Pharmaceutical compositions for use in the preventive and / or therapeutic treatment of L-dopa-induced dyskinesia

Abstract

The present invention relates to the field of medicine, and more particularly to the use of rho kinase inhibitors for the treatment or prevention of L-dopa-induced dyskinesia.

Description

[Technical Field]

[0001] explanation A pharmaceutical composition for use in the preventive and / or therapeutic treatment of L-dopa-induced dyskinesia.

[0002] The present invention relates to the field of medicine, more particularly to the use of Rho kinase inhibitors for treating or preventing L-dopa-induced dyskinesia. [Background technology]

[0003] Parkinson's disease (PD) is one of the most common neurodegenerative disorders in our population. It is characterized by motor symptoms that arise primarily due to degeneration of dopaminergic neurons in the substantia nigra, although other neuronal systems are also involved. The usual, and to date most effective, treatment for this disease consists of administering the dopamine precursor molecule L-dopa. This drug is effective for the first few years but causes long-term complications and side effects, particularly dyskinesia.

[0004] L-dopa-induced dyskinesia consists of rapid, abnormal, involuntary choreoathetoid movements and athetosis, usually affecting the limbs and occasionally the face and neck. Depending on the temporal pattern of onset, several forms of dyskinesia have been described: peak-dose dyskinesia (coinciding with peak plasma dopamine levels), biphasic dyskinesia, and off-period dystonia. These complications significantly reduce the therapeutic efficacy of L-dopa and limit the patient's daily activities, potentially rendering them incapacitated. Approximately 50% of patients have been reported to have dyskinesia five years after treatment, with the rate rising to 90% by 10 years (Olanow CW, Stocchi F. Levodopa: A new look at an old friend. Mov Disord (2018) 33(6):859-866. doi:10.1002 / mds.27216).

[0005] Although the causes of dyskinesia are not fully understood, it is known that the glutamatergic system plays an important role. In fact, the drug currently used to combat dyskinesia is the NMDA glutamate receptor antagonist amantadine. However, this compound is contraindicated in cases of renal failure, heart failure, and psychiatric disorders, and causes complications and numerous side effects, such as confusion, difficulty concentrating, insomnia, loss of appetite, nausea, and psychiatric disorders (confusion, hallucinations, delirium syndrome, psychosis). Over the past decade, it has been demonstrated that other systems, such as the serotonergic system, are also involved in the progression of the disease, as L-dopa is converted to dopamine at serotonergic terminals and released in an uncontrolled manner. However, compounds acting at this level, such as serotonin 5-HT1a receptor agonists (buspirone, salitoxane, tandospirone), have shown antidyskinetic effects in preliminary studies, but they may pose problems because they can affect the antiparkinsonian response in some cases. Alternatively, for example, the 5-HT1a / b agonists (eltoprazine and anpirtoline) have a more favorable pharmacological profile than the former, but may partially reduce the therapeutic effect of L-dopa. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Olanow CW,Stocchi F.Levodopa:A new look at an old friend.Mov Disord(2018)33(6):859-866.doi:10.1002 / mds.27216 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a need to research and develop other preventative and / or therapeutic treatments to combat dyskinesia that are more effective with fewer side effects. [Means for solving the problem]

[0008] The results presented herein demonstrate that inhibition of the RhoA / Rho kinase (ROCK) pathway allows for the treatment and / or prevention of dyskinesias that can occur with chronic treatment with L-dopa administered to Parkinson's disease patients.

[0009] The present invention therefore relates to pharmaceutical compositions comprising compounds capable of inhibiting ROCK for use in the preventive or therapeutic treatment of L-dopa-induced dyskinesia.

[0010] The present invention further relates to pharmaceutical compositions of ROCK inhibitors, their dosage forms for different routes of administration, specific doses useful for preventing dyskinesias, and specific doses useful for treating dyskinesias. [Brief explanation of the drawings]

