a dose of 0.05 to 50 mg per day.
10. Rotigotine, its salts or prodrugs thereof for use according to one of the preceding claims, wherein the medicament comprises, in addition to rotigotine, also an anti-apoptotically effective substance, such as minocycline, FK-506, cyclosporin A or zVAD, and/or neurotrophines.