The present invention relates to the treatment of an ALS patient with oral trimetazidine. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A method of treating amyotrophic lateral sclerosis (ALS), includes: determining for a patient diagnosed with ALS, a pre-treatment amount of neurofilament light chain (NfL) in the patient's serum or plasma; orally administering to the patient a first rho kinase inhibitor in a predetermined amount for a predetermined period of time; determining a post-treatment amount of NfL in the patient's serum or plasma; when the post-treatment of amount of NfL is determined to be lower than the pre-treatment amount of NfL, orally administering to the patient a second rho kinase inhibitor in a therapeutically effective amount for treating ALS; and when the post-treatment of amount of NfL is determined to be not lower than the pre-treatment amount of NfL, withholding administration of the second rho kinase inhibitor to the patient.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
3.
Methods of Using RHO Kinase Inhibitors to Treat Alzheimer's Disease
Disclosed are methods of treating patients with AD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70-140 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 months. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ≤23 and/or a CDR-SOB score of ≥4.5.
A61K 9/00 - Medicinal preparations characterised by special physical form
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
4.
METHODS OF TREATING AMYOTROPHIC LATERAL SCLEROSIS BY ORAL ADMINISTRATION OF FASUDIL
A method includes treatment of a sporadic ALS patient with oral fasudil at a dose exceeding 240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
The present invention relates to the treatment of a sporadic ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
6.
METHODS OF TREATING SPORADIC CEREBRAL SMALL VESSEL DISEASE
The present disclosure provides a method for treating a patient diagnosed with sporadic small vessel disease with a therapeutically effect amount of a rho kinase inhibitor, including fasudil or hydroxyfasudil or a pharmaceutically acceptable salt thereof such as fasudil hydrochloride hemihydrate. Further disclosed are the dosages used for the treatment.
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61P 25/00 - Drugs for disorders of the nervous system
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61P 29/00 - Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agentsNon-steroidal antiinflammatory drugs [NSAID]
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
C07D 243/00 - Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
A taste-masking composition for pharmaceutical uses is provided comprising a rho kinase inhibitor, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste and being present at a concentration above a taste threshold concentration. The rho kinase inhibitor can comprise fasudil. The composition further comprises a taste-masking agent that masks the bitter taste. The taste-masking agent can partially or fully mask the bitter taste of the rho kinase inhibitor. The taste-masking agent can comprise one or more agents. The composition can be formulated to treat a neurodegenerative disease, for example one or more symptoms of such diseases such as wandering. A method of treating a neurodegenerative disease using such a composition is also provided. Methods of manufacturing the compositions of the present disclosure are further provided.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
An oral pharmaceutical composition is provided that can comprise a rho kinase inhibitor, for example, fasudil, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste; and an ion exchange resin. The ion exchange resin can partially or fully mask the bitter taste of the rho kinase inhibitor, making the composition more palatable. The composition can comprise a solid dosage form, and/or a liquid dosage form. The solid dosage form can comprise a powder, granules, a tablet, or a capsule, or any combination thereof. The composition can be present, for example, in a unit dose, in an amount sufficient to treat a neurodegenerative disease. A method of treating the neurodegenerative disease with the oral pharmaceutical composition is provided. The method can ameliorate a symptom of a neurodegenerative disease.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
Provided is a method of reducing caregiver burden associated with Alzheimer's disease by administering to an Alzheimer's disease patient a therapeutically effective amount of fasudil, or a salt or hydrate thereof. Doses of 90 to 180 mg/day of fasudil are contemplated for reducing caregiver burden.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61B 5/16 - Devices for psychotechnicsTesting reaction times
10.
METHODS OF TREATING AGITATION AND OTHER DEMENTIA-ASSOCIATED BEHAVIORAL SYMPTOMS
The invention is based on the discovery that rho kinase inhibitors, particularly fasudil can be used to treat agitation/anxiety in dementia patients, particularly Alzheimer's disease patients. Fasudil treatment of Alzheimer's patients resulted in improvements in agitation that are orders of magnitude to that observed with other potential therapeutic agents.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
The present invention relates to the treatment of a sporadic ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 31/192 - Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
A61K 31/575 - Compounds containing cyclopenta[a]hydrophenanthrene ring systemsDerivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
12.
METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS AND DOSING REGIMEN FOR SAME
The present invention relates to the treatment of an ALS patient with fausdil at a dose of 60-240 mg/day according to specific treatment regimens. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Disclosed is a method of treating patients with NOTCH3 mutation with rho kinase inhibitors. Aberrant NOTCH3 signaling is a pathological actor in small vessel cerebrovascular diseases, including CADASIL. A preferred aspect relates to treating patients orally with the rho kinase inhibitor fasudil or its active metabolite hydroxyfasudil.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
14.