[0011] [Figure 1-1] The effects of L-dopa-induced dyskinesia on the RhoA / ROCK pathway in the substantia nigra (A–C) and striatum (D–F) are shown. In dyskinetic animals treated with both doses of L-dopa (6 mg / kg; LD-6 and 12 mg / kg), significant increases in RhoA and ROCK protein expression (A, B) and ROCK activity (C) were observed in the substantia nigra, whereas in the striatum, the differences were significant only at the high dose (D, E). However, after real-time PCR analysis, significant differences were observed in the striatum at both doses. Results were normalized with respect to values ​​in 6-OHDA-lesioned animals treated with saline. Data are presented as mean ± SEM, with Student's t-test results *p<0.05. [Figure 1-2]The effects of L-dopa-induced dyskinesia on the RhoA / ROCK pathway in the substantia nigra (A–C) and striatum (D–F) are shown. In dyskinetic animals treated with both doses of L-dopa (6 mg / kg; LD-6 and 12 mg / kg), significant increases in RhoA and ROCK protein expression (A, B) and ROCK activity (C) were observed in the substantia nigra, whereas in the striatum, the differences were significant only at the high dose (D, E). However, after real-time PCR analysis, significant differences were observed in the striatum at both doses. Results were normalized with respect to values ​​in 6-OHDA-lesioned animals treated with saline. Data are presented as mean ± SEM, with Student's t-test results *p<0.05. [Figure 1-3] The effects of L-dopa-induced dyskinesia on the RhoA / ROCK pathway in the substantia nigra (A–C) and striatum (D–F) are shown. In dyskinetic animals treated with both doses of L-dopa (6 mg / kg; LD-6 and 12 mg / kg), significant increases in RhoA and ROCK protein expression (A, B) and ROCK activity (C) were observed in the substantia nigra, whereas in the striatum, the differences were significant only at the high dose (D, E). However, after real-time PCR analysis, significant differences were observed in the striatum at both doses. Results were normalized with respect to values ​​in 6-OHDA-lesioned animals treated with saline. Data are presented as mean ± SEM, with Student's t-test results *p<0.05. [Figure 2-1] Abnormal involuntary movements (AIMs) observed after chronic treatment (23 and 32 days) with L-dopa and different doses of fasudil (10 mg / kg; A, C, E, and G, and 30-40 mg; B, D, F, and H). In animals co-treated with fasudil (open circles), these movements were statistically significantly reduced in both the total score (A, B) and the separate components: limb (C, D), axial (E, F), and orolingual (G, H). Data are presented as mean ± SEM (standard error of mean). *p<0.05. [Figure 2-2]Abnormal involuntary movements (AIMs) observed after chronic treatment (23 and 32 days) with L-dopa and different doses of fasudil (10 mg / kg; A, C, E, and G, and 30-40 mg; B, D, F, and H). In animals co-treated with fasudil (open circles), these movements were statistically significantly reduced in both the total score (A, B) and the separate components: limb (C, D), axial (E, F), and orolingual (G, H). Data are presented as mean ± SEM (standard error of mean). *p<0.05. [Figure 2-3] Abnormal involuntary movements (AIMs) observed after chronic treatment (23 and 32 days) with L-dopa and different doses of fasudil (10 mg / kg; A, C, E, and G, and 30-40 mg; B, D, F, and H). In animals co-treated with fasudil (open circles), these movements were statistically significantly reduced in both the total score (A, B) and the separate components: limb (C, D), axial (E, F), and orolingual (G, H). Data are presented as mean ± SEM (standard error of mean). *p<0.05. [Figure 2-4] Abnormal involuntary movements (AIMs) observed after chronic treatment (23 and 32 days) with L-dopa and different doses of fasudil (10 mg / kg; A, C, E, and G, and 30-40 mg; B, D, F, and H). In animals co-treated with fasudil (open circles), these movements were statistically significantly reduced in both the total score (A, B) and the separate components: limb (C, D), axial (E, F), and orolingual (G, H). Data are presented as mean ± SEM (standard error of mean). *p<0.05. [Figure 3-1]Figure 1 shows the cylinder test in animals with unilateral dopaminergic lesions, where less than 20% left limb use was observed at baseline. Recovery of motor asymmetry was observed 60 and 90 min after L-dopa injection in control animals (L-dopa only; black bars) and animals co-treated with fasudil at 10 mg / kg (A), 30, and 40 mg / kg (B) (gray bars). After treatment with fasudil, rotational behavior was also unaffected, indicating that the reduction in dyskinesias was not due to a decrease in motor activity (C–E). Data are presented as mean ± SEM; Student's t-test, *p<0.05. [Figure 3-2] Figure 1 shows the cylinder test in animals with unilateral dopaminergic lesions, where less than 20% left limb use was observed at baseline. Recovery of motor asymmetry was observed 60 and 90 min after L-dopa injection in control animals (L-dopa only; black bars) and animals co-treated with fasudil at 10 mg / kg (A), 30, and 40 mg / kg (B) (gray bars). After treatment with fasudil, rotational behavior was also unaffected, indicating that the reduction in dyskinesias was not due to a decrease in motor activity (C–E). Data are presented as mean ± SEM; Student's t-test, *p<0.05. [Figure 3-3] Figure 1 shows the cylinder test in animals with unilateral dopaminergic lesions, where less than 20% left limb use was observed at baseline. Recovery of motor asymmetry was observed 60 and 90 min after L-dopa injection in control animals (L-dopa only; black bars) and animals co-treated with fasudil at 10 mg / kg (A), 30, and 40 mg / kg (B) (gray bars). After treatment with fasudil, rotational behavior was also unaffected, indicating that the reduction in dyskinesias was not due to a decrease in motor activity (C–E). Data are presented as mean ± SEM; Student's t-test, *p<0.05. [Figure 4]The effect of ROCK inhibition in animals with a stable degree of dyskinesia (chronic treatment with L-dopa for 3 weeks) is shown. In this case, a low dose of fasudil (10 mg / kg, A) had no effect on dyskinesia behavior (A). However, higher doses of the compound (30 and 40 mg / kg) caused a significant decrease in L-dopa, even at a high dose of L-dopa (24 mg / kg) (B). Data are presented as mean ± SEM, and t-Student's *p<0.05.

