Pharmaceutical compositions for use in preventive and / or therapeutic treatment of l-dopa-induced dyskinesia
Inhibiting the Rho kinase pathway with fasudil derivatives effectively prevents and treats L-dopa-induced dyskinesia in Parkinson's disease, reducing its severity and occurrence while maintaining L-dopa's therapeutic benefits.
Patent Information
- Application Number
- JP2025141689
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2019-07-31
- Filing Date
- 2025-08-27
- Publication Date
- 2025-11-12
AI Technical Summary
Current treatments for L-dopa-induced dyskinesia, a common complication in Parkinson's disease, are ineffective in the long term and often cause significant side effects, limiting their therapeutic efficacy and increasing in incidence over time.
Inhibition of the Rho kinase (ROCK) pathway using pharmaceutical compositions, such as fasudil and its derivatives, administered before and during L-dopa treatment to prevent and treat dyskinesia, reducing its occurrence and severity.
Reduces L-dopa-induced dyskinesia by approximately 50% in animal models, with minimal impact on the therapeutic effects of L-dopa, and provides neuroprotection against dopaminergic degeneration.
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Figure 2025169440000001_ABST
Abstract
Description
[Technical Field]
[0001] explanation For use in the preventive and / or therapeutic treatment of L-dopa-induced dyskinesia A pharmaceutical composition for
[0002] The present invention relates to the field of medicine, more specifically to the treatment of L-dopa-induced dyskinesia. The present invention relates to the use of a Rho kinase inhibitor for the treatment or prevention of rheumatoid arthritis. [Background technology]
[0003] Parkinson's disease (PD) is one of the most common neurodegenerative disorders in our population. This is primarily due to the dopaminergic neurons in the substantia nigra, although other neuronal systems are also involved. It is characterized by motor symptoms resulting from the degeneration of the vertebrae. Treatment for this condition consists of administering the dopamine precursor molecule L-dopa. Although these drugs are effective for the first few years, in the long term they can cause complications and side effects, especially dyskinesia. and cause side effects.
[0004] L-dopa-induced dyskinesia is characterized by choreic-type rapid involuntary movements and athetoid arthritis. These consist of multiple lesions, usually affecting the extremities and occasionally the face and neck area. Depending on the temporal pattern of expression, several forms of dyskinesia have been described: Peak-dose dyskinesia (coinciding with peak plasma levels of dopamine), biphasic dyskinesia These complications significantly reduce the therapeutic efficacy of L-dopa and Five years after the procedure, approximately 50% of patients It has been reported that 0% of patients have dyskinesia, and that this rate increases to 90% over 10 years. ru(Olanow CW,Stocchi F.Levodopa:A new loo k at an old friend.Mov Disord(2018)33(6) :859-866.doi:10.1002 / mds.27216).
[0005] The causes of dyskinesia are not fully understood, but the glutamatergic system is known to play an important role. In fact, The drug of choice is amantadine, an NMDA glutamate receptor antagonist. However, this compound is contraindicated in cases of renal failure, heart failure and psychiatric disorders, and complications, as well as and numerous side effects, such as confusion, difficulty concentrating, insomnia, loss of appetite, nausea, and psychiatric disorders (confusion). In the last decade, the incidence of L -Dopa is converted to dopamine by serotonergic terminals and released in an uncontrolled manner It has been demonstrated that other systems, such as the serotonergic system, are also involved. compounds that act at the serotonin receptor 5-HT1a, e.g., serotonin 5-HT1a receptor agonists (buspirone) , salitoxane, tandospirone) have shown anti-dyskinesia effects in preliminary studies, In some cases, these can pose problems as they can affect the anti-Parkinsonian response. For example, 5-HT1a / b agonists (eltoprazine and anpirtoline) It has a more favorable pharmacological profile than the former, but partially reduces the therapeutic effect of L-dopa It can be done. [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, it is more effective in combating dyskinesia with fewer side effects. There is a need to research and develop other preventative and / or therapeutic treatments for [Means for solving the problem]
[0008] The results presented herein demonstrate that inhibition of the RhoA / Rho kinase (ROCK) pathway: Dyskinesias may occur during chronic treatment with L-dopa in patients with Parkinson's disease. It is demonstrated that the present invention enables the treatment and / or prevention of nesia.
[0009] Thus, the present invention provides a preventive or therapeutic treatment for L-dopa-induced dyskinesia. and a pharmaceutical composition comprising a compound capable of inhibiting ROCK for use in a cancer treatment. Regarding.