METHODS OF TREATING TRAUMATIC ENCEPHALOPATHY SYNDROME
Disclosed is a method of treating traumatic encephalopathy syndrome (TES) in a patient in need thereof by administering a therapeutically effective amount of a rho-kinase inhibitor. In one embodiment, the rho-kinase inhibitor is fasudil.
A61K 31/395 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K 31/435 - 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
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
C07D 401/02 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
The present invention relates to the treatment patient with a 4-repeat (4R) tauopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Preferred 4R tauopathies treatable according to the invention include progressive supranuclear palsy with Richardson syndrome (PSP-RS) and corticobasal syndrome with probable sporadic corticobasal degeneration.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
16.
METHODS OF TREATING FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS BY ORAL ADMINISTRATION OF FASUDIL
A method includes treatment of a familial ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
17.
Oral formulations of fasudil with ion exchange resin
An oral pharmaceutical composition is provided that can comprise a rho kinase inhibitor, for example, fasudil, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste; and an ion exchange resin. The ion exchange resin can partially or fully mask the bitter taste of the rho kinase inhibitor, making the composition more palatable. The composition can comprise a solid dosage form, and/or a liquid dosage form. The solid dosage form can comprise a powder, granules, a tablet, or a capsule, or any combination thereof. The composition can be present, for example, in a unit dose, in an amount sufficient to treat a neurodegenerative disease. A method of treating the neurodegenerative disease with the oral pharmaceutical composition is provided. The method can ameliorate a symptom of a neurodegenerative disease.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 47/58 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
The invention relates to the treatment of patients with depression and or anxiety with high doses of rho kinase inhibitors. The maximum dose of a rho kinase inhibitor, based on fasudil hydrochloride as an exemplary agent, is more than 70 mg per day based on an immediate release formulation. Comparable dosing with other inhibitors is selected based on molar equivalents and/or rho kinase binding affinities. Treatable patients have one or more depressive disorders and/or one or more anxiety disorders.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
19.
TREATMENT OF THE CHRONIC EFFECTS OF BRAIN INJURY USING RHO KINASE INHIBITORS
Provided is a method for treating chronic effects of a brain injury, including stroke, using fasudil. The method comprises treating a patient beginning more than three months following the brain injury.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/18 - Antipsychotics, i.e. neurolepticsDrugs for mania or schizophrenia
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
G01N 33/68 - Chemical analysis of biological material, e.g. blood, urineTesting involving biospecific ligand binding methodsImmunological testing involving proteins, peptides or amino acids
The invention relates to the treatment of patients with depression and or anxiety with low doses of rho kinase inhibitors. The maximum dose of a rho kinase inhibitor, based on fasudil hydrochloride as an exemplary agent, is less than 60 mg per day based on an immediate release formulation. Comparable dosing with other inhibitors is selected based on molar equivalents and/or rho kinase binding affinities. Treatable patients have one or more depressive disorders and/or one or more anxiety disorders.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
21.
PREPARATION METHOD OF FASUDIL HYDROCHLORIDE HEMIHYDRATE
Disclosed are methods of synthesizing fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) and intermediates thereof.
C07D 217/16 - Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
C07D 217/02 - Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ringAlkylene-bis-isoquinolines
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
22.
METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS BY ORAL ADMINISTRATION OF FASUDIL
The present invention relates to the treatment of a sporadic ALS patient with oral fasudil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
The invention relates to the treatment of neurodevelopmental disorders using an inhibitor of rho kinase. Preferred methods contemplate the treatment of infants and children. Certain embodiments involve treating a neurodevelopmental disorder is caused by defects of metabolism, including defects of amino acid transport or metabolism, acid-base balance, carbohydrate transport or metabolism, metal homeostasis, neurotransmitter metabolism, or fatty acid transport or metabolism. Methods address a variety of conditions caused by changes in the genetic material that affect the structure and/or expression of certain genes. Preferred methods treat Down syndrome, Fragile X syndrome, oligophrenin 1 deficiency, Rett syndrome, autistic disorder, Asperger's syndrome, pervasive developmental disorder not otherwise specified, and other autism spectrum disorders.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
24.
TREATING AMYOTROPHIC LATERAL SCLEROSIS HAVING ONSET 24 MONTHS PRIOR TO TREATMENT
The present invention relates to the treatment of a ALS patient with oral fausdil at a dose of 180-240 mg/day, wherein the patient is treated beginning at least 24 months following disease onset. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
C07C 311/14 - Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
C07D 217/02 - Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ringAlkylene-bis-isoquinolines
25.
