Methods for treating wandering associated with cortical dementia

Abstract

The invention is based on the discovery that rho kinase inhibitors can be used to treat wandering associated with certain dementias. The method of the invention relates to the use of rho kinase inhibitors in treating patients with wandering associated with cortical dementia. Preferred embodiments of the invention are intended to treat wandering due to cortical vascular dementia and dementia-related wandering when the patient is a persistent wanderer and / or does not exhibit wayfinding deficits.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 958,985, filed January 9, 2020, U.S. Provisional Patent Application No. 62 / 971,697, filed February 7, 2020, and U.S. Provisional Patent Application No. 63 / 004,305, filed April 2, 2020. Each of these applications is incorporated by reference in its entirety. [Background technology]

[0002] Wandering is "frequent, repetitive, temporarily disturbed, and / or spatially disorienting mobile behavior manifested in circling, disorganized, and / or roaming patterns, some of which, when unaccompanied, are associated with disappearance, attempted disappearance, or getting lost." Wandering behavior is associated with degenerative neurological conditions, including a number of conditions, such as Huntington's disease (HD), autism spectrum disorder, Down syndrome, progressive supranuclear palsy, corticobasal degeneration, and dementia.

[0003] The most common underlying cause of wandering is dementia, which can result from, for example, Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), normal pressure hydrocephalus (NPH), and head injury, among others. Wandering occurs in all forms of dementia, regardless of etiology, but occurs with different frequencies and is characterized by different quantities and qualities depending on the type of dementia (Cipriani 2014).

[0004] There are no standardized assessment tools for diagnosing or assessing wandering. Wandering is often captured using the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfield Agitation Inventory, two broad tools for assessing behavioral and psychological symptoms of dementia (Yayama 2013). For example, the NPI has a single item regarding wandering: "Wandering around or circling around the facility for no apparent reason." Therefore, illustrating its limited usefulness, the NPI will only detect recurrent wandering, which is characteristic of FTD but uncommon in AD and rare in VaD (Bathgate 2001; Nakaoko 2010). On the other hand, the Algase Wandering Scale (Algase 2001a) is the only tool for the exclusive assessment of wandering and is not limited to specific types or characteristics of wandering (Yayama 2013).

[0005] Wandering can be described in terms of various characteristics, including frequency (persistence), pattern (circling, disorganized, or wandering), boundary violation (disappearance), and deficits in orientation or wayfinding abilities (spatial disorientation) (Algase 2001a). Wandering is therefore a general term used to describe many different behaviors, and it is well documented that the quantity and quality of wandering varies with different forms and degrees of dementia (Cipriani 2014).

[0006] Wandering is often the reason dementia patients lose their independence and are placed in long-term care facilities, impacting self-esteem and leading to social isolation, as well as representing a significant social cost (Logsdon 1998). Wandering is characterized by excessive, aimless movement that frequently poses a nuisance and, more importantly, a safety concern (Lai 2003; Aud 2004). Wandering, especially when patients are able to escape from controlled environments, increases the risk of injury, or even death, that impacts quality of life through falls and other accidents (Algase 2001a; Wick 2006). Wandering patients have been reported to be "chemically" restrained using antipsychotics or sedatives to prevent escapes and control problematic symptoms like wandering (Human Rights Watch 2018). Clearly, the goal of any wandering treatment would be to avoid chemical restraint. There is currently no treatment available for wandering of any etiology, so there is a significant need for a therapeutic approach to wandering.

[0007] Among dementias, VaD is distinguished from other forms of dementia by the presence of one or more vascular causes, generally in the absence of other pathologies. Specifically, VaD, unlike all other types of dementia, is not a neurodegenerative disease (Salardini 2019). Uniquely, the pathophysiology of VaD is not related to an underlying proteinopathy.

[0008] Kamei (1996a) reported the use of fasudil in two patients with wandering due to VaD. After participating in a chronic stroke study, the patients were treated by investigators for wandering and were treated with fasudil. One patient was diagnosed with Binswanger-type cerebral infarction, confirmed by MRI imaging. Before treatment, the patients had a 3.5-year history of wandering, primarily consisting of wayfinding problems. The patients were unable to find their way home. Subsequently, for approximately 1.5 years prior to treatment initiation, the patients periodically disappeared approximately two to three times per week. Within a few weeks of initiating treatment, the wandering symptoms disappeared and remained free of wandering symptoms for the duration of treatment. When the patients were removed from treatment, the wandering symptoms recurred within a few weeks. Upon re-treatment, the wandering symptoms resolved again. The other patient was diagnosed with sequelae of a cerebral hemorrhage and multiple lacunar infarcts confirmed by MRI and was diagnosed with "lacunar dementia" (Binswanger's synonym, Roman 1985). Approximately 5 months after the hemorrhage, the patient began to exhibit way-finding symptoms, beginning with several episodes of getting lost with increasing frequency of 2-3 times per week over several months. The way-finding symptoms quickly disappeared and remained way-finding-free for the duration of treatment, returning whenever treatment was discontinued.

[0009] The two major subtypes of vascular dementia are i) large cortical infarcts, or multi-infarct dementia (MID), and ii) dementia associated with small vessel disease, or subcortical vascular dementia. Both of the two patients treated by author Kamei had subcortical vascular dementia, which is caused by disruption of the vasculature in the subcortical white matter-rich areas of the brain. The International Classification of Diseases (10th Edition) (ICD-10) criteria for vascular dementia explicitly identify subcortical vascular dementia as a subgroup [Wetterling et al., Dementia. 1994;5(3-4):185-188]. Thus, subcortical vascular dementia incorporates the long-standing "lacunar state" and "Binswanger's disease" concepts and is associated with small vessel disease and hypoperfusion, resulting in focal and diffuse ischemic white matter lesions and incomplete ischemic injury (Erkinjuntti, 1997). On the other hand, most dementia patients suffer from the first type, which results from very different pathophysiological processes, affecting the cortical areas of the brain and representing different defects.

[0010] Furthermore, both patients in Kamei 1996a were sporadic wanderers, wandering 2–3 days per week, primarily exhibiting wayfinding deficits and no other problematic behaviors. Kamei also published another paper in 1996 with essentially identical findings (Kamei 1996b). Prior to these publications, Kamei filed a patent application in Japan (Patent Application No. 6-293643) based on the same two patients and a third patient in the publication. It should also be noted that Kamei 1996a presented two cognitive measures that are very similar and usually yield very similar results: the Mini Mental State Exam (MMSE) and the Hasegawa Dementia Score (HDS). In fact, the HDS typically scores patients with dementia as more severe than the MMSE (Kim 2005), and furthermore, not only are MMSE scores in Kamei 1996a consistently worse than the HDS, but the different scores provide dramatically different understandings of the patient population: the HDS suggests that patients had only mild dementia, whereas the MMSE suggests moderate to severe dementia.

