How to use RHO kinase inhibitors to treat Alzheimer's disease

Abstract

This invention provides a method for treating patients with Alzheimer's disease (AD). [Solution] A method for treating patients with AD using a rho kinase inhibitor is disclosed. The preferred rho kinase inhibitor used according to the present invention is fasudil, typically administered orally at a total daily dose of 70-140 mg. The preferred administration regimen involves administering the daily dose in three equal parts throughout the day. The preferred method is continued for more than one month, typically for at least two or three months. Some preferred methods do not treat mild cognitive impairment, and the patient has an MMSE score of ≤23 and / or a CDR-SOB score of ≥4.5.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority from U.S. Provisional Application No. 63 / 014,272, filed on April 23, 2020, the disclosure of which is incorporated herein in its entirety.

Background Art

[0002] Alzheimer's disease (AD), which affects nearly 50 million people worldwide, is a chronic neurodegenerative disease that accounts for more than 70% of dementia cases. Approximately 95% of cases are sporadic and symptoms appear after the age of 70. Aging is the most important risk factor associated with the onset of AD. A very small fraction of cases, characterized by early onset before approximately 50 years old, are considered to have a genetic background and are familial.

[0003] AD patients develop cognitive changes, namely progressive episodic memory impairment, which ultimately leads to the loss of patient autonomy. Cognitive symptoms may include mental decline, difficulty in thinking and understanding, nocturnal confusion, delusions, disorientation, forgetfulness, confabulation, mental confusion, difficulty in concentration, inability to form new memories, inability to perform simple calculations, or inability to recognize common things. Behavioral symptoms may include aggression, agitation, difficulty in self - care, irritability, repetitive meaningless utterances of one's own words, personality changes, restlessness, lack of inhibition, or wandering and getting lost. AD patients may also experience anger, fatigue, general dissatisfaction, loneliness, mood swings, depression, hallucinations, delusions, involuntary muscle movements, disjointed speech, or loss of appetite.

[0004] Two characteristic pathological findings of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques occur extracellularly, outside of neurons, and consist of aggregated amyloid-beta (Aβ) protein derived from amyloid precursor protein (APP). The normal functional roles of Aβ and APP are unknown, although APP may be involved in synaptic function. NFTs are found within neurons themselves and consist of phosphorylated aggregated tau protein. Tau is normally involved in stabilizing microtubules in the neuronal axon.

[0005] Based on our understanding of genes involved in familial diseases, Aβ is thought to initiate the neurodegenerative process by inducing tau pathology, neuroinflammation, and ultimately, neuronal loss that leads to cognitive decline.

[0006] The role of neuroinflammation in Alzheimer's disease (AD) is unclear. While it may be beneficial in the early stages of the disease, it can develop into a harmful factor through participation in the cycle of pro-inflammatory cytokine production and oxidative stress.

[0007] A central issue with interventions targeting any of these processes is the relevance to causal relationships. For an intervention to be helpful in treating the disease, it needs to break the chain of causality. While Aβ, tau, and neuroinflammation are certainly associated with AD, it is unclear whether they are involved in the causal relationship, and therefore it is unknown whether influencing any of these would have any therapeutic benefit in treating the disease.

[0008] Based on the hypothesis that Aβ initiates the AD protein disorder cascade and is the first point in the causal chain, this is the most studied clinical target. However, despite the overwhelming literature showing promise in animal models, no product has been shown to function in AD (Ceyzeriat 2020). Among the many that have failed are anti-Aβ42+ Freund's adjuvant, bapineuzumab, solanezumab, aducanumab, verbecestat, lanabesestat, atabesestat, CNP520, elenbecestat, γ-secretase inhibitors, bryostatin, and PBT2.

[0009] Because there is evidence that tau is downstream of Aβ, it is less likely to be targeted, and therefore not the causative agent, resulting in a low frequency of clinical trials targeting it. Notably, of the 15 tau-targeted clinical trials that have been initiated, four have already been stopped.

[0010] Neuroinflammation is the most rapidly evolving area in current clinical research, yet the role of neuroinflammation in Alzheimer's disease (AD), and therefore neuroinflammation-oriented therapy, remains unclear. Epidemiological studies suggest that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of developing AD and decrease amyloid load in transgenic models, but predictive studies testing anti-inflammatory drugs to date have not shown beneficial effects on cognition in AD. While research targeting neuroinflammation is ongoing, early results have been unpromising. Neframapimod, a selective inhibitor of p38 mitogen-activated protein kinase, showed efficacy in animal models, but was ineffective against Aβ deposition in humans and failed to meet its primary endpoint of improved episodic memory in phase 2, despite reducing tau in cerebrospinal fluid.

[0011] Given the number of clinical failures of compounds that appeared promising in animal models of Alzheimer's disease (AD), a serious degree of skepticism should be applied to the interpretation of animal data. Even setting aside the obvious problem of differences in brain complexity between rodents and humans, many of the existing models only provisionally carry similarities to the human condition. Many things can cause neurodegeneration in animals, and many putative drugs can halt that neurodegeneration, but the underlying pathophysiology and causal chains remain unclear, which is where disease-modifying interventions need to act. Therefore, it is important that animal models with known deficiencies in the best cases, both pathologically and clinically, are as similar as possible to the human disease.

[0012] Several publications focus on the use of rho kinase inhibitors in various animal models of AD. Established models lack even basic characteristics. Some models involve directly inducing neurotoxicity with drugs like streptozotocin, or even directly injecting amyloid-beta into the brain. While these models may exhibit certain AD-like characteristics, they are merely models of neurodegeneration and cannot predict treatments for AD itself. Even transgenic models are inadequate. For example, there are several transgenic mice that develop only amyloid plaques without NFTs, such as the APP / PS-1 mouse, perhaps the most widely reported transgenic model. There are also mice that develop tauopathy without amyloid plaques, such as the rTG4510 tau mouse. AD is characterized by the presence of both.

[0013] Specifically, animal models do not faithfully reproduce human diseases, partly due to species differences in neuroanatomy (Sasaguri 2017) and partly due to deficiencies in the fundamental pathological basis of the models mentioned above. It is also important to note that a characteristic feature of AD onset is a failure of semantic memory, which cannot be measured in any animal model, so all animal models share this deficiency. For example, Hamano et al., 2019 administered 12 mg / kg / day (68 mg HED) to rTG4510 tau transgenic mice and measured only tau phosphorylation / cleavage and oligomers, but did not describe the outcome. Elliott 2018 used a triple transgenic mouse model (APP Swedish, MAPT P301L, and PSEN1 M146V) and observed in vivo reduction of β-amyloid plaques with a dose of 10 mg / kg / day (intraperitoneal) fasudil (57 mg HED). Sellers 2018 used an AB42 mouse model and administered fasudil intraperitoneally at a dose of 10 mg / kg BID (226 mg HED), but only monitored β-amyloid dendritic spine loss. Couch et al. 2010 used intraventricular injection to observe the effect on dendritic branching, but did not describe outcomes related to wandering. Yu 2017 and Hou 2012 administered 5 and 10 mg / kg / day of fasudil intraperitoneally to APP / PS1 transgenic mice (70 and 140 mg HED) and streptozotocin rats (226 mg HED), respectively, and observed improvements in distance and compartment time reached in a Morris water maze. However, there are also reports that contradict the above. For example, Turk 2018 (dissertation) used triple transgenic mice and observed no improvement in spatial memory when administered fasudil at 30 mg / kg and 100 mg / kg in water at 10 or 12 months of age.

