Woolsey Pharmaceuticals, Inc.

Martin Pharmaceuticals, Inc.

Thomas MacAllister

Sven Jacobson

Qicai Liu

Hemant N Joshi

Sven M Jacobson

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.

Methods of using rho kinase inhibitors to treat alzheimer's disease

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.

Method of treating amyotrophic lateral sclerosis

The invention relates to the treatment of ascites, and especially refractory ascites, with an orally bioavailable prodrug of dopamine. A preferred prodrug of dopamine is docarpamine. The invention preferably contemplates intermittent dosing, wherein a treatment period is followed by an off-treatment period, which is followed by another treatment period.

Methods for treating ascites

The invention relates to the treatment of ascites, and especially refractory ascites, with an orally bioavailable prodrug of dopamine. A preferred prodrug of dopamine is docarpamine. In one embodiment treated patients are, prior to treatment, on doses of furosemide >80 mg/day and/or spironolactone >100 mg/day or equivalent doses of an alternative loop-acting and/or distal-acting diuretic. The ascites treated by the invention are typically caused by liver cirrhosis due to alcohol or non-alcoholic fatty liver disease and generally not due to viral hepatitis or primary biliary cholangitis. Typical patients have an activated renin-angiotensin-aldosterone levels as may be indicated by elevated levels of renin and/or aldosterone. Refractory ascites treatable according to the invention are such that patients beginning treatment require large volume paracentesis at a minimum of: (a) 3 times in 60 days, (b) 4 times in 90 days or (c) at least once every 30 days over a 90-day period. The invention also contemplates treating diuretic intractable ascites. Target plasma dopamine levels are disclosed by with dosing with the contemplated dopamine prodrugs may be guided. Preferred dosing is greater that 2250 mg per day, with more preferred doses exceeding 3500 mg per day.

Methods of treating ascites

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.

Taste-masking oral formulations of fasudil

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.

Oral formulations of fasudil with ion exchange resin

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.

Methods of treating agitation and other dementia-associated behavioral symptoms

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&#x2264;23 and/or a CDR-SOB score of&#x2265;4.5.

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.

Methods of treating cortical dementia 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.

Methods of treating wandering in Lewy dody dementia

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.

Methods of treating 4-repeat tauopathies

Disclosed is a stable oral liquid pharmaceutical composition of trimetazidine having a pH of about pH 4 to about pH 8, comprising a therapeutically effective amount of trimetazidine or a pharmaceutically acceptable salt thereof, one or more orally acceptable buffers, and one or more orally acceptable preservatives that is effective in said pH range. Also disclosed are methods of treating patients with stable oral liquid pharmaceutical composition. The pharmaceutical composition is particularly suitable for treating a patient having a condition treatable by trimetazidine, such as cirrhosis and renal deficiency, and who has a decreased tolerance for acidic or highly basic oral solutions.

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Arlington, VA, United States of America

Thomas MacAllister