[0011] There is no evidence that Kamei's research on subcortical vascular dementia can be extrapolated to cortical or nonvascular forms of dementia, nor to persistent wanderers or wanderers without wayfinding deficits. The etiology, pathology, and symptoms of subcortical and cortical vascular dementia have been well characterized. Large-vessel cortical stroke and subcortical small-vessel disease tend to produce different types of deficits. Characteristic symptoms of subcortical dementia typically include forgetfulness, slowed thought processes, mild intellectual disability, apathy, inertia, depression (sometimes accompanied by tantrums), loss of recall, and inability to manipulate knowledge. In addition, patients with subcortical dementia have mood disorders. Other behavioral abnormalities, such as repetitive and compulsive behaviors, occur in some patients with subcortical dementia. In general, the presentation of subcortical dementia is more subtle, temporally progressive, and often explained as a deficit in executive function in subcortical dementia. This includes deficits in speed and "strategic" processing (ie, attention, planning, and monitoring) in tasks such as memory tasks.

[0012] In contrast, cortical vascular dementia is associated with aphasia, dyslexia, and amnesia.

[0013] Memory is impaired in both subcortical and cortical vascular dementia. However, in cortical vascular dementia, recall abnormalities result from a failure to properly encode information or a decline in memory consolidation. Behavioral changes can include lethargy, lack of spontaneity, and perseveration. In contrast, subcortical disorders exhibit deficits in spontaneous recall, but encoding and memory are largely preserved, allowing for aided recall. Subcortical dementia is characterized by a relatively mild retrograde amnesia that affects all periods equally, as there is erroneous retrieval of normally stored information. It is this recall deficit that results in the wayfinding problems of subcortical vascular dementia.

[0014] Subcortical and cortical dementias are diagnosed separately. White matter hyperintensities (i.e., subcortical) are thought to result from cerebral small vessel disease, particularly in large volumes. This damage can be quantified using the Fazekas scale: 0 (no lesions), 1 (punctate lesions), 2 (early confluent lesions), and 3 (confluent lesions). A Fazekas score of 1 can be considered normal, while scores of 2 and 3 indicate the presence of small vessel disease. A score of 3 is abnormal at any age. The presence of confluent lesions in the frontal and parietal lobes indicates extensive white matter pathology (>25%) and can be used to diagnose (subcortical) vascular dementia. Lacunar infarcts involving multiple basal ganglia and frontal white matter, as well as bilateral thalamic lesions, also aid in the diagnosis of subcortical vascular dementia.

[0015] Strategic large vessel infarction may present with cortical dementia if it involves the following areas: bilateral anterior cerebral arteries, paramedian thalamus, medial inferior temporal lobe, parietotemporal lobe and temporo-occipital association areas, as well as the angular gyrus, superior frontal and parietal watershed areas in the dominant hemisphere.

[0016] A central issue in interventions targeting cortical dementia is the question of association versus causation. For an intervention to be useful in treating the disease, the chain of causation must be broken. AD, the most common form of dementia, provides a highly instructive case study. Two characteristic pathological findings of AD are extracellular amyloid plaques and interneuronal neurofibrillary tangles (NFTs).

[0017] Although Aβ, tau, and neuroinflammation are certainly associated with AD, it is unclear whether they are causally involved, and therefore whether affecting any of them would have any therapeutic benefit in treating the disease. Based on our understanding of familial disease, Aβ is thought to initiate the neurodegenerative process by inducing tau pathology, neuroinflammation, and ultimately neuronal loss, which leads to cognitive decline. In other words, Aβ is at the beginning of the causal chain. By halting Aβ pathology, the disease should be halted, and currently, most therapeutic approaches target Aβ.

[0018] However, despite an overwhelming literature showing promise in targeting Aβ in animal models, no products have been shown to work in AD (Ceyzeriat et al., Current Alzheimer Research 17:1-13 (2020)). These failures notably include anti-Aβ42 plus Freund's adjuvant, bapineuzumab, solanezumab, aducanumab, verubecestat, lanabecestat, atabecestat, CNP520, elenbecestat, γ-secretase inhibitors, bryostatin, and PBT2, among many others.

[0019] Tau is difficult to target because there is evidence that it is downstream of Aβ, and therefore not causative, so clinical trials are infrequent. Notably, of the 15 TAU-targeting clinical trials that have been initiated, four have already been halted.

[0020] The role of neuroinflammation, a third putative intervention target in AD, is unclear. While it is likely beneficial in early disease, it may also have adverse effects through its participation in the proinflammatory cytokine production and oxidative stress loop. Epidemiological studies suggest that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of developing AD and reduce amyloid burden in transgenic models, but prospective studies testing anti-inflammatory drugs to date have not shown beneficial effects on cognition in AD. Research targeting neuroinflammation is ongoing, but early results are not encouraging. Neflamapimod, a selective inhibitor of p38 mitogen-activated protein kinase, demonstrated efficacy in animal models but had no effect on Aβ deposition in humans. Despite reducing tau in cerebrospinal fluid (CSF), it failed to achieve its primary endpoint of improving episodic memory in phase 2 trials.

[0021] Given the number of clinical failures of compounds that appeared promising in animal models, a serious degree of skepticism should be applied to the interpretation of animal data. Even setting aside the obvious issue of differences in brain complexity between rodents and humans, many existing models only bear a passing resemblance to the human condition. While many things can cause neurodegeneration in animals and many putative drugs can halt that neurodegeneration, the underlying pathophysiology and causal chain are unclear, and this is where disease-modifying interventions must operate. Therefore, it is important that animal models with known deficits in the best cases, both pathological and clinical presentation, closely resemble human disease as much as possible.

[0022] Many publications have focused on the use of rho kinase inhibitors in various models of AD / dementia. Most models lack fundamental characterization. Some involve directly inducing neurotoxicity with drugs such as 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 treatment for AD itself. Even transgenic models are inadequate. For example, many transgenic mice exist, such as the APP / PS-1 mouse, which is perhaps the most widely reported transgenic model and develops only amyloid plaques without NFTs. Mice also exist that develop tauopathy without amyloid plaques, such as the rTG4510 tau mouse. AD is characterized by the presence of both. Some publications use impractical routes of administration (e.g., intracerebroventricular injection), and many do not use appropriate doses. In this regard, standard formulas exist for converting doses used in animals to the same dose 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 dosage in successful AD drug development and points out this as a point of failure in AD drug development.

[0023] There is published literature on the administration of fasudil in animal models of dementia. However, these studies are inadequate for many of the same reasons. Namely, the animal models do not faithfully recapitulate human disease, partly due to species differences in neuroanatomy (Sasaguri 2017) and partly due to the lack of fundamental pathological underpinnings of the models. In addition, some did not use physiologically relevant doses, and importantly, outcomes related to wandering were not measured in any of them. It is also important to note that a hallmark of pathogenesis in AD, the paradigmatic cortical dementia, is the failure of semantic memory, which cannot be measured in any animal model, so all animal models share this deficit. 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 oligomerization, but did not describe outcomes. Elliott (2018) used a triple transgenic mouse model (APP Swedish, MAPT P301L, and PSEN1 M146V) and observed in vivo reduction of β-amyloid plaques at a dose of 10 mg / kg / day (ip) of fasudil (57 mg HED). Sellers (2018) used the 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 intracerebroventricular infusion and observed effects on dendritic branching, but did not describe outcomes related to wandering. Aside from the absence of any behavioral outcomes in these references, intracerebroventricular administration is not a therapeutic option for humans. Yu 2017 and Hou 2012 observed that APP / PS1 transgenic mice (70, 140 mg HED) and streptozotocin-treated rats (226 mg HED) were given fasudil intraperitoneally at 5 and 10 mg / kg / day, respectively, and observed improved distance traveled and compartment time in the Morris water maze (a model of spatial learning and memory, but not wandering).Not all patients with cortical dementia wander, so there is no clear link between memory loss and wandering.