[0012] As used herein and in the claims, the term "ROCK pathway" refers to a pathway involving the GTPase RhoA protein and its associated kinase (also known as Rho-kinase). RhoA binds to specific regions of ROCK and activates it. ROCK phosphorylates various target proteins, including myosin light chain, reorganizing the actin cytoskeleton and regulating apoptotic events (Amin E, Dubey BN, Zhang SC, Gremer L, Dvorsky R, Moll JM, Taha MS, Nagel-Steger L, Piekorz RP, Somlyo AV, Ahmadian MR (2013) Rho-kinase: regulation, (dys)function, and inhibition. Biol Chem 394:1399-410. doi:10.1515 / hsz-2013-0181). This pathway is involved in inflammatory responses in certain diseases, including neurodegenerative disorders such as Parkinson's disease. ROCK also acts in the process of autophagy, and inhibition of this pathway leads to axon stabilization and induces neuroprotective effects. Two isoforms have been described, encoded by different genes: ROCK I and ROCK II. ROCK II is preferentially expressed in the brain (for review, see Labandeira-Garcia et al., 2014).

[0013] As used in the present description and claims, the term "compound capable of inhibiting the ROCK pathway" refers to a compound capable of statistically significantly reducing the activity and expression level of an enzyme compared to a corresponding control in which the inhibitor was not administered. Those skilled in the art can test for the inhibition by various methods, such as measuring the activity of the ROCK enzyme by enzyme immunoassay techniques that detect myosin phosphorylation (ROCK Activity Assay kit; Cell Biolabs, Inc., San Diego, CA, USA), measuring the expression level of mRNA by real-time PCR, or measuring the expression level of protein by Western blot. These techniques are described in detail in the following publication, which is incorporated herein by reference in its entirety: Rodriguez-Perez AI, Dominguez-Meijide A, Lanciego JL, Guerra MJ, Labandeira-Garcia JL. Inhibition of Rho kinase mediates the neuroprotective effects of estrogen in the MPTP model of Parkinson's disease. Neurobiol Dis. 2013 58:209-19. doi:10.1016 / j.nbd.2013.06.004.

[0014] According to the present invention, compounds capable of inhibiting the ROCK pathway are capable of directly or indirectly modulating the ROCK pathway.

[0015] As used in this description and claims, the term "L-dopa-induced dyskinesia" should be understood as the abnormal involuntary movements experienced by mammals (e.g., humans) who have Parkinson's disease and are being treated with L-dopa.

