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• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs

Definitions

• composition for use in the prophylactic and / or therapeutic treatment of dyskinesias induced by L-DOPA
• the present invention relates to the pharmaceutical field, more particularly to the use of Rho kinase inhibitors for the treatment or prevention of dyskinesias induced by L-DOPA.
• Parkinson's disease is one of the most frequent neurodegenerative diseases in our population. It is mainly characterized by motor symptoms that occur due to the degeneration of dopaminergic neurons in the substantia nigra, although other neuron systems are also involved.
• the usual and to date the most effective treatment for this disease consists of the administration of the precursor molecule of dopamine, L-DOPA. This drug is effective during the first years, but in the longer term it leads to complications and side effects, among which dyskinesias stand out.
• L-DOPA-induced dyskinesias consist of fast abnormal involuntary movements of the choreic type and athetosis, which usually affect the extremities and sometimes the facial and neck area.
• Various forms of dyskinesia have been described depending on the temporal pattern of expression: peak dose dyskinesias (coinciding with the highest plasma levels of dopamine), biphasic dyskinesias and dystonia in the “off” period. These complications can become disabling, since which greatly reduce the therapeutic effect of L-DOPA by limiting the daily activity of patients. It has been described that after 5 years of treatment around 50% of patients suffer from dyskinesias, while at 10 years the percentage rises to 90% (Olanow CW, Stocchi F. Levodopa: A new look at an o ⁇ d friend. Mov Disord (2016) 33 (6): 859-866. doi: 10.1002 / mds.27216).
• dyskinesias The causes involved in the development of dyskinesias are not fully known, although it is known that the glutamatergic system plays an important role.
• the The drug currently used to combat dyskinesias is amantadine, an antagonist of NMDA glutamate receptors.
• this compound is contraindicated in cases of kidney failure, heart and psychiatric problems and leads to patients developing complications and numerous side effects such as: lightheadedness, difficulty concentrating, insomnia, loss of appetite, nausea and psychiatric problems (confusion hallucinations , delirium syndrome, psychosis).
• the present invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a compound capable of inhibiting ROCK, for use in the prophylactic or therapeutic treatment of dyskinesias induced by L-DOPA.
• the present invention is further directed to pharmaceutical compositions of ROCK inhibitors, their pharmaceutical form for different routes of administration and to certain useful doses for the prevention of dyskinesias, as well as at certain doses useful for the treatment of dyskinesias.
• Figure 1 shows the effect of L-DOPA-induced dyskinesias on the RhoA / ROCK pathway in the substantia nigra (A-C) and striatum (D-F).
• L-DOPA L-DOPA-induced dyskinesias
• a significant increase in protein expression for RhoA and ROCK A, B
• activity for ROCK was observed.
• C in the substantia nigra
• D, E high dose
• significant differences were observed with both doses in the striatum.
• the results were normalized with respect to the values of the 6-OHDA injured animals treated with saline. Data represented as mean ⁇ SEM, t-Student * p ⁇ 0.05
• Figure 2 shows the abnormal involuntary movements (AIMs) observed after chronic treatment with L-DOPA (23 and 32 days) and different doses of Fasudil (10mg / kg; A, C, E and G and 30-40mg; B, D, F, H).
• AIMs abnormal involuntary movements
• Figure 3 shows the cylinder test in animals with unilateral dopaminergic lesion where ⁇ 20% of the use of the left limb is observed in basal conditions, and recovery of motor asymmetry after injection of L-DOPA at 60 and 90 min in control animals (only L-DOPA; black bars) and in those animals co-treated with Fasudil (gray bars) 10 mg / kg (A), 30 and 40 mg / kg (B). Rotational behavior was also not affected after treatment with Fasudil, indicating that the reduction in dyskinesias is not due to a reduction in motor activity (C-E). Data represented as mean ⁇ SEM, t-Student, * p ⁇ 0.05
• Figure 4 shows the effect of ROCK inhibition in animals with a stable degree of dyskinesia (chronic treatment with L-DOPA, 3 weeks).
• Fasudil at the low dose (10mg / kg, A) did not produce any effect on dyskinetic movements (A).
• high doses of the compound (30 and 40 mg / kg) resulted in a significant reduction in L-DOPA even with the high dose of L-DOPA (24 mg / kg) (B).