REGIMEN FOR TREATING AMYOTROPHIC LATERAL SCLEROSIS HAVING ONSET 24 MONTHS PRIOR TO TREATMENT
The present invention relates to the treatment of an ALS patient having disease onset of at least 24 months prior to initiation of treatment with fausdil. Fasudil is administered at a dose of 60-240 mg/day according to specific treatment regimens. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
C07C 311/14 - Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
C07D 217/02 - Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ringAlkylene-bis-isoquinolines
An oral pharmaceutical composition comprising a liposome is provided. The composition can comprise a plurality of liposomes. The liposome can comprise fasudil, alone or in combination with another rho kinase inhibitors, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof. The liposome can comprise a phospholipid and cholesterol. The oral pharmaceutical composition can be formulated as any desired dosage form or combination of dosage forms. The liposome can comprise a coating. A method is provided that can comprise administering to a patient a liposomal composition in an amount sufficient to treat the neurogenerative disease or a symptom thereof. Methods of forming fasudil-containing liposomes formulated for oral administration are also provided, for example, coated liposomes.
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
The present invention relates to the treatment of a sporadic ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
28.
METHODS OF USING RHO KINASE INHIBITORS TO TREAT FRONTOTEMPORAL DEMENTIA
The present invention relates to methods of treating frontotemporal dementia. The methods are preferably accomplished by treatment with a rho kinase inhibitor, such as fasudil or hydroxyfasudil. In particular, the invention contemplates treatment of the behavioral variant frontotemporal dementia and usually treatment begins once symptoms become evident. Usually, patients treated according to the invention have no neuromuscular symptoms and generally have not been diagnosed with amyotrophic lateral sclerosis, corticobasal degeneration, Parkinson's Disease or progressive supranuclear palsy. A preferred method of the invention involves oral treatment with fasudil, administered in a total daily dose of between 70 mg and 140 mg.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
29.
Oral formulations of fasudil with ion exchange resin
An oral pharmaceutical composition is provided that can comprise a rho kinase inhibitor, for example, fasudil, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste; and an ion exchange resin. The ion exchange resin can partially or fully mask the bitter taste of the rho kinase inhibitor, making the composition more palatable. The composition can comprise a solid dosage form, and/or a liquid dosage form. The solid dosage form can comprise a powder, granules, a tablet, or a capsule, or any combination thereof. The composition can be present, for example, in a unit dose, in an amount sufficient to treat a neurodegenerative disease. A method of treating the neurodegenerative disease with the oral pharmaceutical composition is provided. The method can ameliorate a symptom of a neurodegenerative disease.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 47/58 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
A taste-masking composition for pharmaceutical uses is provided comprising a rho kinase inhibitor, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste and being present at a concentration above a taste threshold concentration. The rho kinase inhibitor can comprise fasudil. The composition further comprises a taste-masking agent that masks the bitter taste. The taste-masking agent can partially or fully mask the bitter taste of the rho kinase inhibitor. The taste-masking agent can comprise one or more agents. The composition can be formulated to treat a neurodegenerative disease, for example one or more symptoms of such diseases such as wandering. A method of treating a neurodegenerative disease using such a composition is also provided. Methods of manufacturing the compositions of the present disclosure are further provided.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
Methods of treating subjects with age-related cognitive decline with a rho kinase inhibitor are disclosed. In a preferred embodiment, the rho kinase inhibitor is fasudil and it is administered orally in a daily dose of between 70 and 250 mg per day. Subjects have a cognitive impairment on a global cognitive scale, like the MoCA or the MMSE and/or specific impairments related to different cognitive domains. A method of reducing the rate of age-related cognitive decline, comprising administering to a subject with evidence of age-related cognitive decline an effective amount of a rho kinase inhibitor. The inventive methods slow the rate of cognitive decline and/or improve cognition from baseline in treated individuals. The methods may result in enhancing processing speed, increasing attention, improving memory, improving language, improving visual construction skills and/or improving executive function in subjects experiencing age-related cognitive decline.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
Methods of treating subjects with age-related cognitive decline with a rho kinase inhibitor are disclosed. In a preferred embodiment, the rho kinase inhibitor is fasudil and it is administered orally in a daily dose of between 30 and 60 mg per day. Subjects have a cognitive impairment on a global cognitive scale, like the MoCA or the MMSE and/or specific impairments related to different cognitive domains. A method of reducing the rate of age-related cognitive decline, comprising administering to a subject with evidence of age-related cognitive decline an effective amount of a rho kinase inhibitor. The inventive methods slow the rate of cognitive decline and/or improve cognition from baseline in treated individuals. The methods may result in enhancing processing speed, increasing attention, improving memory, improving language, improving visual construction skills and/or improving executive function in subjects experiencing age-related cognitive decline.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
33.