[0010] The present invention further provides pharmaceutical compositions of ROCK inhibitors, their dosage forms for different administration routes, and Specific doses useful for preventing dyskinesia and those useful for treating dyskinesia and specific dosages. [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 in this description and claims, the term "ROCK pathway" refers to the GTP The enzyme RhoA protein and its associated kinases (also known as Rho-kinases) This refers to a pathway involving RhoA, which binds to a specific region of ROCK and activates it. ROCK phosphorylates various target proteins, including myosin light chain, and promotes cytoskeletal assembly. reorganizes cutin and regulates apoptotic events (Amin E, Dube y BN, Zhang SC, Gremer L, Dvorsky R, Moll JM , Taha MS, Nagel-Steger L, Piekorz RP, Somly o AV, Ahmadian MR (2013) Rho-kinase: regulation ion,(dys)function,and inhibition.Biol Ch em 394:1399-410.doi:10.1515 / hsz-2013-018 1) This pathway is thought to mediate inflammatory responses in certain diseases, including neurodegenerative disorders such as Parkinson's disease. ROCK also plays a role in the autophagy process, inhibiting this pathway. Injury leads to axon stabilization and induces neuroprotective effects. Different gene: ROCK I Two isoforms have been described, encoded by ROCK II and ROCK II. II is preferentially expressed in the brain (for review, see Labandeira-Garc (See ia et al., 2014).
[0013] As used in this description and claims, "capable of inhibiting the ROCK pathway" means The term "compound" refers to a compound that increases the activity of an enzyme relative to its corresponding control in which no inhibitor was administered. The term "anti-cancer drug" refers to a compound that can reduce the activity and expression level of a gene in a statistically significant manner. The authors have used various methods, such as enzyme immunoassay techniques (RIs) to detect phosphorylation of myosin. OCK Activity Assay kit; Cell Biolabs, Inc. The activity of the ROCK enzyme was measured by real-time Measurement of mRNA expression levels by PCR or protein expression by Western blot Such inhibition can be tested by measuring expression levels, etc. These techniques are This is described in detail in the following publications, which are incorporated herein by reference in their entirety: Rodrig uez-Perez AI, Dominguez-Meijide A, Lancieg o JL,Guerra MJ,Labandeira-Garcia JL.Inhi bition of Rho kinase mediates the neurop rotective effects of estrogen in the MPT P model of Parkinson's disease.Neurobiol Dis.2013 58:209-19.doi:10.1016 / j.nbd.20 13.06.004.
[0014] According to the present invention, compounds capable of inhibiting the ROCK pathway are those that directly or indirectly bind to R The OCK pathway can be regulated.
[0015] As used in this description and claims, "L-dopa-induced dyskinesia" means The term "a" refers to a mammal (e.g., a mammalian animal) that has Parkinson's disease and is being treated with L-dopa. It should be understood as an abnormal involuntary movement experienced by a person (e.g., a human).
[0016] In this study, the authors demonstrated that L- The effects of chronic dopa administration on the molecular level were investigated, and the levels of RhoA and ROCK It was demonstrated that the levels of α-glucan were elevated compared to controls (see Figure 1), indicating the activity of this pathway. In these conditions, at the functional level, rats were able to tolerate chronic L-dopa Based on these experiments, the ROCK pathway This is the first time that the relationship between activation of the ROCK pathway and dyskinesia has been demonstrated. Therefore, inhibition of the ROCK pathway may be effective against dyskinesia. Reduces established dyskinesias in animal models treated with GABA (in vitro). See Example 4) or in animal models where treatment with L-dopa has been initiated It has been demonstrated that it is possible to reduce the occurrence of nesia (see Example 2).
[0017] Thus, in one aspect, the present invention provides a preventative treatment for L-dopa-induced dyskinesia. or compounds capable of inhibiting the ROCK pathway for use in therapeutic treatment. The present invention relates to a pharmaceutical composition comprising:
[0018] In certain embodiments, the compositions of the present invention are administered intraperitoneally, orally, or by injection. It is administered in a suitable dosage form. In certain embodiments, injectable administration is by intramuscular, subcutaneous, intravenous, This includes 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-1332 4(Rhopressa), KD-025(Slx2119), LX7101, PG-3 24 (Roclatan), SAR407899.
[0020] In a preferred embodiment, the inhibitor of the ROCK pathway of interest of the present invention is fasudil. Thus, in certain embodiments, the present invention relates to the above-described pharmaceutical composition, wherein said compound The compound is fasudil, a pharmaceutically acceptable salt thereof, or a derivative thereof. In the form, the fasudil derivative is selected from hydroxyfasudil and dimethylfasudil. will be done.