[0016] In this study, the authors investigated the molecular effects of chronic administration of L-dopa in a 6-OHDA-lesioned rat model and demonstrated that RhoA and ROCK levels were elevated compared to controls (see Figure 1), suggesting activation of this pathway. Under these conditions, at the functional level, rats suffer from dyskinesias induced by chronic L-dopa treatment. Based on these experiments, the association between ROCK pathway activation and dyskinesia is demonstrated for the first time. The inventors demonstrated that modulation of the ROCK pathway has an effect on dyskinesias, and thus inhibition of the ROCK pathway can reduce established dyskinesias in an animal model treated with L-dopa (see Example 4) or reduce the occurrence of dyskinesias in an animal model in which L-dopa treatment has been initiated (see Example 2).

[0017] Thus, in one aspect, the present invention relates to a pharmaceutical composition comprising a compound capable of inhibiting the ROCK pathway for use in the preventive or therapeutic treatment of L-dopa-induced dyskinesia.

[0018] In certain embodiments, the compositions of the present invention are administered in a dosage form suitable for intraperitoneal, oral, or injectable administration, which in certain embodiments includes intramuscular, subcutaneous, intravenous, and intradermal administration.

[0019] In certain embodiments, the ROCK inhibitor is fasudil and its derivatives, ripasudil, Y -27632, Y -32885, AMA-0076, AR-12286, AR-13324 (Rhopressa), KD-025 (Slx2119), LX7101, PG-324 (Roclatan), and SAR407899.

[0020] In a preferred embodiment, the ROCK pathway inhibitor of the present invention is fasudil. Thus, in a specific embodiment, the present invention relates to the above-described pharmaceutical composition, wherein the compound is fasudil, a pharmaceutically acceptable salt thereof, or a derivative thereof. In another specific embodiment, the fasudil derivative is selected from hydroxyfasudil and dimethylfasudil.

[0021] The present invention also describes the administration of fasudil to Parkinson's animal models before treatment with L-dopa, and furthermore, when fasudil is administered during L-dopa treatment, a preventive effect against dyskinesia is achieved, reducing its occurrence throughout the treatment. Example 2 further demonstrates that in the case of acute administration of L-dopa, and when dyskinesias are more pronounced, treatment with fasudil is still effective, reducing the occurrence of dyskinesia compared to the absence of fasudil treatment (see Example 2 and Figure 2).

[0022] Thus, in a particular embodiment, the present invention relates to a pharmaceutical composition of the present invention for use in the preventive treatment of L-dopa-induced dyskinesia, comprising (i) administration of a therapeutically effective amount of said pharmaceutical composition before the initiation of treatment with L-dopa, and (ii) administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially with each administration of L-dopa.

[0023] In certain embodiments, the present invention relates to a method for preventing L-dopa-induced dyskinesia, wherein a patient has Parkinson's disease, the method comprising administering a therapeutically effective amount of fasudil prior to the initiation of treatment with L-dopa, and administering a therapeutically effective amount of fasudil simultaneously or sequentially with each administration of L-dopa.

[0024] In a particular embodiment, the present invention relates to a pharmaceutical composition of the present invention for use in the prophylactic treatment of L-dopa-induced dyskinesia.

[0025] In this case, furthermore, at this dose, fasudil has additional benefits, as it provides neuroprotection in Parkinson's disease patients and slows dopaminergic degeneration (Villar-Cheda B, Dominguez-Meijide A, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL. (2012) Involvement of microglial RhoA / Rho-kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors. Neurobiol Dis 47:268-79 doi:10.1016 / j.nbd.2012.04.010).Furthermore, administration of the compositions of the present invention to prevent dyskinesias has the preferred stoichiometry described above, which also enhances the neuroprotective effects of fasudil (Borrajo A, Rodriguez-Perez AI, Villar-Cheda B, Guerra MJ, Labandeira-Garcia JL. (2014) Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death. Neuropharmacology 85:1-8 doi:10.1016 / j.neuropharm.2014.05.021; Villar-Cheda B, Dominguez-Meijide A, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL. (2012) Involvement of microglial RhoA / Rho-kinase pathway activation in the dopaminergic neuron death.Role of angiotensin via angiotensin type 1 receptors.Neurobiol Dis 47:268-79 doi:10.1016 / j.nbd.2012.04.010;Labandeira-Garcia JL, Rodriguez-Perez AI, Villar-Cheda B, Borrajo A, Dominguez-Meijide A, Guerra M.J. (2015) Rho Kinase and Dopaminergic Degeneration: A Promising Therapeutic Target for Parkinson's Disease. Neuroscientist 21:616-29 doi:10.1177 / 1073858414554954).