Methods of using rho kinase inhibitors to treat alzheimer's disease
Disclosed are methods of treating patients with AD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70-140 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 months. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of≤23 and/or a CDR-SOB score of≥4.5.
A61K 9/00 - Medicinal preparations characterised by special physical form
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
34.
METHODS OF USING RHO KINASE INHIBITORS TO TREAT VASCULAR DEMENTIA
Disclosed are methods of treating patients with VaD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70 - 180 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 or even 6 months or more. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ≤ 23.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 9/00 - Medicinal preparations characterised by special physical form
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
The present invention relates to the treatment of conditions associated with a proteinopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Proteinopathies preferably treated according to the invention involve aggregates of one or more of the following: amyloid beta, tau, Tar DNA Binding Protein 43 (TDP-43), Fused in sarcoma (FUS), α-synuclein, Huntingtin, Superoxide dismutase 1 (SOD-1), Prion proteins (PrP), mutant forms of Transthyretin, Atrophin 1 (ATN1), the Androgen receptor (AR), Ataxin 1 (ATXN1), Ataxin 2 (ATXN2), Ataxin 3 (ATXN3), Calcium Voltage-Gated Channel Subunit Alpha1 (ACACNA1A), Ataxin 7 (ATXN7), Protein Phosphatase 2 Regulatory Subunit Bbeta (PPP2R2B), and Tata Box Binding Protein (TBP).
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
36.
ORAL FORMULATIONS OF FASUDIL WITH ION EXCHANGE RESIN
An oral pharmaceutical composition is provided that can comprise a rho kinase inhibitor, for example, fasudil, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste; and an ion exchange resin. The ion exchange resin can partially or fully mask the bitter taste of the rho kinase inhibitor, making the composition more palatable. The composition can comprise a solid dosage form, and/or a liquid dosage form. The solid dosage form can comprise a powder, granules, a tablet, or a capsule, or any combination thereof. The composition can be present, for example, in a unit dose, in an amount sufficient to treat a neurodegenerative disease. A method of treating the neurodegenerative disease with the oral pharmaceutical composition is provided. The method can ameliorate a symptom of a neurodegenerative disease.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A taste-masking composition for pharmaceutical uses is provided comprising a rho kinase inhibitor, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste and being present at a concentration above a taste threshold concentration. The rho kinase inhibitor can comprise fasudil. The composition further comprises a taste-masking agent that masks the bitter taste. The taste-masking agent can partially or fully mask the bitter taste of the rho kinase inhibitor. The taste-masking agent can comprise one or more agents. The composition can be formulated to treat a neurodegenerative disease, for example one or more symptoms of such diseases such as wandering. A method of treating a neurodegenerative disease using such a composition is also provided. Methods of manufacturing the compositions of the present disclosure are further provided.
A taste-masking composition for pharmaceutical uses is provided comprising a rho kinase inhibitor, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste and being present at a concentration above a taste threshold concentration. The rho kinase inhibitor can comprise fasudil. The composition further comprises a taste-masking agent that masks the bitter taste. The taste-masking agent can partially or fully mask the bitter taste of the rho kinase inhibitor. The taste-masking agent can comprise one or more agents. The composition can be formulated to treat a neurodegenerative disease, for example one or more symptoms of such diseases such as wandering. A method of treating a neurodegenerative disease using such a composition is also provided. Methods of manufacturing the compositions of the present disclosure are further provided.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
The invention is based on the discovery that rho kinase inhibitors can be used to treat certain dementia-associated wandering. The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with cortical dementia-associated wandering. Preferred aspects of the invention contemplate treating wandering due to cortical vascular dementia and wandering due to dementia where the patient is a persistent wanderer and/or where the patient does not display a wayfinding defect.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
40.
METHODS OF TREATING PROTEINOPATHY ASSOCIATED WANDERING
The invention is based on the discovery that rho kinase inhibitors can be used to treat proteinopathy associated wandering. A number of degenerative neurological diseases are thought to be caused, at least in part, by the formation of protein aggregates that cause neurotoxicity and progressive decline in function. The inventive methods related to the use of rho kinase inhibitors in the treatment of patients with proteinopathy-associated wandering. The patients may be suffering from Huntington's disease, a traumatic brain injury, autism spectrum disorder, Down syndrome or a proteinopathy-associated dementia, such as Alzheimer disease or frontotemporal dementia.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
41.