[0021] The present invention also provides a method for administering fasudil to an animal model of Parkinson's disease before treatment with L-dopa. Furthermore, when fasudil is administered during treatment with L-dopa, dyskinesias are reduced. A preventive effect against nesia is achieved, and its occurrence is reduced through treatment. Furthermore, with acute administration of L-dopa and when dyskinesia is more pronounced, Treatment with fasudil was still effective and was significantly less severe than no treatment with fasudil. It has been demonstrated that the incidence of dyskinesia is reduced compared to that of placebo (see Example 2 and Figure 2).
[0022] Thus, in certain embodiments, the present invention provides a method for treating a patient suffering from atopic dermatitis, comprising: (i) administering to the patient a dose of 100 mg / kg of L-dopa prior to the initiation of treatment with L-dopa; (ii) administering a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially with each administration of L-dopa. and subsequently administering a therapeutically effective amount of said pharmaceutical composition to treat L-dopa-induced rheumatoid arthritis. The present invention relates to a pharmaceutical composition of the present invention for use in the preventive treatment of dyskinesia.
[0023] In certain embodiments, the present invention provides a method for preventing L-dopa-induced dyskinesia. wherein the patient has Parkinson's disease, and the method comprises treatment with L-dopa. A therapeutically effective amount of fasudil should be administered prior to the start of treatment and concurrently with each dose of L-dopa. and administering, either simultaneously or sequentially, a therapeutically effective amount of fasudil.
[0024] In certain embodiments, the present invention provides a method for the prophylactic treatment of L-dopa-induced dyskinesia. The present invention relates to a pharmaceutical composition of the present invention for use in
[0025] In this case, furthermore, at this dose, fasudil provides neuroprotection in Parkinson's disease patients. and slows dopaminergic degeneration, which has additional benefits (Villar-Che da B, Dominguez-Meijide A, Joglar B, Rodrig uez-Perez AI, Guerra MJ, Labandeira-Garcia J.L. (2012) Involvement of microglial RhoA / Rho-kinase pathway activation in the d opaminergic neuron death.Role of angiote nsin via angiotensin type 1 receptors.Ne urobiol Dis 47:268-79 doi:10.1016 / j.nbd. Furthermore, the administration of the composition of the present invention for preventing dyskinesia has been reported. The administration of fasudil has a favorable posology as described above, which also enhances the neuroprotective effects of fasudil (B orrajo A, Rodriguez-Perez AI, Villar-Cheda B, Guerra MJ, Labandeira-Garcia JL. (2014) Inhibition of the microglial response is essential for the neuroprotective effect Effects of Rho-kinase inhibitors on MPTP-indu ced dopaminergic cell death. Neuropharmac ology 85:1-8 doi:10.1016 / j.neuropharm.20 14.05.021; Villar-Cheda B, Dominguez-Meiji de A, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL. (2012) Involvemen t of microglial RhoA / Rho-kinase pathway activation in the dopaminergic neuron de ath. Role of angiotensin via angiotensin type 1 receptors. Neurobiol Dis 47:268-79 doi:10.1016 / j.nbd.2012.04.010; Labandeir a-Garcia JL, Rodriguez-Perez AI, Villar-Ch eda B, Borrajo A, Dominguez-Meijide A, Guer ra MJ. (2015) Rho Kinase and Dopaminergic Degeneration: A Promising Therapeutic Tar get for Parkinson’s Disease. Neuroscienti st 21:616-29 doi:10.1177 / 107385841455495 4).
[0026] In addition, the present invention relates to the The usefulness of the composition is also described. In Example 4, when dyskinesia is already established However, it has been demonstrated that a composition containing a ROCK inhibitor can reduce this. By increasing the dose of acetaminophen (40 mg / kg), dyskinesias were observed in patients already suffering from movement disorders. In animals treated regularly with L-dopa for 3-4 weeks, the reduction is approximately 50%. Dyskinesia may also occur after acute administration of L-dopa if it is accompanied by administration of the compositions of the present invention. In some cases, it is further reduced.
[0027] Thus, in certain embodiments, the present invention provides a method for administering L-dopa simultaneously or sequentially with each administration. and a method for treating L-dopa-induced dyspraxia, comprising administering a therapeutically effective amount of the pharmaceutical composition. The present invention relates to a pharmaceutical composition of the present invention for use in the therapeutic treatment of kinesia.