[0026] The present invention also describes the utility of the compositions of the present invention for the therapeutic treatment of L-dopa-induced dyskinesia. Example 4 demonstrates that a composition containing a ROCK inhibitor can reduce dyskinesia even when dyskinesia is already established. By increasing the dose of fasudil (40 mg / kg), dyskinesia is reduced by nearly 50% in animals with existing movement disorders (treated regularly with L-dopa for 3 to 4 weeks). Even after acute administration of L-dopa, dyskinesia is further reduced when it is accompanied by administration of the compositions of the present invention.

[0027] Thus, in a particular embodiment, the present invention relates to a pharmaceutical composition of the present invention for use in the therapeutic treatment of L-dopa-induced dyskinesia, comprising the administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially with each administration of L-dopa.

[0028] In certain embodiments, the present invention relates to a method for treating L-dopa-induced dyskinesia, wherein a patient has Parkinson's disease, the method comprising administering a therapeutically effective amount of fasudil concurrently or sequentially with each administration of L-dopa.

[0029] In a particular embodiment, the present invention relates to a pharmaceutical composition of the present invention for use in the therapeutic treatment of L-dopa induced dyskinesia.

[0030] One of the preferred routes of administration in the present invention is injectable, and therefore in a particular embodiment of the present invention, the present invention relates to a pharmaceutical composition as described above, the dosage form of which is suitable for injectable administration for use in the prevention or treatment of L-dopa-induced dyskinesia.

[0031] Another preferred route of administration according to the present invention is the oral route, and therefore in a particular embodiment of the present invention, the present invention relates to a pharmaceutical composition as described above, the dosage form of which is suitable for oral administration for use in the prevention or treatment of L-dopa-induced dyskinesia. [Example]

[0032] The following examples serve to illustrate the invention and do not represent a limitation thereof.

[0033] Methods and experimental design In the following examples, we used Sprague-Dawley rats injected with the neurotoxin 6-hydroxydopamine (6-OHDA) via stereotactic surgery in the medial forebrain bundle. This technique is one of the most widely used experimental models for studying Parkinson's disease (PD) and its potential treatments (Ungerstedt U. 6-Hydroxy-dopamine-induced degeneration of central monoamine neurons. Eur J Pharmacol. (1968) 5(1):107-10; Cenci MA, Crossman AR. Animal models of l-dopa-induced dyskinesia in Parkinson's disease. Mov Disord (2018) 33(6):889-899. doi:10.1002 / mds.27337).

[0034] To establish an animal model of dyskinesia, animals were chronically treated with L-dopa 6 mg / kg (therapeutic dose) and benserazide (10 mg / kg) for 3–4 weeks, during which time abnormal involuntary movements (AIMs) were assessed using a special test (Cenci MA, Lundblad M. Ratings of L-DOPA-induced dyskinesia in the unilateral 6-OHDA lesion model of Parkinson's disease in rats and mice. Curr Protoc Neurosci. (2007) Chapter 9: Unit 9.25. doi:10.1002 / 0471142301).

[0035] Example 1. Examination of a movement disorder model PD animal model groups were injected daily with different doses of L-dopa (6 mg / kg and 12 mg / kg) until the level of dyskinesia stabilized (3-4 weeks). At autopsy, the striatum and substantia nigra were dissected and the expression levels of RhoA and ROCK were analyzed by Western blot and real-time PCR.

[0036] It was observed that there was a significant increase in the levels of RhoA and ROCK proteins in dyskinetic animals, and that the increase in the levels of these proteins was greater in animals treated with higher doses of L-dopa and that showed earlier and more severe dyskinesias (see Figure 1).

[0037] This experiment demonstrates that the ROCK pathway is activated in movement-impaired animals.

[0038] Example 2. Treatment with Fasudil During Chronic Treatment with L-Dopa In this study, the L-dopa-treated rat group was used as a control. In addition to L-dopa, one group received fasudil, a ROCK pathway inhibitor, at a dose of 10 mg / kg / day via intraperitoneal route, 30 minutes before each L-dopa administration, starting 5 days before the start of L-dopa treatment (although it could also be administered orally after appropriate dose adjustment). In addition to L-dopa, another group received fasudil at doses of 30 and 40 mg / kg / day via intraperitoneal route at the same frequency as the previous group. In all cases, treatment was chronically administered for 3 weeks, during which abnormal involuntary movements were evaluated.