[0014] Some publications use unrealistic routes of administration (e.g., intracerebroventricular injection), and many do not use appropriate doses. In this regard, there are standard formulas for converting doses used in animals to the same doses in humans. Human equivalent doses can be calculated, for example, using Table 1 in Nair & Jacob, J Basic Clin Pharm. 7:27-31 (2016), which are the same conversions used by the US FDA. Becker, Alzheimers Dis. 15:303-325 (2008) discusses the importance of dose in the success of AD drug development and points this to a failure in AD drug development.

[0015] Based on currently available but inadequate animal modeling, various therapeutic strategies targeting the pathological features of Alzheimer's disease (AD) have been tested, but have not demonstrated beneficial effects in humans. Currently, available drugs are limited to acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, which show only slight improvements in some symptoms. Furthermore, the benefits of approved drugs have only been demonstrated in patients with mild cognitive impairment, not in patients with established AD. There is a significant and unmet need for novel disease-modifying therapies that demonstrate benefits not only in animals but also in humans.

[0016] Finally, Kamei (1996a and 1996b) reported the use of fasudil in two patients with wandering due to vascular dementia. One patient was diagnosed with Binswanger's stroke, as confirmed by MRI. The other patient was diagnosed with sequelae of cerebral hemorrhage and multiple lacunar infarcts, as confirmed by MRI. Despite preliminary results for wandering in several patients with subcortical vascular dementia, there is no evidence that this observation can be extrapolated to the treatment of underlying dementias in the cortical regions of the brain, such as AD, even if confirmed by clinical studies. [Overview of the Initiative]

[0017] This invention aims to treat patients with Alzheimer's disease (AD) using a rho kinase inhibitor. The preferred rho kinase inhibitor used in accordance with this invention is fasudil, typically administered orally at a total daily dose of 70–140 mg. The preferred administration regimen involves administering the daily dose in three equal parts throughout the day. The preferred method is continued for more than one month, typically at least two or three months.

[0018] Preferably, patients treatable according to the present invention are those diagnosed with dementia, not merely mild cognitive impairment. A preferred method involves treating patients having a CDR score of at least 2 and / or a CDR-SOB score of at least 4.5 or even at least 6.5 and / or an MMSE score of ≤23, and some preferred embodiments treat patients having an MMSE score of ≤20. The ADAS-COG score is typically ≥21 and sometimes ≥37. In addition to a clinical diagnosis of AD or “likely” AD, patients treated according to the present invention will generally have biomarker evidence of AD, including abnormalities in CSF and / or β and / or tau pathology as measured by PET. Other biomarker abnormalities include hyper and / or asymmetric cortical atrophy and focal hypoperfusion. Preferred embodiments of the present invention exclude patients with pure vascular dementia, patients meeting the NINDS-AIREN criteria and / or having a Hutchinskiy ischemia score >7. The preferred method does not intend to treat patients with nimodipine.

[0019] In one embodiment, AD patients treated with fasudil exhibit delayed disease progression. In one embodiment, fasudil delays progression from mild to moderate cognitive decline. In another embodiment, fasudil delays progression from moderate to severe cognitive decline.

[0020] In certain embodiments, treatment with fasudil delays the progression of patients to mild to moderate AD by at least 6 months, preferably at least 1 year, and more preferably more than 1 year.

[0021] In another specific embodiment, treatment of a patient with Fasudil delays progression to moderate to severe AD by at least 6 months, preferably by at least 1 year, and more preferably by more than 1 year. In certain embodiments, progression is measured using the Clinical Dementia Rating (CDR-SOB) scale.

[0022] In certain embodiments, patients treated with Fasudil exhibit delayed memory loss. In certain embodiments, delayed memory loss is evaluated by improvement in MMSE or ADAS-Cog.

[0023] In another embodiment, treatment with Fasudil delays worsening of cognitive symptoms other than memory, as evaluated by a statistical difference in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL).

[0024] In certain embodiments, treatment with Fasudil delays progression of driving impairment.

[0025] In yet another embodiment, Fasudil reduces the rate of emergence of undesirable behaviors in patients with AD who were asymptomatic at baseline, such as aggression, agitation, difficulty with self-care, irritability, repetitive meaningless utterances of one's own words, personality changes, restlessness, lack of inhibition, or wandering and getting lost.

[0026] In another embodiment, Fasudil treatment reduces the occurrence of gait apraxia or balance deficits.

[0027] In another specific embodiment, treatment with Fasudil eliminates or delays the need for institutionalization of AD patients. In certain embodiments, the patient exhibits agitation.

[0028] <​​

[0029] In another embodiment, the patient being treated with fasudil is also being treated with an antidepressant such as trazodone and an SSRI such as citalopram or escitalopram, paroxetine, fluoxetine, or sertraline. In a further embodiment, treatment with fasudil reduces the progression of neurodegeneration from the olfactory cortex and hippocampus to the prefrontal cortex.

[0030] In another embodiment, the patient being treated has limbic-predominant AD disease. In a further embodiment, the limbic-predominant patient is female.

[0031] In another embodiment, the AD patient being treated with fasudil has neurodegeneration mainly in the hippocampal region of the brain. In another embodiment, the patient being treated has neurodegeneration mainly in the cortical region of the brain rather than the hippocampal region. In a particular embodiment, the hippocampal-preserved patient is male. In a further particular embodiment, the male patient with hippocampal-preserved AD being treated has early-onset AD.

[0032] In a further embodiment, the patient being treated with fasudil has posterior cortical atrophy (PCA).

[0033] In a particular embodiment, the patient is male. In another particular embodiment, the patient has early-onset dementia. In a particular embodiment, the patient has a deficiency in the presenilin-1 gene, the amyloid precursor protein (APP) gene, and / or the presenilin gene. In a further embodiment, the patient being treated has a deficiency or differential expression of the ApoE ε4 allele.

[0034] In another embodiment, the patient being treated with fasudil exhibits a deficiency in at least one of memory, executive function, language, and visuospatial function.

[0035] In another embodiment, the patient being treated with fasudil exhibits deficiencies in all of memory, executive function, language, and visuospatial function.

[0036] In further embodiments, patients treated with fasudil exhibit greater deficits in memory compared to executive function, language, and visuospatial function. In certain embodiments, such patients have a deficiency or differential expression of the ApoE ε4 allele. In another embodiment, the memory deficit lies in episodic memory.