[0024] There are also contradictory reports. For example, Turk 2018 (dissertation) used triple transgenic mice and did not observe any improvement in spatial memory in 10- or 12-month-old mice treated with fasudil at 30 mg / kg and 100 mg / kg in water.

[0025] Based on currently available animal modeling, different therapeutic strategies targeting the pathological features of dementia have been tested, but none have been able to demonstrate beneficial effects in humans. Currently, available medications are limited to acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, which only show modest improvements in some cognitive symptoms. None of the existing or even proposed therapies address the problem of wandering in dementia, which is not treated by the aforementioned approved therapeutics. There is a significant unmet need to provide new therapies that demonstrate benefit not only in animals but also in humans. Summary of the Invention

[0026] One embodiment of the invention comprises a method of treating a patient with wandering due to cortical dementia, comprising treating the patient with a therapeutically effective amount of fasudil. In certain aspects of this embodiment, the dementia is multi-infarct dementia caused by ischemia and / or not caused by hemorrhage. In certain aspects of this embodiment, the patient does not have subcortical dementia. In another embodiment, the patient has mixed dementia (vascular dementia associated with dementia associated with proteinopathy). In another embodiment, the patient does not have mixed dementia. In a particular embodiment, the patient is female. In another particular embodiment, the patient has early-onset dementia. In yet a further particular embodiment, the patient has dementia associated with Down syndrome. In a further embodiment, the patient has Korsakoff syndrome. In another particular embodiment, the patient being treated has at least one ApoE ε4 allele.

[0027] A preferred aspect of the invention contemplates a method of treating a patient with wandering due to cortical vascular dementia, comprising treating the patient with a therapeutically effective amount of fasudil. In certain aspects of this embodiment, the dementia is multi-infarct dementia caused by ischemia and / or not caused by hemorrhage.

[0028] Another embodiment relates to treating a patient with wandering due to vascular dementia that is not Binswanger's disease or lacunar dementia, comprising treating the patient with a therapeutically effective amount of fasudil. In another embodiment, a patient being treated for wandering associated with cortical dementia does not exhibit emotional dysregulation or emotional incontinence, including, but not limited to, compulsive or inappropriate laughing and / or crying.

[0029] In certain preferred embodiments, the methods of the invention include methods of treating a patient with dementia-induced wandering, comprising treating the patient with a therapeutically effective amount of fasudil, wherein the patient has not previously been treated with fasudil for chronic stroke.

[0030] Yet another aspect of the invention includes a method of treating a patient with wandering due to dementia, wherein the patient does not exhibit wayfinding deficits, comprising treating the patient with a therapeutically effective amount of fasudil.

[0031] Another preferred embodiment includes a method of treating a patient with dementia-related wandering, wherein the patient engages in absconding, escapes, or boundary violations, comprising treating the patient with a therapeutically effective amount of fasudil. According to this embodiment, the patient may be a sporadic or persistent wanderer.

[0032] Yet another embodiment includes a method of treating a patient with wandering dementia, wherein the patient is a persistent wanderer who is active for at least 20% of their waking hours, comprising treating the patient with a therapeutically effective amount of fasudil.

[0033] In a further embodiment, the invention includes a method of treating a patient in which the progression of wayfinding deficits to absconding, escapes, or boundary violations is delayed or prevented upon treatment with fasudil.

[0034] In another embodiment, the invention includes a method of treating a patient for wandering, wherein the treatment precludes the use of chemical restraints, such as the use of antipsychotic medications (e.g., aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone).

[0035] In another embodiment, a patient being treated for wandering is in an unfamiliar environment, such as being moved from home to a nursing home, hi certain embodiments, treatment with fasudil reduces room intrusions of co-residents in the nursing home.

[0036] In a further embodiment, the patient being treated has recently undergone a change in medication, including antipsychotic medications, particularly those that induce akathisia.

[0037] In another embodiment, the patent being treated for wandering has a history of depression, anxiety, or schizophrenia. DETAILED DESCRIPTION OF THE INVENTION

[0038] The invention is based on the discovery that rho kinase inhibitors can be used to treat wandering in dementia patients whose dementia is cortical rather than subcortical. Multi-infarct dementia is considered a type of cortical dementia, even though there may be subcortical involvement. A preferred embodiment of the invention contemplates treating wandering in cortical vascular dementia. Another aspect of the invention contemplates treating wandering in dementia patients who are persistent wanderers who spend an excessive amount of their waking time engaged in activities. An additional important aspect of the invention includes treating wandering in dementia patients who do not exhibit wayfinding deficits.

[0039] ROCK inhibitors The method of the invention contemplates the administration of rho kinase (ROCK) inhibitors in the treatment of diseases or conditions. Two mammalian ROCK homologs are known: ROCK1 (also known as ROKβ, Rho kinase β, or p160ROCK) and ROCK2 (also known as ROKα) (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 the homology in the kinase domain is even higher (92%) (Jacobs 2006, Yamaguchi 2006). Both ROCK isoforms are serine / threonine kinases and have similar structures.

[0040] 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). Fasudil's distinctive chemical structure 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 undergoes hepatic metabolism to its active metabolite, hydroxyfasudil (also known as M3). Other examples of isoquinolone-derived ROCK inhibitors include dimethylfasudil and ripasudil.

[0041] 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. Still other preferred ROCK inhibitors include indazoles, pyrimidines, pyrrolopyridines, pyrazoles, benzimidazoles, benzothiazoles, benzthiophenes, benzamides, aminofurazans, quinazolines, and boron derivatives (Feng et al., 2015).

[0042] Some exemplary ROCK inhibitors are shown below: [ka]

[0043] 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 for ROCK1 or ROCK2 and have much lower activity against PKA, PKG, PKC, and MLCK.

[0044] Particularly preferred ROCK inhibitor is fasudil.Fasudil can exist as free base or salt, and can be in the form of hydrate such as hemihydrate.As used herein, it will be understood that the method of identifying the active moiety of ROCK inhibitor equally applies to their free acid or free base, salt, hydrate, polymorph and prodrug derivative.