Methods of treating agitation and other dementia-associated behavioral symptoms
The invention is based on the discovery that rho kinase inhibitors, particularly fasudil can be used to treat agitation/anxiety in dementia patients, particularly Alzheimer's disease patients. Fasudil treatment of Alzheimer's patients resulted in improvements in agitation that are orders of magnitude to that observed with other potential therapeutic agents.
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 9/00 - Medicinal preparations characterised by special physical form
42.
Methods of using rho kinase inhibitors to treat alzheimer's disease
Disclosed are methods of treating patients with AD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70-140 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 months. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ≤23 and/or a CDR-SOB score of ≥4.5.
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 9/00 - Medicinal preparations characterised by special physical form
43.
METHODS OF TREATING AGITATION AND OTHER DEMENTIA-ASSOCIATED BEHAVIORAL SYMPTOMS
The invention is based on the discovery that rho kinase inhibitors, particularly fasudil can be used to treat agitation/anxiety in dementia patients, particularly Alzheimer's disease patients. Fasudil treatment of Alzheimer's patients resulted in improvements in agitation that are orders of magnitude to that observed with other potential therapeutic agents.
A61K 31/395 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K 31/40 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
A61K 31/403 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
44.
METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS AND DOSING REGIMEN FOR SAME
The present invention relates to the treatment of an ALS patient with fausdil at a dose of 60-240 mg/day according to specific treatment regimens. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
The present invention relates to the treatment of a sporadic ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 31/472 - Non-condensed isoquinolines, e.g. papaverine
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
The present invention relates to the treatment of a sporadic ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
47.
METHODS OF TREATING PSEUDOBULBAR AFFECT AND OTHER EMOTIONAL DISTURBANCES
The invention is based on the discovery that rho kinase inhibitors can be used to treat pseudobulbar affect (PBA). The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with PBA. Preferred aspects of the invention contemplate treating PBA due to dementia, especially cortical dementia, such as AD, FTD and cortical vascular dementia.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
The invention relates to the treatment of patients with depression and or anxiety with high doses of rho kinase inhibitors. The maximum dose of a rho kinase inhibitor, based on fasudil hydrochloride as an exemplary agent, is more than 70 mg per day based on an immediate release formulation. Comparable dosing with other inhibitors is selected based on molar equivalents and/or rho kinase binding affinities. Treatable patients have one or more depressive disorders and/or one or more anxiety disorders.
A61K 31/192 - Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
The invention relates to the treatment of patients with depression and or anxiety with low doses of rho kinase inhibitors. The maximum dose of a rho kinase inhibitor, based on fasudil hydrochloride as an exemplary agent, is less than 60 mg per day based on an immediate release formulation. Comparable dosing with other inhibitors is selected based on molar equivalents and/or rho kinase binding affinities. Treatable patients have one or more depressive disorders and/or one or more anxiety disorders
A61K 31/192 - Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
The present invention relates to the treatment patient with a 4-repeat (4R) tauopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Preferred 4R tauopathies treatable according to the invention include progressive supranuclear palsy with Richardson syndrome (PSP-RS) and corticobasal syndrome with probable sporadic corticobasal degeneration.
The present invention relates to the treatment patient with a 4-repeat (4R) tauopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Preferred 4R tauopathies treatable according to the invention include progressive supranuclear palsy with Richardson syndrome (PSP-RS) and corticobasal syndrome with probable sporadic corticobasal degeneration.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
Methods of treating subjects with age-related cognitive decline with a rho kinase inhibitor are disclosed. In a preferred embodiment, the rho kinase inhibitor is fasudil and it is administered orally in a daily dose of between 70 and 250 mg per day. Subjects have a cognitive impairment on a global cognitive scale, like the MoCA or the MMSE and/or specific impairments related to different cognitive domains. A method of reducing the rate of age-related cognitive decline, comprising administering to a subject with evidence of age-related cognitive decline an effective amount of a rho kinase inhibitor. The inventive methods slow the rate of cognitive decline and/or improve cognition from baseline in treated individuals. The methods may result in enhancing processing speed, increasing attention, improving memory, improving language, improving visual construction skills and/or improving executive function in subjects experiencing age-related cognitive decline.
Methods of treating subjects with age-related cognitive decline with a rho kinase inhibitor are disclosed. In a preferred embodiment, the rho kinase inhibitor is fasudil and it is administered orally in a daily dose of between 30 and 60 mg per day. Subjects have a cognitive impairment on a global cognitive scale, like the MoCA or the MMSE and/or specific impairments related to different cognitive domains. A method of reducing the rate of age-related cognitive decline, comprising administering to a subject with evidence of age-related cognitive decline an effective amount of a rho kinase inhibitor. The inventive methods slow the rate of cognitive decline and/or improve cognition from baseline in treated individuals. The methods may result in enhancing processing speed, increasing attention, improving memory, improving language, improving visual construction skills and/or improving executive function in subjects experiencing age-related cognitive decline.