[0037] In a further embodiment, patients treated with fasudil exhibit greater deficits in language compared to executive function, memory, and visuospatial function.

[0038] In further embodiments, patients treated with fasudil exhibit greater deficits in executive function compared to memory, language, and visuospatial function.

[0039] In further embodiments, patients treated with fasudil exhibit greater deficits in visuospatial function compared to executive function, language, and memory. [Modes for carrying out the invention]

[0040] Alzheimer's disease (AD) is a neurodegenerative disorder that manifests as a latent and progressive impairment of semantic memory. In the early stages, when memory impairment is the primary presentation feature, personality and social skills often appear preserved. As AD progresses, other aspects of cognition and behavior are impaired, with the appearance of aphasia and dyslexia. Language impairments, in the early stages, may include naming and word-finding difficulties and are accompanied by progressive impairments in oral and written comprehension and expression. Visuospatial abilities, analytical and synthetic abilities, judgment, and insight are all progressively affected, and patients may experience delusions and hallucinations. Behavioral changes that may appear may include restlessness, irritability, agitation, verbal or physical aggression, wandering, pacing, and disinhibition. In the final stages, cognitive function deteriorates completely, patients may exhibit marked limb rigidity, resulting in loss of mobility, urinary and fecal incontinence, and typically death due to infections, often leading to pneumonia.

[0041] ROCK inhibitors The method of the invention aims to administer a rho kinase (ROCK) inhibitor in the treatment of a disease or condition. Two mammalian ROCK homologs, ROCK1 (also known as ROKβ, Rho kinase β, or p160ROCK) and ROCK2 (also known as ROKα), are known (Nakagawa 1996). In humans, both ROCK1 and ROCK2 genes are located on chromosome 18. The two ROCK isoforms share 64% identity in their primary amino acid sequences, but their homology in the kinase domain is even higher (92%) (Jacobs 2006, Yamaguchi 2006). Both ROCK isoforms are serine / threonine kinases and have similar structures.

[0042] Numerous pharmacological ROCK inhibitors are known (Feng, LoGrasso, Defert, & Li, 2015). Isoquinoline derivatives are a preferred class of ROCK inhibitors. The isoquinoline derivative fasudil is the first small molecule ROCK inhibitor developed by Asahi Chemical Industry (Tokyo, Japan). The characteristic chemical structure of fasudil consists of an isoquinoline ring connected to a homopiperazine ring via a sulfonyl group. Fasudil is a potent inhibitor of both ROCK isoforms. In vivo, fasudil is metabolized in the liver to its active metabolite, hydroxyfasudil (also known as M3). Other examples of isoquinoline-derived ROCK inhibitors include dimethylfasudil and ripasudil.

[0043] Other preferred ROCK inhibitors are based on the 4-aminopyridine structure. These were first developed by Yoshitomi Pharmaceutical (Uehata et al., 1997) and are exemplified by Y-27632. Other preferred ROCK inhibitors include indazoles, pyrimidines, pyrrolopyridines, pyrazoles, benzimidazoles, benzothiazoles, benzathiophenes, benzamides, aminoflazanes, quinazolines, and boron derivatives (Feng et al., 2015). Some exemplary ROCK inhibitors are listed below. [ka]

[0044] The ROCK inhibitors according to the invention may have more selective activity against either ROCK1 or ROCK2, and will typically have varying levels of activity against PKA, PKG, PKC, and MLCK. Some ROCK inhibitors may be highly specific to ROCK1 and / or ROCK2, and have much lower activity against PKA, PKG, PKC, and MLCK.

[0045] A particularly preferred ROCK inhibitor is fasudil. Fasudil may exist as a free base or salt, or in the form of a hydrate such as a hemihydrate. Where used herein, unless otherwise noted, the name of any active site, such as fasudil, should be considered to include all forms of the active site, including the free acid or base, salt, hydrate, polymorph, and prodrug of the active site. [ka] Hexahydro-1-(5-isoquinoline sulfonyl)-1H-1,4-diazepine monohydrochloride hemihydrate

[0046] Fasudil is a selective inhibitor of protein kinases such as ROCK, PKC, and MLCK, and treatment with it results in potent relaxation of vascular smooth muscle and improved blood flow (Shibuya 2001). ROCK, a particularly important mediator of vasospasm, induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus reducing MLC phosphatase activity and improving vascular smooth muscle contraction. Furthermore, there is evidence that fasudil increases eNOS expression by stabilizing the mRNA of endothelial nitric oxide synthase, which contributes to an increase in the levels of the potent vasodilator nitric oxide (NO), thereby improving vasodilation (Chen 2013).

[0047] Fasudil has a short half-life of approximately 25 minutes, but is substantially converted in vivo to its 1-hydroxy(M3) metabolite. M3 has similar effects to the parent molecule of fasudil, with slightly increased activity and a half-life of approximately 8 hours (Shibuya 2001). Therefore, M3 is likely responsible for the majority of the molecule's in vivo pharmacological activity. M3 exists as two tautomers, as shown below. [ka]

[0048] ROCK inhibitors used in the present invention, such as fasudil, include pharmaceutically acceptable salts and hydrates. These salts can be formed by reaction with inorganic and organic acids. Examples of such inorganic and organic acids include: hydrochloric acid, hydrobromide acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, maleic acid, maleic acid, oxalic acid, oxalic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid, or p-toluenesulfonic acid.

[0049] Pharmaceutical composition The pharmaceutically acceptable compositions of ROCK inhibitors usable in the present invention are generally orally administered and may be in the form of tablets or capsules, and may be immediate-release formulations (i.e., formulations without elements designed to substantially control or delay the release of the ROCK inhibitor at the time of administration), or controlled-release formulations or sustained-release formulations, and may contain pharmaceutically acceptable excipients such as corn starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose, and similar substances. The pharmaceutically acceptable compositions containing ROCK inhibitors and / or salts thereof may contain one or more pharmaceutically acceptable excipients known in the art. Formulations include oral films, orally disintegrating tablets, effervescent tablets, and granules or beads that can be sprinkled on food, mixed with liquids as a slurry, or poured directly into the mouth.

[0050] Pharmaceutical compositions comprising ROCK inhibitors, salts thereof, and hydrates may be prepared by any method known in the field of pharmacy. Generally, such preparation methods include the steps of associating a ROCK inhibitor or a pharmaceutically acceptable salt thereof with a carrier or excipient and / or one or more other accessories, and then, if necessary and / or desirable, forming and / or packaging the product into desired single-dose or multi-dose units.

[0051] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as single unit doses and / or as multiple single unit doses. As used herein, “unit dose” refers to a distinct amount of a pharmaceutical composition containing a given amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dose, such as half or one-third of such a dose.

[0052] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical composition of the present invention will vary depending on the uniqueness, size, and / or condition of the target being treated, and further depending on the route through which the composition is administered. Compositions used according to the method of the present invention may contain 0.001% to 100% (w / w) of the active ingredient.