[0045] [ka] Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine monohydrochloride hemihydrate

[0046] Fasudil is a selective inhibitor of protein kinases, including ROCK, PKC, and MLCK, and treatment 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, thereby reducing MLC phosphatase activity and improving vascular smooth muscle contraction. Furthermore, there is evidence that fasudil increases eNOS expression by stabilizing the mRNA for endothelial nitric oxide synthase, which contributes to increased 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 fasudil molecule, with slightly enhanced activity and a half-life of approximately 8 hours (Shibuya 2001). Therefore, M3 likely accounts for most of the molecule's pharmacological activity in vivo. M3 exists as two tautomers, shown below: [ka]

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

[0049] Pharmaceutical Compositions Pharmaceutical compositions of ROCK inhibitors that can be used in the invention are generally oral and can be in the form of tablets or capsules, immediate release formulations, or controlled or sustained release formulations, and can contain pharmaceutically acceptable excipients such as corn starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose, and similar substances. Pharmaceutical compositions containing ROCK inhibitors and / or salts thereof can 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 liquid as a slurry, or poured directly into the mouth.

[0050] Pharmaceutical compositions containing ROCK inhibitors, their salts and hydrates can be prepared by any method known in the field of pharmacy. Generally, such preparation methods include bringing the ROCK inhibitor or its pharmaceutically acceptable salt into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single-dose unit or multiple-dose unit.

[0051] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses.As used herein, " unit dose " is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of active ingredient that will be administered to subject, and / or a convenient fraction of such dosage, such as half or one-third of such dosage.

[0052] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. Compositions used in accordance with the methods of the invention may contain from 0.001% to 100% (w / w) of the active ingredient.

[0053] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfumes may also be present in the compositions.

[0054] In certain embodiments, the pharmaceutical composition used in the method of the present invention may contain a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, 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 contain a granulating agent and / or dispersing agent.Exemplary granulating agents and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (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 compositions used in the methods of the present invention may include a binder. Exemplary 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, extract of Irish moss, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM.RTM.), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0057] In certain embodiments, the pharmaceutical composition used in the method of the present invention may contain a preservative. Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol 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 compositions used in the methods of the present invention may contain an antioxidant. 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 can contain a chelating agent.Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salt and hydrate (for example, edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salt and hydrate (for example, citric acid monohydrate), fumaric acid and its salt and hydrate, malic acid and its salt and hydrate, phosphoric acid and its salt and hydrate, and tartaric acid and its salt and hydrate. Exemplary antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0060] In certain embodiments, the pharmaceutical composition may contain a buffering agent together with the ROCK inhibitor or its salt.Exemplary buffering agents 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 compositions used in the methods of the present invention may contain 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, the pharmaceutical composition containing a ROCK inhibitor or its salt will 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 active ingredients, liquid dosage forms can contain 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 oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, 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 mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) a humectant, such as glycerol; (d) a disintegrating agent, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) a solution retarder, such as paraffin. (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants 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 comprise buffering agents.

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

[0065] Certain patients with dementia may exhibit swallowing difficulties and require formulations such as semi-solid dosage forms (gels and jellies), orally disintegrating tablets, or sublingual dosage forms.

[0066] How to treat Dementia, broadly defined, results from damage to one of two areas of the brain: the cerebral cortex (also known as the cerebral cortex) and the subcortical area. Distinguishing between cortical and subcortical forms of dementia can often be done by observing the deficits and relating them to brain structures related to their function.

[0067] The lower cerebral cortex consists of three major divisions. The first is the basal ganglia, which is involved in motor control and skill learning. Deficits in this region result in either hypokinesia or hyperkinesia. Parkinson's disease and Huntington's disease affect the basal ganglia. The second is the limbic system, which primarily functions in the detection and expression of emotions. It consists of the amygdala, which detects frightening or threatening objects, and the hippocampus, which is involved in laughter. Connections between the amygdala, thalamus (part of the diencephalon), and hippocampus are associated with positive emotions. The hippocampus also plays an important role in learning, memory, and novelty detection. The third is the diencephalon, which consists of the thalamus and hypothalamus. The thalamus is the primary sensory transmitter between the sense organs for all senses except smell. The hypothalamus regulates body temperature, hunger, sexual behavior, and thirst.

[0068] The cerebral cortex is the outermost layer of the cerebrum. It is composed of four lobes and is involved in complex brain functions, including memory, attention, sensory awareness, "thinking," language, and consciousness. It also controls voluntary motor functions. Therefore, the cerebral cortex is often described in terms of its major sensory and motor areas.

[0069] The parietal, temporal, and occipital lobes are involved in generating perceptions resulting from what the eyes see, the ears hear, and other sensory organs provide information about the location of different parts of the body and relate them to the location of other objects in the environment. The parietal-temporal-occipital complex, especially in the left hemisphere, is responsible for understanding and using language. The frontal lobes are involved in planning actions and movements, as well as abstract thinking. The limbic area is involved in emotion and memory.

[0070] Motor areas are located in both hemispheres of the cerebral cortex. The primary motor cortex controls the execution of voluntary movements. The supplementary motor area and premotor cortex are involved in the selection of voluntary movements. The posterior parietal cortex guides voluntary movements in space. The dorsolateral prefrontal cortex is involved in deciding which voluntary movement to perform according to higher-level instructions, rules, and self-generated thoughts.

[0071] The table below shows some of the broad differences between the deficits seen in cortical versus subcortical forms of dementia. [Table 1]

[0072] Examples of cortical dementia include Alzheimer's disease (AD), vascular dementia, Lewy body dementia (LBD), frontotemporal dementia (FTD, Pick's disease), and frontotemporal dementia (FTD, primary progressive aphasia (PPA)).

[0073] Examples of subcortical dementias include Binswanger's disease (BD, lacunar dementia), Parkinson's disease (PD), Huntington's disease (HD) and multiple sclerosis (MS).

[0074] Just as dementia is not a single condition, wandering, which results from various underlying forms of dementia, is clearly not a single condition. Wandering is not simply a cognitive decline. Indeed, cognitive impairment correlates with the frequency of wandering cycles but not with wandering in other areas (Algase 2001b). Several lines of evidence demonstrate that wandering is a reflection of specific underlying pathologies of dementia types, or even subtypes.

[0075] First, wandering is more common in certain types of dementia than in others. Cooper (1993) found in a study of 1,312 dementia patients that wandering occurred in 26% of AD patients compared with 17% of VaD patients, a difference that reached statistical significance. The severity of wandering was related to the progression of dementia, but the higher prevalence of wandering in AD compared with VaD was consistent across the early, middle, and late stages of the disease. Klein (1999) confirmed differences in wandering rates between different forms of dementia in a study of 638 community-dwelling dementia patients, observing wandering in 14.1% of VaD patients and 21.4% of AD patients. Knuffman (2001) found that wandering was significantly more common in DLB than in AD.

[0076] Second, differences in wandering patterns across different forms of dementia suggest differences in pathology. Routine wandering, such as repetitive pacing and circling, is very common in FTD, whereas wandering tends to be rare and unpatterned in AD, and patterned wandering in VaD is even rarer than in either AD or FTD (Bathgate 2001). As the disease progresses, repetitive pacing and circling that develop into routine routes strongly predicts FTD and can be used to help distinguish FTD from AD (Nakaoka 2010). Furthermore, patients with AD become lost outside the home at a much higher rate than patients with VaD (41% vs. 20%) (Ballard 1991). Even between forms of AD, patterns can differ. Nakaoka (2010) observed that excessive (>10 km per day) unpatterned wandering was restricted to early-onset AD patients with significant levels of cognitive impairment.