[0028] In certain embodiments, the present invention provides a method for treating L-dopa-induced dyskinesia. and a method for treating Parkinson's disease, wherein the patient has Parkinson's disease and the method comprises administering a dose of L-dopa to the patient. This involves administering a therapeutically effective amount of fasudil simultaneously or sequentially.
[0029] In certain embodiments, the present invention provides a method for the therapeutic treatment of L-dopa-induced dyskinesia. The present invention relates to a pharmaceutical composition of the present invention for use in
[0030] One of the preferred routes of administration in the present invention is injectable, and therefore certain In one embodiment, the present invention relates to the pharmaceutical composition as described above, wherein the dosage form contains L-dopa. Suitable for injectable administration for use in the prevention or treatment of dyskinesias induced by is doing.
[0031] Another preferred route of administration in the present invention is the oral route, and therefore certain In an embodiment, the present invention relates to the pharmaceutical composition described above, wherein the dosage form is L-dopa Suitable for oral administration for use in the prevention or treatment of dyskinesias induced by . [Example]
[0032] The following examples serve to illustrate the invention and do not represent limitations thereof. stomach.
[0033] Methods and experimental design In the following examples, the neurotoxin 6-hydroxybenzoate was administered following stereotactic surgery in the medial forebrain bundle. Sprague-Dawley rats injected with 6-hydroxydopamine (6-OHDA) This technique was used to study Parkinson's disease (PD) and its possible treatment pathways. The Ungerstedt U.6-Hydroxy -dopamine induced degeneration of centra l monoamine neurons.Eur J Pharmacol.(196 8)5(1):107-10;Cenci MA,Crossman AR.Anima l 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, L-dopa 6 mg / kg (therapeutic dose) and The animals were treated chronically with benserazide (10 mg / kg) for 3-4 weeks, during which time special Abnormal involuntary movements (AIM) were assessed using a variety of tests (Cenci MA, Lundbl ad M.Ratings of L-DOPA-induced dyskinesi a in the unilateral 6-OHDA lesion model of Parkinson's disease in rats and mice. Curr Protoc Neurosci.(2007)Chapter 9:Uni t 9.25.doi:10.1002 / 0471142301).
[0035] Example 1. Examination of a movement disorder model Animal models of PD were administered different doses until the level of dyskinesia stabilized (3-4 weeks). The animals were injected daily with L-dopa at doses of 6 mg / kg and 12 mg / kg. The striatum and substantia nigra were dissected and analyzed for RhoA by Western blot and real-time PCR. and the expression levels of ROCK were analyzed.
[0036] In movement-impaired animals, the levels of RhoA and ROCK proteins were significantly decreased. It was also observed that the higher the dose of L-dopa treated, the earlier and more effective the The increase in the levels of this protein was greater in animals that showed more severe dyskinesia. It was also observed that the
[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, the ROCK pathway inhibitor fasudil was administered at the start of L-dopa treatment. 10 mg / kg / day by intraperitoneal route, 30 minutes before each dose of L-dopa, starting 5 days before (but may be administered by oral route after appropriate adjustment of the dose) In addition to L-dopa, another group received fasudil at doses of 30 and 40 mg / kg / day as previously described. In all cases, treatment was carried out chronically for 3 weeks, and this During the period, abnormal involuntary movements were evaluated.
[0039] In animals treated with low doses of fasudil (10 mg / kg) and L-dopa, L-dopa A statistically significant reduction in the occurrence of dyskinesias was observed compared to animals treated with PG alone. The results were: a reduction of approximately 25% in dyskinesias in the limbs, a 30% reduction in oral and lingual dyskinesias, and a 35% reduction in dyskinesias in the oral and lingual dyskinesias. % axial reduction. Reduction of dyskinesia was observed from day 5 onwards.
[0040] Increasing doses of fasudil (30 mg / kg) reduced all of the analyzed movement disorder components. A greater reduction in dyskinesias was observed in the oral-lingual group (70%, axial-60%, and limb- 60%). When the fasudil dose was increased to 40 mg / kg, the reduction in dyskinesia was 70%. reached %.
[0041] At the end of treatment, the dose of L-dopa was increased to 24 mg / kg, and fasudil was administered to treat severe diazepam. We also tested whether it was effective in cases of skin irritation, and found a significant reduction of approximately 50%. was observed (see Figure 2).