[0053] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavorings, and fragrances may also be present in the composition.

[0054] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, monocalcium phosphate, sodium lactose phosphate, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0055] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include granulators and / or dispersants. Exemplary granulators and / or dispersants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, partially pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0056] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a binder. Examples of binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucus, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (VEEGUM.RTM.), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, water, alcohol, and / or mixtures thereof.

[0057] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a preservative. Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoan preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0058] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include antioxidants. Exemplary antioxidants include alpha-tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl formate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0059] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a chelating agent. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Examples of antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, propylene glycol, and thimerosal.

[0060] In certain embodiments, the pharmaceutical composition may include a buffer along with a ROCK inhibitor or a salt thereof. Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dicalcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0061] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a lubricant. Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0062] In other embodiments, a pharmaceutical composition containing a ROCK inhibitor or a salt thereof may be administered in liquid dosage form. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may include inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, peanut, corn, germ, olive, castor, and sesame oils); glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrance agents. In certain embodiments for parenteral administration, the conjugate of the present invention is mixed with a solubilizer such as Cremophor®, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0063] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is an active ingredient, at least one inert and pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or (a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; and (e) solution retarding agents such as paraffin. (f) an absorption enhancer such as a quaternary ammonium compound, (g) a wetting agent such as cetyl alcohol and glycerol monostearate, (h) an absorbent such as kaolin and bentonite clay, and (i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffer.

[0064] Some compositions of the present invention relate to sustained-release or controlled-release formulations. These may be, for example, diffusion-controlled products, dissolution-controlled products, erosion products, osmotic pump systems, or ionic resin systems. Diffusion-controlled products include water-insoluble polymers that control the flow of water and the subsequent elution of the dissolved drug from the dosage form. Dissolution-controlled products control the rate of drug dissolution by using slowly solubilizing polymers or by controlling release using microencapsulation of the drug—variable thickness. Erosion products control the release of the drug by the rate of erosion of a carrier matrix. Osmotic pump systems release the drug based on a constant inflow of water through a semipermeable membrane into a reservoir containing a penetrating agent. Ion exchange resins may be used to bind to the drug so that, once ingested, the release of the drug is determined by the ionic environment in the gastrointestinal tract.

[0065] Treatable patients This invention aims to utilize rho kinase inhibitors in the treatment of patients with Alzheimer's disease (AD). The intended therapy is considered disease-modifying, and therefore, the method of this invention is specifically intended to treat or alleviate various clinical symptoms and symptoms of the disease, along with improving markers of AD.

[0066] Patients with AD who are treatable according to the present invention may exhibit one or more of the following deficits, and the present invention aims to provide a method for improving each of these deficits. Deficiencies may include impairments in semantic memory (personality and / or social skills being preserved or not), aphasia, dyslexia, naming difficulties, word-finding difficulties, oral comprehension difficulties, written comprehension difficulties, written expression difficulties, visuospatial impairments, analytical abilities, synthetic abilities, judgment difficulties, insight difficulties, delusions, hallucinations, restlessness, irritability, agitation, verbal aggression, physical aggression, wandering, pacing, and disinhibition.

[0067] The American Psychiatric Association distinguishes between mild and severe neurocognitive disorders: Mild neurocognitive impairment is defined as a cognitive decline of one to two standard deviations from normal on formal cognitive tests, which does not impair independence and is not attributable to delirium or other medical or mental disorder. Severe neurocognitive impairment is defined as a cognitive decline of two standard deviations or more from normal on formal cognitive tests, which impairs independence and is not attributable to delirium or other medical or mental disorder.

[0068] Patients treatable according to the present invention will typically have severe neurocognitive impairment that meets these criteria, such that the impairment interferes with their independence. Impairment of independence can be assessed using scales that measure activities of daily living (ADL), including scales such as the Barthel Index. Often, patients treatable according to the present invention will have limited independence in that they are residents of assisted living or memory therapy facilities and do not live in the community or at home due to their condition.

[0069] The Mental Disorders of Diagnostic and Statistical Manual Fifth Edition (DSM-V) provides a useful framework for identifying patients who can be treated according to the present invention. The DSM-V provides definitions of cognitive syndromes and probable Alzheimer's disease dementia.

[0070] Dementia syndrome requires objective cognitive or behavioral impairment in: memory, reasoning and processing of complex tasks, visuospatial abilities, language function, and at least two of the following: personality, behavior, or components. It also requires a decline and impairment from a previous level of functioning.

[0071] A probable diagnosis of Alzheimer's disease requires that the criteria for dementia syndrome are met, that there is an insidious onset, gradual progression, initial amnesic or non-amnesic (language or executive) symptoms, and that there are no other neurological, psychiatric, or general medical impairments of a severity that may impair cognition. The DSM-V indicates that the certainty of diagnosis can be increased by positive biomarkers (e.g., CSF Aβ / tau, amyloid positron emission tomography, and hippocampal atrophy on MRI). According to the DSM-V, the present invention is particularly intended to treat patients who are probable to have Alzheimer's disease and who have also been shown to be positive for one or more AD biomarkers.

[0072] A working group convened by the National Institute on Aging (NIA) and the Alzheimer's Association has presented widely accepted diagnostic criteria for AD dementia (McKhann 2011). The NIA criteria first establish a diagnostic framework for diagnosing dementia (the appearance of cognitive or behavioral symptoms that negatively affect a person's functional abilities), regardless of cause. High probability AD dementia is diagnosed by the progression of symptoms and the presentation of certain cognitive deficits, most commonly amnesic (learning difficulties and recall of recent information), but also various non-amnesic deficits such as word retrieval, spatial cognition, and executive function impairments. High probability AD also requires the exclusion of other causes such as VaD, Lewy body dementia (DLB), behavioral frontotemporal dementia (bvFTD), semantic primary progressive aphasia or non-fluent / agrammatic primary progressive aphasia, and other active neurological disorders, or non-neurological comorbidities or drug use that may negatively affect cognition. If one or more biomarkers of AD pathology are shown to be present, a more certain diagnosis of AD dementia is made.

[0073] As part of the NIA or DSM-V diagnosis, or independently thereof, the diagnosis of AD patients treatable according to the present invention can be facilitated using imaging and measurement of biomarkers in cerebrospinal fluid (CSF). The most widely used CSF biomarkers for Alzheimer's disease measure certain proteins: beta-amyloid-42 (a major component of amyloid plaques in the brain), tau, and phosphotau (a major component of tau changes in the brain). In Alzheimer's disease, beta-amyloid-42 levels in CSF are lower, and tau and phosphotau levels are higher compared to levels in people without Alzheimer's disease or other causes of dementia.