[0077] Wandering can generally be characterized by two domains. The first domain is generally activity in the form of walking, unless the patient is disabled, e.g., wheelchair-bound. The second domain is problematic behavior, usually in the form of boundary violations and / or wayfinding problems. This may, however, be reflected in the activity itself, such as pacing or circling. This may include inappropriate following of a caregiver. Common problem behaviors are escape or disappearance attempts. A certain amount of activity can also be considered problematic behavior. Because a normal person engages in activity approximately 10% of their waking time, activity exceeding this threshold amount can be considered problematic behavior. If a patient engages in activity for at least 20% of their waking time, but preferably more than 30% of their waking time, the patient would be considered to be suffering from wandering. If a patient spends more time engaged in activity, the behavior becomes particularly problematic because there is a risk of fatigue and therefore a risk of falls and serious injury. Thus, some wandering patients are active for 40% or 50% of their waking time, some for more than 60%, 70%, or even 80%.

[0078] Wandering can be persistent or sporadic, and the present method can be used to treat either population. Persistent wanderers exhibit excessive activity nearly every day, typically at least 4-5 days per week. Sporadic wanderers, on the other hand, do not exhibit excessive activity; rather, they generally remain motionless with occasional activity, typically associated with absconding, boundary violations, escapes, or wayfinding deficits. Sporadic wanderers may exhibit this behavior infrequently, monthly, or frequently, two, three, or even four, five, six, or more times per week. Unlike persistent wanderers, sporadic wanderers do not spend an abnormally large amount of time moving. In a preferred embodiment of the invention, the treated patient wanders due to any form of dementia and does not exhibit wayfinding deficits; such patients may be persistent or sporadic wanderers.

[0079] In one specific embodiment, treatment with fasudil reduces the amount of repetitive wandering behavior (e.g., circling, pacing) in a patient by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces the amount of repetitive wandering behavior by 50% or more. In a preferred embodiment, treatment with fasudil reduces repetitive wandering behavior by at least 75%. In a preferred embodiment, treatment with fasudil reduces the amount of repetitive wandering behavior to 10% of normal behavior during waking hours.

[0080] In a further embodiment, treatment with fasudil reduces the number of occurrences of repetitive wandering behavior per day by at least 1 per day, preferably at least 2 per day, and more preferably at least 3 per day.

[0081] In a further embodiment, treatment with fasudil reduces the number of days on which repetitive wandering behavior occurs by at least 1 day per week, preferably at least 2 days per week, and more preferably at least 3 days per week.

[0082] In another specific embodiment, treatment with fasudil reduces persistent wandering by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces persistent wandering by 50% or more. In a preferred embodiment, treatment with fasudil hydrochloride hemihydrate reduces persistent wandering by at least 75%. In a preferred embodiment, treatment with fasudil reduces persistent wandering to 10% of normal activity during waking hours.

[0083] In a further embodiment, treatment with fasudil reduces the number of days of wandering occurring in persistent wandering by at least 1 day per week, preferably at least 2 days per week, more preferably at least 3 days per week.

[0084] In another embodiment, treatment with fasudil reduces sporadic wandering by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces sporadic wandering by 50% or more. In a preferred embodiment, treatment with fasudil reduces sporadic wandering by at least 75%. In a preferred embodiment, treatment with fasudil reduces sporadic wandering to 10% of normal activity during waking hours.

[0085] In another embodiment, treatment with fasudil reduces walking or circling by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces walking or circling by 50% or more. In a preferred embodiment, treatment with fasudil reduces walking or circling by at least 75%.

[0086] In another embodiment, treatment with fasudil reduces absconding behavior by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces absconding behavior by 50% or more. In a preferred embodiment, treatment with fasudil reduces absconding behavior by at least 75%.

[0087] In another embodiment, treatment with fasudil reduces spatial disorientation by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces spatial disorientation by 50% or more. In a preferred embodiment, treatment with fasudil reduces spatial disorientation by at least 75%.

[0088] In another embodiment, treatment with fasudil reduces caregiver burden associated with wandering by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces caregiver burden associated with wandering by 50% or more. In a preferred embodiment, treatment with fasudil reduces caregiver burden associated with wandering by at least 75%.

[0089] In another embodiment, treatment with fasudil reduces caregiver burden associated with one or more of persistent wandering, ambulation, disappearances, and spatial disorientation by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In another embodiment, treatment with fasudil reduces caregiver burden associated with one or more of persistent wandering, ambulation, disappearances, and spatial disorientation by 50% or more. In a preferred embodiment, treatment with fasudil reduces caregiver burden associated with one or more of persistent wandering, ambulation, disappearances, and spatial disorientation by at least 75%.

[0090] In a further embodiment, treatment with fasudil reduces the number of days of wandering occurring in sporadic wandering by at least 1 day per week, preferably at least 2 days per week, more preferably at least 3 days per week.

[0091] In another embodiment, treatment with fasudil reduces wandering that occurs at sunset or during the evening. In another embodiment, treatment with fasudil reduces wandering that occurs during the night. In one embodiment, the amount of wandering to determine the reduction can be measured using electronic motion and / or activity tracking devices, including fitness trackers such as Fitbit. Fitness trackers can be used alone or in combination with GPS devices to measure location.

[0092] The Revised Algase Wandering Scale (Long Term Care Version) is the preferred instrument for measuring wandering (Nelson and Algase 2006). It is divided into three distinct domains based on three major wandering typologies: persistent wandering (PW), expulsive behavior (EB), and spatial disorientation (SD). Each domain is assessed by individual items on a scale that can be quantified with a score of 1 to 4.

[0093] The overall domain score is calculated based on the number of questions with valid answers. Therefore, the individual scores are summed and divided by the number of questions in the domain that had valid answers. It is highly preferred that at least 75% of the items in the domain have valid responses. The result will be a score of 1 to 4.

[0094] Similarly, an overall scale score can be obtained by averaging each of the three domains, resulting in an overall score of 1 to 4. Alternatively, each individual item within the domain at the highest level of granularity may be rated individually.

[0095] RAWS may be completed by staff or caregivers.

[0096] The PW domain consists of nine individual items that focus on the amount of spontaneous walking, pacing and restless walking (which may indicate agitation), and the timing of wandering relative to mealtimes, which may indicate provocation to wander, both in absolute terms and compared with other similarly situated patients.

[0097] The EB domain consists of four items that measure escape, entering unauthorized areas, leaving authorized areas, and returning to authorized areas after leaving undetected.

[0098] The SD domain consists of six items and assesses getting lost, aimless walking, bumping into people and objects, and inability to locate a particular room.