[0042] This study demonstrated that dyskinesias can occur even when triggered by acute doses of L-dopa. Inhibitors of the ROCK pathway, such as fasudil, are useful for reducing the occurrence of dyskinesia. Demonstrate that this is the case.
[0043] Example 3. Study of the interaction between inhibition of the ROCK pathway and the therapeutic effects of L-dopa To investigate whether fasudil can interfere with the therapeutic effects of L-dopa, we investigated the effects of 6-OHD Analysis of movement asymmetries affecting animals after unilateral lesions by A. based cylinder test (Schallert T, Kozlowski DA, Humm JL, Co (cke RR. (1997) 73:229-38). In this study, all of the doses studied At doses (10, 30, and 40 mg / kg), fasudil-treated animals exhibited a significant reduction in L-dopa One hour after injection, the lesion-induced motor asymmetry was reversed, and the L-dopa alone was administered. No differences were observed compared to the animals treated with L-dopa, indicating that this compound does not alter the therapeutic effect of L-dopa. Furthermore, in experiments evaluating rotational behavior, different doses of No differences were observed in L-dopa-induced rotations in fasudil-treated animals. It was demonstrated that the reduction in skeletal muscle activity was not due to a decrease in motor activity (see Figure 3C-E). ).
[0044] This experiment demonstrated that the inhibition of the ROCK pathway by fasudil administration, even at high doses, was not associated with L- Demonstrate that it does not interfere with the therapeutic effects of dopa.
[0045] Example 4. Investigation of therapeutic effects Groups of animals with unilateral 6-OHDA lesions were treated with daily L-dopa for 3 weeks. However, when dyskinesia was already established, patients were treated with L-dopa and fasudil. We investigated whether inhibition of the OCK pathway reduces dyskinesia.
[0046] No improvement in animals was observed when a dose of 10 mg / kg / day of fasudil was used (Treatment up to 7 days).
[0047] However, when a fasudil dose of 40 mg / kg / day was used, the There was an approximately 45% reduction in dyskinesia.
[0048] The dose of L-dopa was increased to 24 mg / kg, which caused a severe dyskinetic state. When the α-glucan was added, the reduction was even greater, about 50%, which was maintained until the end of treatment (Figure 4 (See
Claims
1. For use in the prophylactic or therapeutic treatment of L-dopa-induced dyskinesia A pharmaceutical composition comprising a compound capable of inhibiting the ROCK pathway.
2. The compounds capable of inhibiting the ROCK pathway include fasudil and its derivatives, lipase inhibitors, and Suzil, Y-27632, Y-32885, AMA-0076, AR-12286, AR -13324 (Rhopressa), KD-025 (Slx2119), LX7101 PG-324 (Rocratan), SAR407899. and a pharmaceutical composition for the use thereof as described.
3. The compound capable of inhibiting the ROCK pathway is fasudil, its pharmaceutically acceptable derivatives, 2. The pharmaceutical composition for use thereof according to claim 1, wherein the compound is a salt thereof, or an analog thereof.
4. 4. The composition according to claim 1, wherein the composition is administered in a dosage form suitable for oral or injectable administration.
10. A composition for use thereof according to any one of claims 1 to 9.
5. For use in the prevention of L-dopa-induced dyskinesia, the compound Fasudil or a pharmaceutically acceptable salt thereof, the dosage form of which is oral or injectable.
2. A pharmaceutical composition for use thereof according to claim 1, suitable for administration.
6. (i) administering a therapeutically effective amount of said pharmaceutical composition prior to the initiation of treatment with L-dopa; (ii) a therapeutically effective amount of said pharmaceutical composition, either simultaneously or sequentially with each administration of L-dopa. and administering to said patient a dose of 100 mg of L-dopa-induced dyskinesia. The composition according to any one of claims 1 to 5.
7. The compound is fasudil or a pharmaceutically acceptable salt thereof, and the dosage form is oral or 7. The pharmaceutical composition for its use according to claim 6, which is suitable for injectable administration.
8. administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially with each administration of L-dopa. for use in the therapeutic treatment of L-dopa-induced dyskinesia, including administration of The composition according to any one of claims 1 to 5.
9. The compound is fasudil or a pharmaceutically acceptable salt thereof, and the dosage form is oral or 9. The pharmaceutical composition for its use according to claim 8, which is suitable for injectable administration.
10. For use in the treatment of L-dopa-induced dyskinesia, the compound Fasudil or a pharmaceutically acceptable salt thereof, the dosage form of which is oral or injectable.
2. A pharmaceutical composition for use thereof according to claim 1, suitable for administration.