The present invention relates to the treatment of conditions associated with a proteinopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Proteinopathies preferably treated according to the invention involve aggregates of one or more of the following: amyloid beta, tau, Tar DNA Binding Protein 43 (TDP-43), Fused in sarcoma (FUS), α-synuclein, Huntingtin, Superoxide dismutase 1 (SOD-1), Prion proteins (PrP), mutant forms of Transthyretin, Atrophin 1 (ATN1), the Androgen receptor (AR), Ataxin 1 (ATXN1), Ataxin 2 (ATXN2), Ataxin 3 (ATXN3), Calcium Voltage-Gated Channel Subunit Alpha1 (ACACNA1A), Ataxin 7 (ATXN7), Protein Phosphatase 2 Regulatory Subunit Bbeta (PPP2R2B), and Tata Box Binding Protein (TBP).
The invention relates to the treatment of neurodevelopmental disorders using an inhibitor of rho kinase. Preferred methods contemplate the treatment of infants and children. Certain embodiments involve treating a neurodevelopmental disorder is caused by defects of metabolism, including defects of amino acid transport or metabolism, acid-base balance, carbohydrate transport or metabolism, metal homeostasis, neurotransmitter metabolism, or fatty acid transport or metabolism. Methods address a variety of conditions caused by changes in the genetic material that affect the structure and/or expression of certain genes. Preferred methods treat Down syndrome, Fragile X syndrome, oligophrenin 1 deficiency, Rett syndrome, autistic disorder, Asperger's syndrome, pervasive developmental disorder not otherwise specified, and other autism spectrum disorders.
Disclosed are methods of treating patients with VaD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70 – 180 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 or even 6 months or more. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ≤ 23.
Disclosed are methods of treating patients with AD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70-140 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 months. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ≤ 23 and/or a CDR-SOB score of ≥ 4.5.
The invention is based on the discovery that rho kinase inhibitors can be used to treat proteinopathy associated wandering. A number of degenerative neurological diseases are thought to be caused, at least in part, by the formation of protein aggregates that cause neurotoxicity and progressive decline in function. The inventive methods related to the use of rho kinase inhibitors in the treatment of patients with proteinopathy-associated wandering. The patients may be suffering from Huntington's disease, a traumatic brain injury, autism spectrum disorder, Down syndrome or a proteinopathy-associated dementia, such as Alzheimer disease or frontotemporal dementia.
A61K 31/407 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with heterocyclic ring systems, e.g. ketorolac, physostigmine
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
The invention is based on the discovery that rho kinase inhibitors can be used to treat proteinopathy associated wandering. A number of degenerative neurological diseases are thought to be caused, at least in part, by the formation of protein aggregates that cause neurotoxicity and progressive decline in function. The inventive methods related to the use of rho kinase inhibitors in the treatment of patients with proteinopathy-associated wandering. The patients may be suffering from Huntington's disease, a traumatic brain injury, autism spectrum disorder, Down syndrome or a proteinopathy-associated dementia, such as Alzheimer disease or frontotemporal dementia.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
60.
METHODS OF USING RHO KINASE INHIBITORS TO TREAT FRONTOTEMPORAL DEMENTIA
The present invention relates to methods of treating frontotemporal dementia. The methods are preferably accomplished by treatment with a rho kinase inhibitor, such as fasudil or hydroxyfasudil. In particular, the invention contemplates treatment of the behavioral variant frontotemporal dementia and usually treatment begins once symptoms become evident. Usually, patients treated according to the invention have no neuromuscular symptoms and generally have not been diagnosed with amyotrophic lateral sclerosis, corticobasal degeneration, Parkinson's Disease or progressive supranuclear palsy. A preferred method of the invention involves oral treatment with fasudil, administered in a total daily dose of between 70 mg and 140 mg.
The invention is based on the discovery that rho kinase inhibitors can be used to treat pseudobulbar affect (PBA). The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with PBA. Preferred aspects of the invention contemplate treating PBA due to dementia, especially cortical dementia, such as AD, FTD and cortical vascular dementia.
The invention is based on the discovery that rho kinase inhibitors can be used to treat certain dementia-associated wandering. The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with cortical dementia-associated wandering. Preferred aspects of the invention contemplate treating wandering due to cortical vascular dementia and wandering due to dementia where the patient is a persistent wanderer and/or where the patient does not display a wayfinding defect.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
63.