[0099] In certain embodiments, patients treated according to the invention will show improvement in at least one item on the RAWS. In preferred embodiments, patients will show improvement in at least one domain of the RAWS. In particularly preferred embodiments, patients will show improvement in the PW and / or EB domains of the RAWS. Such improvement will generally be in the range of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. [Table 2] TIFF0007766935000006.tif231144 TIFF0007766935000007.tif202149

[0100] Another useful measurement tool for wandering is the Woolsey Wandering Questionnaire (WWQ), presented below. A significant feature of the WWQ is that it also captures caregiver burden with wandering behavior. This burden is assessed globally as a global impression and for each domain. It is administered weekly. Question 1 is a global impression of burden. Question 2 specifically focuses on persistent or spontaneous wandering. Question 3 specifically focuses on absconding. Question 4 focuses on wandering, a type of spontaneous walking that may be associated with agitation. Question 5 concerns spatial disorientation.

[0101] Each response is assigned a numerical value, with higher scores being assigned to more problematic behaviors (first responses). Thus, question 1, for example, would be scored as a 4 for very problematic behavior and a 1 if no wandering was observed. Question 2 would be scored on a 5-point scale, with a 5 being assigned for non-sedentary and above-average walking and a 1 for clearly below-average walking. In this manner, each question may be assessed individually, or the tool may be assessed as a whole. The overall assessment may be in terms of an overall score (all questions), a burden score (only the caregiver burden question), or a wandering score (only the behavioral portion of questions 2-5). [Table 3] TIFF0007766935000009.tif175150

[0102] According to the treatment methods of the present invention, an effective amount of a ROCK inhibitor or a pharmaceutically acceptable salt thereof for administration once or more times daily may comprise about 10 mg to about 1000 mg. Fasudil hydrochloride hemihydrate is suitably administered, for example, in amounts of 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, or about 20 mg to about 10 mg per day. One preferred dosing regimen involves treatment with 25, 30, or 40 mg of fasudil hydrochloride hemihydrate three times per day for a total daily dose of 75 to 120 mg, using an immediate-release formulation. Most preferred doses exceed a daily dose of 60 mg, with the most preferred daily dose range being 70 mg to 120 mg, administered in three equal doses over the course of a day. A particularly preferred daily dose is 90 mg per day. Further dosage regimens include treatment with 35-60 mg of fasudil hydrochloride hemihydrate only twice daily using an immediate-release formulation for a total daily dose of 70-120 mg. A preferred embodiment is 45 mg of fasudil hydrochloride hemihydrate twice daily using an immediate-release formulation. Most preferably, the ROCK inhibitors of the invention are administered orally using an immediate-release formulation, as described above.

[0103] Certain patient subpopulations, such as renal impairment and / or elderly patients (e.g., 65 years of age or older), may require lower doses or sustained-release formulations instead of immediate-release formulations. Fasudil hydrochloride hemihydrate, when given at normal doses to patients with renal disease, may have higher steady-state concentrations and may require lower doses to reduce Cmax or delay the time to Cmax (increase Tmax).

[0104] Renal dysfunction occurs with age as a result of numerous disorders, including liver cirrhosis, chronic kidney disease, acute kidney injury (e.g., due to the administration of contrast agents), diabetes (type 1 or type 2), autoimmune diseases (such as lupus and IgA nephropathy), genetic diseases (such as polycystic kidney disease), renal syndromes, urinary tract problems (from conditions such as prostate enlargement, kidney stones, and some cancers), heart attack, illicit drug use and abuse, ischemic kidney conditions, urinary tract problems, high blood pressure, glomerulonephritis, interstitial nephritis, bladder and ureter, pyelonephritis, and sepsis. Renal dysfunction can also occur in other diseases and syndromes that are not related to kidney function, including, for example, pulmonary arterial hypertension, heart failure, and cardiomyopathy, among others.

[0105] Renal function is most often assessed using serum (and / or urinary) creatinine. Creatinine is a product of the breakdown of creatine phosphate within muscle cells and is produced at a constant rate. It is excreted unchanged by the kidneys, primarily through glomerular filtration. Therefore, elevated serum creatinine is a marker of renal dysfunction and is used to estimate glomerular filtration rate.

[0106] Normal blood creatinine levels are approximately 0.6-1.2 mg / dL for adult men and 0.5-1.1 mg / dL for adult women. If the creatinine level exceeds these figures, the subject has renal dysfunction and is therefore treatable according to the invention. Mild renal impairment / impairment occurs in the range of 1.2 mg / dL-1.5 mg / dL. Moderate renal impairment / impairment 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). Treating subjects with mild, moderate, and severe renal impairment is specifically contemplated.

[0107] As indicated, creatinine levels are considered a surrogate for glomerular filtration rate, and serum creatinine levels alone may be used to estimate glomerular filtration rate using the Cockroft-Gault equation.

[0108] In general, a creatinine clearance of less than 60 mL / min (roughly corresponding to a creatinine of >1.2 mg / dL) is considered moderate renal impairment. A glomerular filtration rate of less than 40 mL / min (roughly corresponding to a creatinine level of more than 1.5 mg / dL), or especially less than 30 mL / min, is considered severe renal impairment.

[0109] In general, creatinine clearance (estimated glomerular filtration rate) can be derived directly from serum creatinine using the Cockroft-Gault equation: Creatinine clearance = (((140 - age) x (weight in kg)) x 1.23) / (serum creatinine in μmol / L)

[0110] For women, multiply the result by 0.85.

[0111] Additionally, by noting serum creatinine and urinary creatinine levels, empirically measured creatinine clearance can be used directly as an estimate of glomerular filtration rate. Specifically, urine is collected over a 24-hour period, and the following equation is applied to determine creatinine clearance: Creatinine clearance (mL / min) = urinary creatinine concentration (mg / mL) * 24-hour urine volume (mL) / plasma creatinine concentration (mg / mL) * 24 hours * 60 minutes

[0112] In one embodiment, the dose of fasudil for mild to moderate renal impairment is reduced to 50-80 mg per day, while in another embodiment, the dose of fasudil is not reduced but is administered once daily in a sustained release dosage form.

[0113] In another embodiment, the dose is not reduced in mild to moderate renal impairment.

[0114] In one embodiment, the dose of fasudil is reduced to 30-45 mg in severe renal impairment. In another embodiment, the dose of fasudil is not reduced, but instead is administered once daily in a sustained release dosage form.

[0115] In a further embodiment, the dose is reduced if serum creatinine (SCr) is >2, and / or the increase in SCr from baseline is >1.5-fold, and / or the decrease in eGFR from baseline is >25%.

[0116] Patient size is an important factor to consider when using creatinine-based estimates of renal function. The units for drug clearance are volume / time (mL / min), whereas the units for estimated GFR in chronic kidney disease are volume / time / standard size (mL / min / 1.73m). 2). In general, the dose may be adjusted downward for smaller patients (e.g., 40-50 mg per day) and upward for larger patients (e.g., 120 mg per day) in obese patients. A small male patient would weigh about 160 pounds or less. A small female patient would weigh about 130 pounds or less. Patients with a body mass index of 30 or greater are considered obese.