[0074] Imaging, particularly computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), are useful tools for diagnosing dementia. Neurodegeneration leads to brain atrophy, which can be detected and quantified. Patients treatable according to the present invention may exhibit whole brain atrophy, which can be measured on the whole cortical atrophy (GCA) scale. A score of 1 on the scale may be considered normal in elderly patients, while a score of 2 or 3 should generally be considered abnormal. Subjects with a GCA score of 2 or 3 are preferably treatable according to the present invention. Severe atrophy cases may show marked ventricular dilation, and such patients are suitably treated using the methods of the present invention. Asymmetric and / or focal atrophy detected by MRI, particularly in the temporal and / or parietal regions, strongly suggests AD. Automated tools capable of performing these functions to detect abnormal brain atrophy indicative of AD are becoming increasingly available.

[0075] Fluorodeoxyglucose (FDG) PET scans measure glucose use in the brain. Glucose, a type of sugar, is the primary energy source for cells. Studies have shown that people with dementia often have abnormal patterns of reduced glucose use in certain areas of the brain. FDG PET scans can reveal patterns that may support the diagnosis of specific causes of dementia. This invention aims to treat patients with evidence of AD pathology detected by PET, including but not limited to FDG PET. FDG PET detects areas of reduced glucose metabolism and indicates metabolic impairment. AD patients treatable according to this invention often show reduced metabolism in the temporal and parietal regions.

[0076] Amyloid PET scans measure the abnormal deposition of a protein called beta-amyloid. Higher levels of beta-amyloid are consistent with the presence of amyloid plaques, a characteristic feature of Alzheimer's disease. Several tracers, including florbetapil, flutemetamol, florbetaben, and Pittsburgh compound B, can be used in amyloid PET scans. This invention aims to treat patients who have evidence of amyloid deposition by PET scans using one or more of the aforementioned tracers.

[0077] Tau PET scans detect the abnormal accumulation of the protein tau, which forms changes in nerve cells in Alzheimer's disease and many other dementias. Several tau tracers, such as AV-1451, PI-2620, and MK-6240, have been studied in clinical trials and other research settings. This invention aims to treat patients with evidence of NFT by PET scans using one or more of the aforementioned tracers.

[0078] Localized hypoperfusion is also associated with the functional deficits seen in Alzheimer's disease (AD). Hypoperfusion can be detected by several methodologies, including spin-labeled MRI and single-photon emission computed tomography (SPECT). This invention aims to treat patients with evidence of localized hypoperfusion detected by spin-labeled MRI, SPECT, and other methods known to those skilled in the art.

[0079] In one embodiment, the present invention excludes patients with vascular dementia (VaD). While some patients may have mixed pathologies, true VaD is dementia caused by a cardiovascular event such as ischemic or hemorrhagic stroke, or by a chronic cardiovascular condition such as Binswanger's disease or mottled dementia. Excluded patients can be easily identified using the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et 1'Enseignement en Neurosciences (AIREN) (NINDS-AIREN criteria) (Wetterling 1996; Roman 1993). Therefore, patients identified according to the NINDS-AIREN criteria are excluded. Another useful tool in excluding VaD patients is the Hutchinski ischemia score, where diagnosed stroke, acute onset, variable course, and focal symptoms and symptoms all indicating stroke are given greater weight. According to Hutchinski, the following characteristics of patients with dementia—sudden onset, fluctuating course, history of stroke, focal neurological symptoms, and focal neurotic signs—are scored on a scale of 2 points. The following elements, which are less likely to be associated with cardiovascular events (and therefore VaD), are scored on a scale of 1 point each: emotional lability, gradual deterioration, history of hypertension, nocturnal confusion, evidence of associated atherosclerosis, relative preservation of personality, depression, and physical malaise. Typically, a score > 7 indicates that the patient has VaD. Therefore, patients treated according to the present invention typically have a Hutchinski score of ≤ 7, and patients with a Hutchinski score of ≤ 7 and those with a Hutchinski score > 7 are excluded.

[0080] Patients treatable according to the invention will typically have low scores on cognitive scales such as the Mini Mental State Exam (MMSE). A threshold of ≤23 on the MMSE is set for dementia, and a score of ≤15 represents severe dementia. Patients with an MMSE score of 24-27 may have “pre” AD or “prodromal” AD, but they do not yet have AD and are generally not treated according to the invention. Patients treated according to the invention preferably have an MMSE score of less than 23, and some patients have a minimum MMSE of 15. In certain embodiments of the invention, treated patients will have an MMSE score of ≤20, ≤18, or ≤16. When the MMSE is below 15, the Severe Impairment Battery (SIB) is also a useful evaluation criterion.

[0081] Other short tools for assessing dementia / cognitive decline and measuring cognitive improvement include the Age-Defensive and Dementia-Assessment (AD8) eight-item informant interview, annual wellness visits (AWV), general practitioner cognitive assessment (GPCOG), health risk assessment (HRA), memory impairment screening (MIS), Montreal Cognitive Assessment (MoCA), Saint Louis University Mental State Test (SLUMS), and the Short IQCODE, a short informant questionnaire on cognitive decline in older adults.

[0082] Other cognitive or functional scales designed for Alzheimer's disease include the Clinical Dementia Assessment (CDR), the Cognitive Subscales of the Alzheimer's Disease Assessment Scale (ADAS-Cog), and the Collaborative Study on Alzheimer's Disease – Global Clinical Impression of Change (ADCS-CGIC) (including their variants).

[0083] Another useful scale for measuring some of the symptoms of dementia in Alzheimer's disease is the Cohen-Mansfield Agitation Scale (CMAI).

[0084] The CDR Dementia Staging Instrument is a 5-point scale used to characterize six domains of cognitive and functional performance in AD: memory, orientation, judgment and problem-solving, community issues, home and hobbies, and personal care. It is scored according to the following scale: 0 = normal, 0.5 = very mild dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia. Patients treatable according to the present invention will preferably have a CDR score of 2 or 3. The CDR is generally scored according to an algorithm that differentially weights subscores (0, 0.5, 1, 2, or 3) from various domains. The CDR can also be scored in an alternative form that simply sums the subscores for each domain. The so-called box sum (SOB) method is equally effective but has higher resolution and can yield scores from 0 (normal) to 18 (score of 3 in all domains). Patients treatable according to the present invention will generally obtain a score of at least 4.5 using CDR-SOB scoring.

[0085] Administration regimen The therapeutic method of the present invention is particularly suitable for oral administration, while considering various routes of administration. According to the therapeutic method of the present invention, an effective amount of ROCK inhibitor or a pharmaceutically acceptable salt thereof for administration once or more daily may contain about 10 mg to about 1000 mg. The method of the present invention is preferably achieved using fasudil administered orally in a total daily dose of 70 mg to 140 mg. Fasudil hydrochloride hemihydrate is preferably administered in daily amounts of, for example, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, and about 20 mg to about 10 mg. One preferred dose regimen involves treatment with 25, 30, or 40 mg of fasudil hydrochloride hemihydrate three times daily, with a total daily dose of 70 to 120 mg, using an immediate-release formulation. The most preferred dose is greater than 60 mg per day, with the most preferred daily dose range being 70 mg to 120 mg, administered in three equal doses throughout the day. Other preferred daily doses are in the range of 90 mg to 120 mg per day or 80 mg to 140 mg per day. Further dose regimens involve treatment with 35 to 60 mg of fasudil hydrochloride hemihydrate twice daily, using an immediate-release formulation, for a total daily dose of 75 to 120 mg. Based on ROCK inhibitory activity, those skilled in the art can readily estimate the dosage range provided for fasudil for other ROCK inhibitors. A preferred embodiment is 45 mg of fasudil hydrochloride hemihydrate twice daily, using an immediate-release formulation.