METHODS OF TREATING CORTICAL DEMENTIA ASSOCIATED WANDERING
The invention is based on the discovery that rho kinase inhibitors can be used to treat certain dementia-associated wandering. The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with cortical dementia-associated wandering. Preferred aspects of the invention contemplate treating wandering due to cortical vascular dementia and wandering due to dementia where the patient is a persistent wanderer and/or where the patient does not display a wayfinding defect.
A61K 31/407 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with heterocyclic ring systems, e.g. ketorolac, physostigmine
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Methods of treating subjects with age-related cognitive decline with a rho kinase inhibitor are disclosed. In a preferred embodiment, the rho kinase inhibitor is fasudil and it is administered orally in a daily dose of between 70 and 250 mg per day. Subjects have a cognitive impairment on a global cognitive scale, like the MoCA or the MMSE and/or specific impairments related to different cognitive domains. A method of reducing the rate of age-related cognitive decline, comprising administering to a subject with evidence of age-related cognitive decline an effective amount of a rho kinase inhibitor. The inventive methods slow the rate of cognitive decline and/or improve cognition from baseline in treated individuals. The methods may result in enhancing processing speed, increasing attention, improving memory, improving language, improving visual construction skills and/or improving executive function in subjects experiencing age-related cognitive decline.
The present invention relates to the treatment of an ALS patient with fausdil at a dose of 60-240 mg/day according to specific treatment regimens. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A taste-masking composition for pharmaceutical uses is provided comprising a rho kinase inhibitor, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste and being present at a concentration above a taste threshold concentration. The rho kinase inhibitor can comprise fasudil. The composition further comprises a taste-masking agent that masks the bitter taste. The taste-masking agent can partially or fully mask the bitter taste of the rho kinase inhibitor. The taste-masking agent can comprise one or more agents. The composition can be formulated to treat a neurodegenerative disease, for example one or more symptoms of such diseases such as wandering. A method of treating a neurodegenerative disease using such a composition is also provided. Methods of manufacturing the compositions of the present disclosure are further provided.
The invention is based on the discovery that rho kinase inhibitors can be used to treat certain dementia-associated wandering. The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with cortical dementia-associated wandering. Preferred aspects of the invention contemplate treating wandering due to cortical vascular dementia and wandering due to dementia where the patient is a persistent wanderer and/or where the patient does not display a wayfinding defect.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
68.
METHODS OF TREATING PSEUDOBULBAR AFFECT AND OTHER EMOTIONAL DISTURBANCES
The invention is based on the discovery that rho kinase inhibitors can be used to treat pseudobulbar affect (PBA). The inventive methods relate to the use of rho kinase inhibitors in the treatment of patients with PBA. Preferred aspects of the invention contemplate treating PBA due to dementia, especially cortical dementia, such as AD, FTD and cortical vascular dementia.
The present invention relates to methods of treating frontotemporal dementia. The methods are preferably accomplished by treatment with a rho kinase inhibitor, such as fasudil or hydroxyfasudil. In particular, the invention contemplates treatment of the behavioral variant frontotemporal dementia and usually treatment begins once symptoms become evident. Usually, patients treated according to the invention have no neuromuscular symptoms and generally have not been diagnosed with amyotrophic lateral sclerosis, corticobasal degeneration, Parkinson's Disease or progressive supranuclear palsy. A preferred method of the invention involves oral treatment with fasudil, administered in a total daily dose of between 70 mg and 140 mg.
The invention is based on the discovery that rho kinase inhibitors can be used to treat proteinopathy associated wandering. A number of degenerative neurological diseases are thought to be caused, at least in part, by the formation of protein aggregates that cause neurotoxicity and progressive decline in function. The inventive methods related to the use of rho kinase inhibitors in the treatment of patients with proteinopathy-associated wandering. The patients may be suffering from Huntington's disease, a traumatic brain injury, autism spectrum disorder, Down syndrome or a proteinopathy-associated dementia, such as Alzheimer disease or frontotemporal dementia.
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
Disclosed are methods of treating patients with AD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70-140 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 months. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ? 23 and/or a CDR-SOB score of ? 4.5.
Disclosed are methods of treating patients with VaD using a rho kinase inhibitor. A preferred rho kinase inhibitor used according to the invention is fasudil, which is typically administered orally in a total daily dose of 70 ? 180 mg. A preferred dosing regimen involves administering the daily dose in three equal portions throughout the day. Preferred methods continue for more than one month and typically at least 2 or 3 or even 6 months or more. Some preferred methods do not treat mild cognitive impairment and patients have and MMSE score of ? 23.