• Rho A As used in the description and the appended claims the term "ROCK pathway” refers to the pathway in which the RhoA GTPase protein and its associated kinase participate, (also known as Rho-kinase). Rho A binds to a specific ROCK region by activating it.
• ROCK phosphorylates various target proteins, including the myosin light chain, which acts by reorganizing the actin of the cytoskeleton and regulating apototic events (Amin E, Dubey BN, Zhang SC, Gremer L, Dvorsky R, Mol ⁇ 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 the inflammatory response in certain diseases, including neurodegenerative diseases such as Parkinson's disease.
• ROCK also acts in autophagy processes and the inhibition of this pathway produces axonal stabilization, leading to neuroprotective effects.
• Two isoforms encoded by different genes have been described: ROCK I and ROCK II.
• ROCK II is preferentially expressed in the brain (see as a review, Labandeira-Garcia et al., 2014).
• the term "compound capable of inhibiting the ROCK pathway” refers to a compound capable of reducing the activity of the enzyme and its expression levels in a statistically significant way with respect to its corresponding controls. those who have not been given the inhibitor.
• a person skilled in the art can test such inhibition through different methods, such as the measurement of the activity of the ROCK enzyme itself through enzyme-immunoassay techniques (ROCK Activity Assay kit; Cell Biolabs, Inc, San Diego, CA, USA) where myosin phosphorylation, mRNA expression levels are detected by real-time PCR or protein expression levels through Western Blot.
• a compound capable of inhibiting the ROCK pathway can directly or indirectly regulate the ROCK pathway.
• L-DOPA-induced dyskinesias is to be understood as abnormal involuntary movements experienced by a mammal (for example human) suffering from Parkinson's disease and being treated with L- DOPA.
• the authors have investigated the effect that chronic administration of L-DOPA produces at the molecular level in a rat model injured with 6-OHDA, demonstrating that the levels of Rho A and ROCK increased compared to the control (see Figure 1), which implies an activation of this pathway. Under these conditions, at the functional level the rats suffered dyskinesias caused by the chronic treatment of L-DOPA. On the basis of these experiments, a relationship between ROCK pathway activation and dyskinesias is demonstrated for the first time.
• the authors of the present invention have shown that the regulation of the ROCK pathway has an effect on dyskinesias, so that by inhibiting the ROCK pathway it is possible to reduce the dyskinesias already established in an animal model treated with L-DOPA (see example 4 ) or reduce the development of dyskinesias in an animal model that is started to be treated with L-DOPA (see example 2).
• the invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a compound capable of inhibiting the ROCK pathway, for use in the prophylactic or therapeutic treatment of dyskinesias induced by L-DOPA.
• composition of the invention is administered in a pharmaceutical form suitable for intraperitoneal, oral or injectable administration.
• injectable administration comprises intramuscular, subcutaneous, intravenous and intradermal administration.
• the ROCK inhibitor is selected from Fasudil and its derivatives, Ripasudil, Y-27632, Y-32885, AMA-0076, AR-12286, AR-13324 (Rhopressa), KD-025 (Slx2119), LX7101, PG-324 (Roclatan), SAR407899.
• an inhibitor of the ROCK pathway of interest for the present invention is Fasudil.
• the invention relates to the pharmaceutical composition described above, where said compound is Fasudil, a pharmaceutically acceptable salt thereof, or a derivative thereof.
• the Fasudil derivative is selected from Hydroxyfasudil and Dimethylfasudil.
• the present invention also describes that the administration of Fasudil to an animal model of Parkinson's prior to being treated with L-DOPA, and also if during the treatment with L-DOPA Fasudil is also administered, a preventive result of dyskinesias is achieved, reducing its development throughout the treatment.
• Fasudil is still effective reducing the development of dyskinesias compared to the case without treatment with Fasudil (see example 2 and figure 2).
• the invention relates to the pharmaceutical composition of the invention for use in the prophylactic treatment of dyskinesias induced by L-DOPA, comprising: (i) the administration of said pharmaceutical composition in a therapeutically effective amount prior to initiation of L-DOPA treatment, and (ii) the administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially to each administration of L-DOPA.
• the invention refers to a method to prevent dyskinesias induced by L-DOPA, where the patient is suffering from Parkinson's disease, the method comprises administering a therapeutically effective amount of Fasudil prior to the start of L-treatment. DOPA, and administering a therapeutically effective amount of Fasudil simultaneously or sequentially with each administration of L-DOPA.