[0086] Certain patient subgroups, such as patients with renal impairment and / or elderly patients (e.g., those 65 years of age or older), may require lower doses or sustained-release formulations instead of immediate-release formulations. Fasudil hydrochloride hemihydrate may have higher steady-state concentrations when administered at normal doses to patients with renal disease, and lower doses may be required to lower Cmax or delay the time to reach Cmax (increase Tmax).

[0087] Renal dysfunction develops with age as a result of numerous disorders, including cirrhosis, chronic kidney disease, acute kidney injury (e.g., due to contrast agent administration), diabetes mellitus (type 1 or type 2), autoimmune diseases (such as lupus and IgA nephropathy), genetic disorders (such as polycystic kidney disease), renal syndromes, urinary tract problems (from conditions such as benign prostatic hyperplasia, kidney stones, and certain cancers), heart attack, illegal drug use and abuse, ischemic kidney condition, urinary tract problems, hypertension, glomerulonephritis, interstitial nephritis, vesicoureteral disorders, pyelonephritis, and sepsis. Renal dysfunction can also occur in other diseases and syndromes, including non-renal-related diseases that may occur with renal dysfunction, such as pulmonary arterial hypertension, heart failure, and cardiomyopathy, among others.

[0088] Kidney function is most often assessed using serum (and / or urine) creatinine. Creatinine is a breakdown product of creatine phosphate in muscle cells and is produced at a constant rate. It remains unchanged and is excreted by the kidneys primarily through glomerular filtration. Therefore, elevated serum creatinine is a marker of kidney dysfunction and is used to estimate glomerular filtration rate.

[0089] Normal levels of creatinine in the blood are approximately 0.6–1.2 mg / dL in adult males and 0.5–1.1 mg / dL in adult females. If creatinine levels exceed these figures, the subject has renal impairment and is therefore treatable according to the invention. Mild renal impairment / dysfunction occurs in the range of 1.2 mg / dL–1.5 mg / dL. Moderate renal impairment / dysfunction is considered to occur at creatinine levels above 1.5 mg / dL. Severe renal impairment, including what is considered renal failure, is defined as a serum creatinine level of ≥2.0 mg / dL or the use of renal replacement therapy (such as dialysis). The invention is specifically intended to treat subjects with mild, moderate, and severe renal impairment.

[0090] As shown, creatinine levels can be considered a substitute for glomerular filtration rate, and glomerular filtration rate may be estimated using only serum creatinine levels and the Cockroft-Gault equation.

[0091] Generally, a creatinine clearance of less than 60 mL / min (roughly equivalent to a creatinine level of >1.2 mg / dL) is considered moderate renal impairment. A glomerular filtration rate of 40 mL / min (roughly equivalent to a creatinine level greater than 1.5 mg / dL), or especially less than 30 mL / min, is considered severe renal impairment.

[0092] Generally, creatinine clearance (estimated glomerular filtration rate) can be directly derived from serum creatinine using the Cockroft-Gault equation: Creatinine clearance = (((140 - age) × (body weight in kg)) × 1.23) / (serum creatinine in μmol / L)

[0093] For women, multiply the calculation result by 0.85.

[0094] Furthermore, by focusing on serum and urinary creatinine levels, creatinine clearance measured empirically can be directly used as an estimate of glomerular filtration rate. Specifically, urine is collected over 24 hours, and creatinine clearance is determined by applying the following equation: Creatinine clearance (mL / min) = Urinary creatinine concentration (mg / mL) * 24-hour urine volume (mL) / Plasma creatinine concentration (mg / mL) * 24 hours * 60 minutes

[0095] In one embodiment, the dose of fasudil for mild to moderate renal impairment is reduced to 50-80 mg per day. In another embodiment, the dose of fasudil is not reduced, but it is administered once daily in a sustained-release form.

[0096] In another embodiment, the dose is not reduced in mild to moderate renal impairment.

[0097] In one embodiment, the dose of fasudil is reduced to 30-45 mg in patients with severe renal impairment. In another embodiment, the dose of fasudil is not reduced, but instead, it is administered once daily in a sustained-release form.

[0098] In a further embodiment, the dose is reduced when serum creatinine (SCr) is >2, and / or the increase in SCr from baseline is >1.5 times, and / or the decrease in eGFR from baseline is >25%.

[0099] Patient size is an important factor to consider when using creatinine-based estimates of renal function. The unit for drug clearance is volume / hour (mL / min), while the unit for estimated GFR in chronic kidney disease is volume / hour / standard size (mL / min / 1.73m³). 2 Generally, the dosage may be adjusted downwards for smaller patients (e.g., 40-50 mg per day) and upwards for larger patients, such as obese patients (e.g., 120 mg per day). Small men would weigh approximately 160 pounds or less. Small female patients would weigh approximately 130 pounds or less. Patients with a body mass index of 30 or higher are considered obese.

[0100] In addition, elderly patients may require a lower dose at the start and gradually increase to the recommended dose after several days or weeks. In another embodiment, elderly patients may require a lower dose for the duration of treatment. The elderly population includes “early elderly” aged 65–74 years, “late elderly” aged 75–84 years, and “bedridden elderly” aged 85 years and older. For example, an initial dose of 30 mg per day for two weeks, followed by 60 mg per day for four weeks, and then 90 mg per day. Further doses up to approximately 120 mg per day may be guaranteed by titration.

[0101] Another embodiment involves treatment with 60-120 mg of fasudil hydrochloride semihydrate once daily in a sustained-release dosage form. Treatment with a total daily dose of 90 mg of sustained-release fasudil hydrochloride semihydrate once daily is preferred. It will be understood that the dose ranges described herein provide guidance for administering the provided pharmaceutical composition to adults. For example, the dose administered to children or adolescents may be determined by a physician or a person skilled in the art and may be lower than or the same as the dose administered to adults.

[0102] It will be understood that the dose ranges described herein are intended to provide guidance for administering the provided pharmaceutical compositions to adults. For example, the dose administered to children or adolescents may be determined by a physician or a person skilled in the art and may be lower or the same as the dose administered to adults.

[0103] The method of administering the composition according to the present invention will generally be continued for at least one day. Some preferred methods involve treatment for up to 30 days, or up to 60 days, or even up to 90 days, or even longer. Treatment for more than 60 days is preferred, and treatment for at least 6 months is particularly preferred. The exact duration of treatment will depend on the patient's condition and response to treatment. The most preferred method is to initiate treatment after the onset or appearance of symptoms.