[0039] A statistically significant reduction in the occurrence of dyskinesias was observed in animals treated with low-dose fasudil (10 mg / kg) and L-dopa compared to animals treated with L-dopa alone: ​​approximately a 25% reduction in limb dyskinesias, a 30% reduction in oral-lingual dyskinesias, and a 35% reduction in axial dyskinesias. The reduction in dyskinesias was observed from day 5 onwards.

[0040] With increasing doses of fasudil (30 mg / kg), greater reductions in dyskinesias were observed in all analyzed movement disorder components (oral 70%, axial 60%, and limb 60%). With increasing doses of fasudil to 40 mg / kg, the reduction in dyskinesias reached 70%.

[0041] At the end of treatment, the dose of L-dopa was increased to 24 mg / kg to test whether fasudil was also effective in severe dyskinetic conditions, and a significantly greater reduction of approximately 50% was observed (see Figure 2).

[0042] This study demonstrates that inhibitors of the ROCK pathway, such as fasudil, are useful for reducing the occurrence of dyskinesias, even when the occurrence is caused by acute doses of L-dopa.

[0043] Example 3. Study of the interaction between inhibition of the ROCK pathway and the therapeutic effects of L-dopa To investigate whether fasudil could interfere with the therapeutic effects of L-dopa, we performed a cylinder test based on the analysis of the motor asymmetry that affects animals after unilateral 6-OHDA lesions (Schallert T, Kozlowski DA, Humm JL, Cocke RR. (1997) 73:229-38). In this experiment, animals treated with fasudil at all doses studied (10, 30, and 40 mg / kg) recovered the lesion-induced motor asymmetry 1 hour after L-dopa injection, with no differences observed compared to animals injected with L-dopa alone, indicating that this compound does not alter the therapeutic effects of L-dopa (see Figure 3A-B). Furthermore, in experiments assessing rotational behavior, no differences were observed in L-dopa-induced rotations in animals treated with different doses of fasudil, demonstrating that the reduction in dyskinesia was not due to a decrease in motor activity (see Figure 3C-E).

[0044] This experiment demonstrates that inhibition of the ROCK pathway by administration of fasudil does not interfere with the therapeutic effects of L-dopa, even at high doses.

[0045] Example 4. Investigation of therapeutic effects Groups of animals with unilateral 6-OHDA lesions were treated with daily L-dopa for 3 weeks, followed by L-dopa and fasudil to investigate whether inhibition of the ROCK pathway reduces dyskinesias once they are already established.

[0046] No improvement in animals was observed when a fasudil dose of 10 mg / kg / day was used (up to 7 days of treatment).

[0047] However, when a fasudil dose of 40 mg / kg / day was used, there was a reduction in dyskinesia of approximately 45% from the third day of treatment.

[0048] When the dose of L-dopa was increased to 24 mg / kg, which produces a severe dyskinetic state, the reduction was even greater, about 50%, which was maintained until the end of treatment (see Figure 4).

Claims

1. A pharmaceutical composition comprising an effective amount of fasudil or hydroxyfasudil, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of L-dopa-induced dyskinesia.

2. 2. The pharmaceutical composition for its use according to claim 1, wherein said composition is administered in a dosage form suitable for oral or injectable administration.

3. 2. The pharmaceutical composition for use in the prevention of L-dopa-induced dyskinesia according to claim 1, wherein the dosage form of fasudil or hydroxyfasudil, or a pharmaceutically acceptable salt thereof, is suitable for oral or injectable administration.

4. (i) administering a therapeutically effective amount of said pharmaceutical composition prior to the initiation of treatment with L-dopa; (ii) administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially with each administration of L-dopa.

5. 3. The pharmaceutical composition according to claim 1 or 2 for use in the therapeutic treatment of L-dopa-induced dyskinesia, comprising administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially with each administration of L-dopa.

6. 3. The pharmaceutical composition for use thereof according to claim 1 or 2, wherein said dyskinesia is peak dose dyskinesia.

7. 3. The pharmaceutical composition for use as described in claim 2, wherein said administration slows dopaminergic degeneration.

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