[0117] Additionally, elderly patients may require a lower dose initially, gradually increasing to the recommended dose after several days or weeks. In another embodiment, elderly patients may require a lower dose for the duration of treatment. Elderly populations include "early elderly" (65-74 years old), "late elderly" (75-84 years old), and "bedridden elderly" (85 years old or older). For example, a starting dose of 30 mg per day for two weeks, followed by 60 mg per day for four weeks, then 90 mg per day. Titration may be warranted, even up to approximately 120 mg per day.

[0118] Another embodiment involves treatment with 60 to 120 mg of fasudil hydrochloride hemihydrate in sustained-release form once daily. Treatment with sustained-release fasudil hydrochloride hemihydrate at a total daily dose of 90 mg once daily is preferred. It will be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents can be determined by a physician or skilled artisan and may be lower than or the same as the amount administered to adults.

[0119] The method of administering the composition of the invention will generally last 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, with treatment for at least 6 months being particularly preferred. The exact duration of treatment will depend on the patient's condition and response to treatment.

[0120] Patients treatable according to the invention will typically have low scores on cognitive scales such as the Mini-Mental State Examination (MMSE). A threshold of ≦23 on the MMSE is established for dementia, with a score of ≦15 representing severe dementia. Thus, the invention specifically contemplates treating patients with an MMSE score ≦23, including moderately demented patients with an MMSE score of 16-23 and severely demented patients with an MMSE score of ≦15. Generally, patients with an MMSE score below 9 may develop walking problems, and treatment of patients with an MMSE score below 5 is not recommended. Below an MMSE score of 15, the Severe Impairment Battery (SIB) is also a useful assessment metric. Treatment using the methods of the invention generally results in improved cognitive function. Patients typically show at least a 3-point improvement on the MMSE and SIB during the initial phase of treatment, and cognitive decline is slower compared to control patients.

[0121] The MMSE is fully described in Folstein (1975, 1987, 2007). Generally, an MMSE score of 24-30 indicates no cognitive impairment, a score of 18-23 indicates mild cognitive impairment, and a score of 0-17 indicates severe cognitive impairment.

[0122] The methods of the invention also contemplate administering a ROCK inhibitor with other compounds used to treat dementia or other symptoms of dementia, which may be administered in combination in a single dosage form in a common dosage regimen or may be administered to the same patient at different times of day using different dosage regimens.

[0123] In some embodiments, patients are administered fasudil in combination with other active agents approved for treating cortical 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 3-25 mg per day, more preferably 6-12 mg per day. In another embodiment, the NMDA receptor antagonist is memantine. In certain embodiments, memantine is administered at a dose of 5-28 mg per day, preferably 15-20 mg per day. In a further embodiment, the co-administered active is a combination of donepezil and memantine at doses of 28 mg memantine and 10 mg donepezil.

[0124] In certain embodiments, the combination of fasudil and a cholinesterase inhibitor is administered to a wandering patient with cortical dementia associated with proteinopathy. In further embodiments, the combination of fasudil and a cholinesterase inhibitor is administered to a wandering patient with mixed dementia. In yet further embodiments, the combination of fasudil and a cholinesterase inhibitor is not administered to a wandering patient with only vascular cortical dementia.

[0125] Dextromethorphan hydrobromide is another uncompetitive NMDA receptor antagonist that also has activity as a sigma-1 receptor agonist. Its marketed product, Nudexta, in combination with quinidine sulfate (a CYP450 2D6 inhibitor), is indicated for the treatment of emotional dysregulation that occurs in many forms of dementia.

[0126] In further embodiments, the patient treated with fasudil is also not being treated with active agents including mood stabilizers, benzodiazepines, antipsychotics, antistimulants, or sleep aids. In certain embodiments, the patient treated with fasudil is not being treated with risperidone, aripiprazole, quetiapine, carbamazepine, gabapentin, prazosin, trazodone, or lorazepam.

[0127] In a further embodiment, the patient being treated with fasudil is being treated for depression, hi a particular embodiment, the patient is being treated with an antidepressant, such as citalopram or escitalopram.

[0128] Example 1 A clinical trial will be conducted to determine the effectiveness of oral fasudil in reducing the frequency of wandering in patients with Alzheimer's dementia (AD) and cortical vascular dementia (VaD).

[0129] Twenty patients, 10 with AD and 10 with VaD (confirmed by MRI) characterized as wanderers, will be enrolled in the study and observed for two weeks to confirm wandering behavior. Confirmed wanderers will be administered open-label fasudil at 90 mg / day (30 mg TID) for six weeks to assess the effect on wandering, followed by a six-week double-blind phase in which they will receive either the test drug at 90 mg / day (30 mg TID) or a matching placebo (TID). The double-blind phase will be followed by another six-week treatment period with the opposite treatment assignment (placebo or test drug taken with food).

[0130] The following inclusion criteria apply: 1. Patients aged 50 to 90 years. 2. Diagnosis of dementia (AD or VaD or mixed type) for at least 6 months. 3. During the run-in period and the open-label treatment period: Wanderer: a. Gait that is significantly above average compared to others of the same age and ability; and / or b. ≥ 3 absconding behaviors per week in the opinion of the investigator Criteria for entry into the first double-blind treatment period: Wanderer: Walking less than half the average distance measured during the observation period, and / or b. <1 absconding behavior per week in the opinion of the investigator, and / or c. Wandering has improved in the opinion of the investigator. 4. During the run-in period and the open-label treatment period: a.MMSE of 10 to 25.

[0131] Wandering is measured using electronic tracking devices in terms of patterns such as time engaged in activity and distance traveled (measures of continued wandering), attempted and successful boundary violations (measures of absconding), and circumambulation (indicating continued wandering and / or agitation or anxiety). A typical tracking device would use a combination of accelerometry and position determination, using technologies such as RFID or Bluetooth in indoor environments and GPS outdoors. Other instances of wandering related to wayfinding, orientation, and memory are observed and manually recorded.

[0132] The Mini Mental State Exam (MMSE), Woolsey Wandering Questionnaire, and Revised Algase Wandering Scale will be administered at baseline and at the end of each treatment period. Alterations in antipsychotic or anxiolytic medication use that may affect performance during the study are strongly discouraged.