[0104] The method of the present invention also intends to administer ROCK inhibitors together with other compounds used to treat dementia or other symptoms of dementia. They may be administered in combination, in single dosage forms, in a common dose regimen, or in different dose regimens, at different times of day to the same patient.

[0105] To treat dementia, two classes of drugs are used: acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, which have been shown to improve cognition. Generally used in the early stages of the disease, acetylcholinesterase inhibitors prevent the breakdown of the neurotransmitter acetylcholine. These drugs include piperidines such as donepezil (Aricept), phenanthrene derivatives such as galantamine (Razadine), and carbamates such as rivastigmine (Exelon). An example of an NMDA receptor antagonist is the non-competitive inhibitor memantine (Namenda). A combination of memantine and donepezil (Namzalic) is also available.

[0106] In some embodiments, patients are administered fasudil in combination with other activators approved for the treatment of dementia, including, but not limited to, cholinesterase inhibitors and NMDA receptor antagonists. In one embodiment, the cholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, and galantamine. Exemplary doses of the cholinesterase inhibitor include 3 to 25 mg per day, more preferably 6 to 12 mg per day. In another embodiment, the NMDA receptor antagonist is memantine. In certain embodiments, memantine is administered in doses of 5 to 28 mg per day, preferably 15 to 20 mg per day. In further embodiments, the co-administered activator is a combination of donepezil and memantine at doses of 28 mg of memantine and 10 mg of donepezil.

[0107] In certain embodiments, the combination of fasudil and a cholinesterase inhibitor is administered to patients with AD. In further embodiments, the combination of fasudil and a cholinesterase inhibitor is administered to patients with mixed dementia, primarily of the AD type. In yet another embodiment, the combination of fasudil and a cholinesterase inhibitor is not administered to patients with vascular dementia alone.

[0108] Dextromethorphan hydrobromide is another non-competitive NMDA receptor antagonist and also possesses activity as a sigma-1 receptor agonist. The product Nudexta, marketed in combination with quinidine sulfate (a CYP450 2D6 inhibitor), has been shown for the treatment of emotional dysregulation occurring in many forms of dementia. In one embodiment, the patient is treated with products useful for treating emotional dysregulation, such as Nudexta, and fasudil.

[0109] In further embodiments, patients treated with fasudil are also treated with activators including mood stabilizers, benzodiazepines, antipsychotics, antistimulants, or hypnotics. In certain embodiments, patients treated with fasudil are not treated with risperidone, aripiprazole, quetiapine, carbamazepine, gabapentin, prazosin, trazodone, or lorazepam.

[0110] In further embodiments, patients treated with fasudil are being treated for depression. In specific embodiments, patients are being treated with an antidepressant such as citalopram or escitalopram.

[0111] In another embodiment, fasudil is administered in combination with an antioxidant such as α-tocopherol. In a specific embodiment, α-tocopherol is administered at a dose of 1000-2000 IU per day.

[0112] In further embodiments, fasudil is administered within the range of NSAIDs. In certain embodiments, the NSAID is ibuprofen, naproxen, diclofenac, or indomethacin, and is administered together with fasudil.

[0113] The method of the invention in certain embodiments, particularly the method intended for parenteral administration, does not involve the administration of statins (especially rosuvastatin) to patients also receiving RHO kinase inhibitors. The method of the invention in certain embodiments, particularly the method intended for parenteral administration, does not involve the administration of nimodipine to patients also receiving RHO kinase inhibitors.

[0114] Results of the method The methods of the present invention are considered disease-modifying in that they result in improvement of all relevant signs and symptoms. Such improvement may be absolute in that the treated patient actually shows improvement over time compared to previous measurements. Improvement is more typically measured against control patients. Control patients may be based on a known natural history of patients in the past and / or similar circumstances, or they may be controls in the sense that they receive a placebo or simply standard treatment in the same clinical trial. Comparison with controls is particularly useful because the outcome is measured in terms of a reduction in deterioration compared to the control / expectation, as it is unlikely that the course of the disease will be completely reversed.

[0115] Improvement can be assessed using one or more of the following scales: MMSE, SIB, AD8, AWV, GPCOG, HRA, MIS, MoCA, SLUMS, Short IQCODE, CDR, ADAS-Cog, ADCS-CGIC, and CMAI (including their variations).

[0116] The improvement obtained from the method of the present invention will generally be at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, either absolute or compared to a control. In another embodiment, the improvement obtained from the method of the present invention will be at least 50% or more, either absolute or compared to a control. In a preferred embodiment, the improvement obtained from the method of the present invention will be at least 75%, either absolute or compared to a control. In a particular embodiment, the improvement is observed in the same patient before treatment with fasudil.

[0117] Treatment using the method of the present invention generally results in improved cognitive function. Patients generally show an improvement of at least 3 points in MMSE and / or SIB during the initial stages of treatment, and cognitive decline slows down compared to control patients, generally maintaining a difference of at least 1 or 2 points between the treated and control patients.

[0118] A typical patient treated according to the present invention may show an improvement of at least 0.5 points in CDR-SOB, but in any event, it will show a reduced rate of reduction, which will manifest as a difference of at least 1 point between CDR-SOB and an untreated control after at least 6 months of treatment.

[0119] Patients treated in accordance with the present invention are also expected to show improvement in one or more of the following: semantic memory (with or without preservation of personality and / or social skills), aphasia, dyslexia, naming, word retrieval, oral comprehension, written comprehension, written expression, visuospatial ability, analytical ability, synthetic ability, judgment, insight, delusions, hallucinations, restlessness, irritability, agitation, verbal aggression, physical aggression, wandering, pacing, and disinhibition. [Examples]

[0120] We will recruit 80 patients diagnosed with Alzheimer's disease (AD) who are likely to have at least one positive AD biomarker (aβ and / or tau abnormality). Patients with VaD, DLB, bvFTD, or semantic primary progressive aphasia or non-fluent / agrammatic primary progressive aphasia will be excluded, along with patients with another concurrently active neurological disorder. Patients with non-neurological comorbidities or those using medications that may adversely affect cognition will also be excluded. Patients must have a maximum MMSE score of 23 and a minimum MMSE score of 15.

[0121] A cohort of 20 patients will be treated orally with either fasudil or placebo in a dose-escalation manner. Each group will be randomized to receive either placebo or the drug, with 10 patients per group, for 60 days. At the end of day 30, the next cohort will be initiated with a higher dose based on an assessment of adverse events. At the end of day 60, patients will be evaluated for efficacy and safety and re-randomized to the next higher dose if there are no dose-limiting adverse events. Oral administration using 10 mg immediate-release tablets will begin with the first cohort at 60 mg per day (administered in three equal doses throughout the day), the second cohort at 90 mg per day (administered in three equal doses throughout the day), the third cohort at 120 mg per day (administered in three equal doses throughout the day), and the third cohort with a maximum planned dose of 150 mg (administered in three equal doses throughout the day).