The invention relates to the treatment of neurodevelopmental disorders using an inhibitor of rho kinase. Preferred methods contemplate the treatment of infants and children. Certain embodiments involve treating a neurodevelopmental disorder is caused by defects of metabolism, including defects of amino acid transport or metabolism, acid-base balance, carbohydrate transport or metabolism, metal homeostasis, neurotransmitter metabolism, or fatty acid transport or metabolism. Methods address a variety of conditions caused by changes in the genetic material that affect the structure and/or expression of certain genes. Preferred methods treat Down syndrome, Fragile X syndrome, oligophrenin 1 deficiency, Rett syndrome, autistic disorder, Asperger's syndrome, pervasive developmental disorder not otherwise specified, and other autism spectrum disorders.
The present invention relates to the treatment of conditions associated with a proteinopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Proteinopathies preferably treated according to the invention involve aggregates of one or more of the following: amyloid beta, tau, Tar DNA Binding Protein 43 (TDP-43), Fused in sarcoma (FUS), ?-synuclein, Huntingtin, Superoxide dismutase 1 (SOD-1), Prion proteins (PrP), mutant forms of Transthyretin, Atrophin 1 (ATN1), the Androgen receptor (AR), Ataxin 1 (ATXN1), Ataxin 2 (ATXN2), Ataxin 3 (ATXN3), Calcium Voltage-Gated Channel Subunit Alpha1 (ACACNA1A), Ataxin 7 (ATXN7), Protein Phosphatase 2 Regulatory Subunit Bbeta (PPP2R2B), and Tata Box Binding Protein (TBP).
Methods of treating subjects with age-related cognitive decline with a rho kinase inhibitor are disclosed. In a preferred embodiment, the rho kinase inhibitor is fasudil and it is administered orally in a daily dose of between 30 and 60 mg per day. Subjects have a cognitive impairment on a global cognitive scale, like the MoCA or the MMSE and/or specific impairments related to different cognitive domains. A method of reducing the rate of age-related cognitive decline, comprising administering to a subject with evidence of age-related cognitive decline an effective amount of a rho kinase inhibitor. The inventive methods slow the rate of cognitive decline and/or improve cognition from baseline in treated individuals. The methods may result in enhancing processing speed, increasing attention, improving memory, improving language, improving visual construction skills and/or improving executive function in subjects experiencing age-related cognitive decline.
The present invention relates to the treatment patient with a 4-repeat (4R) tauopathy using a therapeutically effect amount of a rho kinase inhibitor. One preferred inhibitor is fasudil and preferred methods involve the daily oral administration of between 20 and 250 mg of fasudil. Preferred 4R tauopathies treatable according to the invention include progressive supranuclear palsy with Richardson syndrome (PSP-RS) and corticobasal syndrome with probable sporadic corticobasal degeneration.
The present invention relates to the treatment of a sporadic ALS patient with oral fausdil at a dose of 180-240 mg/day. This results in an anticipated 25-50% reduction in the average decline over at least three months as measured using the revised ALS Functional Rating Scale.
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
78.
METHODS OF TREATING AGITATION AND OTHER DEMENTIA-ASSOCIATED BEHAVIORAL SYMPTOMS
The invention is based on the discovery that rho kinase inhibitors, particularly fasudil can be used to treat agitation/anxiety in dementia patients, particularly Alzheimer's disease patients. Fasudil treatment of Alzheimer's patients resulted in improvements in agitation that are orders of magnitude to that observed with other potential therapeutic agents.
A61K 31/395 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K 31/40 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
A61K 31/403 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
79.
ORAL FORMULATIONS OF FASUDIL WITH ION EXCHANGE RESIN
An oral pharmaceutical composition is provided that can comprise a rho kinase inhibitor, for example, fasudil, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, the rho kinase inhibitor having a bitter taste; and an ion exchange resin. The ion exchange resin can partially or fully mask the bitter taste of the rho kinase inhibitor, making the composition more palatable. The composition can comprise a solid dosage form, and/or a liquid dosage form. The solid dosage form can comprise a powder, granules, a tablet, or a capsule, or any combination thereof. The composition can be present, for example, in a unit dose, in an amount sufficient to treat a neurodegenerative disease. A method of treating the neurodegenerative disease with the oral pharmaceutical composition is provided. The method can ameliorate a symptom of a neurodegenerative disease.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
C07C 311/14 - Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
C07D 217/02 - Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ringAlkylene-bis-isoquinolines
81.
METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS BY ORAL ADMINISTRATION OF FASUDIL
patents