[0133] Treatment with fasudil is associated with a significant reduction in wandering on at least one item of the RAWS and / or WWQ. Persistent wanderers reduced their activity level while on medication by approximately 50% compared to placebo, which was accompanied by a mean increase in MMSE score of more than 3 points. Sporadic wanderers showed significant reductions in wayfinding errors and other problematic behaviors while on medication, with similar improvements on the MMSE. Measures of caregiver burden also showed significant effects, indicating fewer problems with wandering. Reference list Algase DL, Beattie ER, Bogue EL, Yao L. 2001a. The Algase Wandering Scale: initial psychometrics of a new caregiver reporting tool. Am J Alzheimers Dis Other Demen. 16:141-152. Algase DL, Beattie ER, Therrien B.2001b.Impact of cognitive impairment on wandering behavior.West J Nurs Res.23:283-95. Aud MA.Dangerous wandering:elopements of older adults with dementia from long-term care facilities.Am J Alzheimers Dis Other Demen.2004;19(6):361-368. Ballard CG, Mohan RNC, Bannister C, Handy S, Patel A. 1991. Wandering in Dementia Sufferers. Int J Geriatr Psych 6:611-614. Bathgate D,Snowden JS,Varma A,et al.2001.Behaviour in frontotemporal dementia,Alzheimer’s disease and vascular dementia.Acta Neurol Scand.103:367-378. 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. Cipriani G,Lucetti C,Nuti A,Danti S.2014.Wandering and dementia.Psychogeriatrics. 14:135-42. Cooper JK,Mungas D.1993.Risk factor and behavioral differences between vascular and Alzheimer’s dementias:the pathway to end-stage disease.J Geriatr Psychiatry Neurol.6:29-33. 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. Erkinjuntti T,Inzitari D,Pantoni L,Wallin A,Scheltens P,Rockwood K,Desmond DW.2000.Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials. Ann NY Acad Sci.903:262–72. [ PMC free article ] [ PubMed ] [ Cross Ref ] Feng Y, LoGrasso P, Defert O, Li R, Rho Kinase (ROCK) Inhibitors.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; 89:41-5 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. Human Rights Watch.2018.They Want Docile:How Nursing Homes in the United States Overmedicate People with Dementia.ISBN:978-1-623-135720.Downloaded 17 May 2019 from http: / / www.hrw.org. 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. Kim KW,Lee DY,Jhoo JH,Youn JC,Suh YJ,Jun YH,Seo EH,Woo JI,Diagnost accuracy of mini-mental status examination and revised Hasegawa dementia scale for Alzheimer’s disease.Dement Geriatr Cogn Disord.2005;19(5-6):324-30. Klein DA,Steinberg M,Galik E,Steele C,Sheppard JM,Warren A,Rosenblatt A,Lyketsos C,Wandering behaviour in community-residing persons with dementia.Intl J Geriatric Psychiatry.1999.14(4):272-279. Knuffman J,Mohsin F,Feder J,Grossberg GT.2001.Differentiating between lewy body dementia and Alzheimer’s disease:a retrospective brain bank study.J Am Med Dir Assoc.2:146-8. Lai CK,Arthur DG.Wandering behaviour in people with dementia.J Adv Nurs.2003;44(2):173-182. Logsdon R,Teri L,Mccurry S,Gibbons LE,Kukull WA,Larson EB,Wandering:A Significant Problem among Community Residing Individuals with Alzheimer’s Disease.The Journals of Gerontology Series B Psychological Sciences and Social Sciences.1998; 53(5):P294-9. 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 among institutionalized patients with dementia.Am J Alzheimers Dis Other Demen.25:167-72. Nelson & Algase (Eds) Evidence-based Protocols for Wandering Behaviour (2006),Springer:NY.Risk Model. Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al. Roman GC.2004.Facts,myths,and controversies in vascular dementia.J Neurol Sci.226:49-52. Rovner BW,Folstein MF.Mini-mental state examination in clinical practice.Hosp Pract.1987;22(1A):99,103,106,110. Salardini A.2019.An Overview of Primary Dementias as Clinicopathological Entities.Semin Neurol.39:153-166. 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.Alzeimer's & Dementia.2018; 14:306-3 Shibuya M,Asano T,Sasaki Y.2001.Effect of Fasudil HCl,a protein kinase inhibitor,on cerebral vasospasm.Acta 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,Inui J,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. US Census:www.census.gov 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. Yayama S,Yamakawa M,Suto S,Greiner C,Shigenobu K,Makimoto K.2013.Discrepancy between subjective and objective assessments of wandering behaviours in dementia as measured by the Algase Wandering Scale and the Integrated Circuit tag monitoring system.Psychogeriatrics.13:80-7. 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.

[0134] The disclosure of each reference cited herein is incorporated herein by reference in its entirety. The present invention includes the following aspects and embodiments. [Item 1] A method for treating a patient with wandering due to cortical dementia, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 2] The method according to Item 1, wherein the dementia is multi-infarct dementia. [Item 3] The method according to Item 1, wherein the dementia is caused by ischemia. [Item 4] The method according to Item 1, wherein the dementia is not caused by bleeding. [Item 5] A method for treating a patient with wandering due to cortical vascular dementia, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 6] The method according to Item 5, wherein the dementia is multi-infarct dementia. [Item 7] The method according to Item 5, wherein the dementia is caused by ischemia. [Item 8] The method according to Item 5, wherein the dementia is not caused by bleeding. [Item 9] A method for treating a patient with wandering due to vascular dementia that is not Binswanger's disease or lacunar dementia, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 10] A method for treating a patient with wandering due to vascular dementia, comprising treating the patient with a therapeutically effective amount of fasudil, wherein the patient has not previously been treated with fasudil for chronic stroke. [Item 11] A method for treating a patient with wandering due to vascular dementia resulting from hemorrhagic stroke without ischemic cerebral infarction, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 12] A method of treating a patient with wandering due to dementia, wherein the patient does not exhibit wayfinding deficits, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 13] A method of treating a patient with dementia-related wandering, wherein the patient has engaged in absconding, escapes, or boundary violations, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 14] The method according to Item 13, wherein the patient is a sporadic wanderer. [Item 15] A method of treating a patient with wandering dementia, wherein the patient is a persistent wanderer who is active for at least 20% of their waking hours, comprising treating the patient with a therapeutically effective amount of fasudil. [Item 16] The method according to Item 1, wherein the patient does not have subcortical dementia. [Item 17] The method according to Item 1, wherein the patient does not have an emotional dysregulation disorder.

Claims

1. A pharmaceutical composition comprising fasudil for treating wandering in patients with Alzheimer's disease, wherein fasudil is administered orally at a dose of at least 60 mg / day.

2. 10. The pharmaceutical composition of claim 1, wherein the patient has not been previously treated with fasudil for chronic stroke.

3. 10. The pharmaceutical composition of claim 1, wherein the patient does not exhibit a wayfinding defect.

4. 10. The pharmaceutical composition of claim 1, wherein the patient is involved in absconding, desertion, or boundary violations.

5. The pharmaceutical composition of claim 1, wherein the patient is a sporadic wanderer.

6. 10. The pharmaceutical composition of claim 1, wherein the patient is a persistent wanderer who is active for at least 20% of his waking hours.

7. The pharmaceutical composition of claim 1, wherein the patient does not have an emotional dysregulation disorder.

8. A pharmaceutical composition described in any one of claims 1 to 7, wherein fasudil is orally administered at a dose of 70 to 120 mg / day as fasudil hydrochloride hemihydrate.

9. The pharmaceutical composition of claim 8, wherein fasudil is administered orally at a dose of 90 mg / day.

10. The pharmaceutical composition of claim 1, wherein fasudil is administered orally two or three times daily.

11. A pharmaceutical composition described in any one of claims 1 to 10, wherein fasudil reduces the number of days per week that the patient wanders.

12. A pharmaceutical composition described in any one of claims 1 to 11, wherein fasudil is fasudil hydrochloride hemihydrate.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the patient is treated for at least 6 months.

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