[0122] At a 60 mg dose over 60 days, no cognitive effect was observed, but each of the other doses showed improvement compared to the control over 60 days. When the first cohort was escalated to 90 mg per day, a cognitive difference between treatment and control was observed in that cohort. Cognition improved in a dose-dependent manner across all doses. A dose-dependent increase in creatinine was observed, suggesting possible renal impairment. Only 50% of those escalated to a 120 mg per day dose were also escalated to 150 mg, and 25% of patients treated with 150 mg per day had their dose reduced due to elevated creatinine levels.

[0123] The optimal dose for cognitive improvement in AD dementia is determined to be 90 mg to 120 mg per day. Less than 90 mg is ineffective, and elevated creatinine levels above 120 mg become a dose limiting factor in many patients.

[0124] List of References Becker RE, Greig NH, Giacobini H, Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices? Alzheimers Dis. 15:303-325 (2008). Ceyzeriat et al., Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer's Disease. Current Alzheimer Research. 2020; 17: 1-13. Chen M, Liu A, Ouyang Y, Huang Y, Chao X, Pi R. 2013. Fasudil and its analogs: a new powerful weapon in the long war against central nervous system disorders? Expert Opin Investig Drugs. 22:537-50. Couch BA, DeMarco GJ, Gourley SL, Koleske AJ, Increased Dendrite Branching in AβPP / PS1 Mice and Elongation of Dendrite Arbors by Fasudil Administration. Alzheimers Dis. 2010; 20(4): 1003-1008. Elliott C, Rojo A, Ribe E, Broastock M, Xia W, Morin P, Semenov M, Baillie G, Cuadrado A, Al-Shawi R, Ballard C, Simons P, Killick R, A role for APP in Wnt signalling links synapse loss with β-amyloid production. Translational Psychiatry. 2018; 8(179). Feng Y, LoGrasso P, Defert O, Li R, Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J Med Chem. 2016; 59(6): 2269-2300. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. Hamano T, Shirafuji N; Yen S; Yoshida H, Kanaan N, Hayashi K, Ikawa M, Yamamura O, Fujita Y; Kuriyama M, Nakamoto Y, Rho-kinase ROCK inhibitors reduce oligomeric tau protein. Neurobiology of Aging; 2020; 89: 41-54. Hou Y, Zhou L, Yang QD, Du XP, Li M, Yuan M, Zhou ZW, Changes in hippocampal synapses and learning-memory abilities in a streptozotocin-treated rat model and intervention by using fasudil hydrochloride. Neuroscience. 2012; 200: 120-129. Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J, The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J Biol Chem. 2006; 281(1): 260-68. Kamei S, Oishi M, Takasu T. 1996a. Evaluation of fasudil hydrochloride treatment for wandering symptoms in cerebrovascular dementia with 31P-magnetic resonance spectroscopy and Xe-computed tomography. Clin Neuropharmacol. 19:428-38. Kamei S, Toshiaki T, Oishi M, Effect of fasudil hydrochloride on wandering symptoms of c cerebrovascular dementia patients. Neurotherapy. 1996b 13:43-50. Nair & Jacob, A simple practice guide for dose conversion between animals and human.J Basic Clin Pharm. 7:27-31 (2016). [ PMC free article ] [ PubMed ] Nakagawa O, Fukisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine / threonine kinase in mice. FEBS Lett. 1996 Aug 26;392(2):189-93. Nakaoka A, Suto S, Makimoto K, Yamakawa M, Shigenobu K, Tabushi K. 2010. Pacing and lapping movements in institutionalized patients with dementia. Am J Alzheimer's Disease. 25:167-7 Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al. 1993. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 43:250-6 Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B, Hardy J, Vassar R, Winblad B, Saido TC, APP mouse models for Alzheimer's disease preclinical studies. EMBO J. 2017; 36(17): 2473–2487. Sellers K, Elliott C, Jackson J, Ghosh A, Ribe E, Rojo A, Jarosz-Griffiths HH, Watson AA, Xia W, Semenov M, Morin P, Hooper N, Porter R, Preston J, Al-Shawi R, Baillie G, Lovestone S Square A, Harate M, Simons P, Srivastava DP, Killick R, Amyloid β Synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimer's & Dementia. 2018; 14: 306-317. Shibuya M, Asano T, Sasaki Y. 2001. Effect of Fasudil HCl, a protein kinase inhibitor, on cerebral vasospasm. Act Neurochir Suppl. 77:201-4 Turk M. The Effect of Rho Kinase Inhibitors on Alzheimer's Disease, Dissertation. Arizona State University. May 2017. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Maekawa M, Narumiya S, Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997 Oct 30;389(6654):990-4. Wetterling T, Kanitz RD, Borgis KJ. 1996. Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke. 27:30-6. Wick JY, Zanni GR. Aimless excursions: wandering in the elderly. Consult Pharm. 2006;21(8):608-612, 615-618. Yamaguchi H, Miwa Y, Kasa M, Kitano K, Amano M, Kaibuchi K, Hakoshima T, Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632. J Biochem. 2006 Sep;140(3):305-11. Yu J, Gu Q, Yan Y, Yu H, Guo M, Liu C, Song G, Chai Z, Wang Q, Zia B, Zhang H, Jiang Y, Cungen MA, Fausidil improves cognition of APP / PS1 transgenic mice via inhibiting the activation of microglia and shifting microglia phenotypes from M1 to M2. Chin J Cell Mol Immunol. 2017; 33(12): 1585-1593. The disclosures of each reference cited herein are incorporated herein by reference in their entirety.

Claims

1. A method for improving semantic memory, comprising treating a patient with semantic memory impairment with a therapeutically effective dose of a rhogenase inhibitor.

2. A method for improving cognition in patients with Alzheimer's disease, comprising orally administering a pharmacologically effective amount of a rho kinase inhibitor to a patient suffering from Alzheimer's disease.

3. A method for improving memory in a patient with Alzheimer's disease, comprising orally administering a pharmacologically effective amount of a rhogenase inhibitor to a patient suffering from Alzheimer's disease.

4. A method for improving activities of daily living in patients with Alzheimer's disease, comprising orally administering a pharmacologically effective amount of a rho kinase inhibitor to a patient suffering from Alzheimer's disease.

5. A method for improving cognition in patients with Alzheimer's disease, comprising orally administering a pharmacologically effective amount of a rho kinase inhibitor to a patient suffering from Alzheimer's disease.

6. The method according to any one of claims 1 to 5, wherein the rho kinase inhibitor is fasudil, and fasudil is administered orally in an immediate-release formulation at a dose of 70 to 140 mg per day.

7. The method according to any one of claims 1 to 5, wherein the patient has an MMSE score of ≤23.

8. The method according to any one of claims 1 to 5, wherein the patient has a CDR-SOB score of ≥ 4.

5.

9. The method according to any one of claims 1 to 5, wherein the method is continued for at least two months.

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