• the invention is directed to a pharmaceutical composition of the invention for use in a prophylactic treatment of dyskinesias induced by L-DOPA.
• Fasudil provides neuroprotection to Parkinson's disease patients and stops 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).
• the administration of the composition of the invention for the prevention of dyskinesias has a preferred dosage as described above that also favors the neuroprotective effect 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.
• the present invention also describes the utility of the compositions of the present invention for the therapeutic treatment of dyskinesias induced by L-DOPA.
• example 4 it is shown that even in cases where dyskinesias are already established, the composition with a ROCK inhibitor is capable of reducing them.
• Fasudil 40mg / kg
• dyskinesias are reduced to almost 50% in those animals that are already dyskinetic (periodically treated with L-DOPA for 3-4 weeks).
• dyskinesias are more reduced when accompanied by the administration of the compositions of the invention.
• the invention relates to the pharmaceutical composition of the invention for use in the therapeutic treatment of dyskinesias induced by L-DOPA that comprises the administration of a therapeutically effective amount of said pharmaceutical composition simultaneously or sequentially to each administration. of L- DOPA.
• the invention refers to a method for the treatment of dyskinesias induced by L-DOPA, where the patient is suffering from Parkinson's disease, the method comprises administering a therapeutically effective amount of Fasudil simultaneously or sequentially to each administration of L-DOPA.
• the invention is directed to a pharmaceutical composition of the invention for use in a therapeutic treatment of dyskinesias induced by L-DOPA.
• One of the preferred routes of administration of the present invention is injectable, and thus in a particular embodiment the invention refers to the pharmaceutical composition as described above, the pharmaceutical form of which is suitable for injectable administration for use in the prevention or in the treatment of dyskinesias induced by L-DOPA.
• Another of the preferred routes of administration of the present invention is the oral route, and thus in a particular embodiment the invention refers to the pharmaceutical composition as described above, the pharmaceutical form of which is suitable for oral administration for use in the prevention or in the treatment of dyskinesias induced by L-DOPA.
• Example 1 Study of the dyskinetic model.
• a group of PD model animals was injected daily with different doses of L-DOPA (6mg / kg and 12mg / kg), until dyskinesia levels were stable (3-4 weeks).
• L-DOPA 6mg / kg and 12mg / kg
• the striatum and substantia nigra were dissected and the expression levels of RhoA and ROCK were analyzed by western blot and real-time PCR.
• a group of rats treated with L-DOPA as described above was used as a control.
• One group was administered, in addition to L-DOPA, a ROCK pathway inhibitor, Fasudil, at a dose of 10 mg / kg / day, intraperitoneally (although it could be administered orally by adjusting the dose appropriately), starting 5 days before starting treatment with L-DOPA, and 30 minutes before each L-DOPA administration.
• Another group was administered, in addition to L-DOPA, Fasudil at a dose of 30 and 40 mg / kg / day, intraperitoneally with the same frequency as the previous group. In all cases, the treatment was carried out chronically for 3 weeks, and during this period abnormal involuntary movements were evaluated.
• Fasudil When the dose of Fasudil was increased (30 mg / kg), a greater reduction in dyskinesias was observed in all dyskinetic components analyzed (70% orolingual, 60% axial and 60% limb). Increasing the dose of Fasudil to 40 mg / kg reduced dyskinesia up to 70%.
• the L-DOPA dose was raised to 24mg / kg to check if Fasudil is also effective in conditions of severe dyskinesia, observing a large significant reduction of approximately 50% (see figure 2).
• a group of animals with unilateral lesions with 6-OHDA were treated daily with L-DOPA for 3 weeks and then treated with L-DOPA and Fasudil to investigate whether inhibition of the ROCK pathway allows reducing dyskinesias once they are already established.
• a Fasudil dose of 10 mg / kg / day was used, no improvement was observed in the animals (up to 7 days of treatment).
• a Fasudil dose of 40 mg / kg / day was used, there was a reduction in dyskinesias of around 45% from the third day of treatment.
• Increasing the L-DOPA dose to 24 mg / kg causing a severe dyskinesia condition the reduction was even greater, of approximately 50%, which was maintained until the end of the treatment (see figure 4).

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