Methods for Treating Agitation and Other Dementia-Related Behavioral Symptoms - Patent application

Abstract

The present invention is based on the discovery that rho kinase inhibitors, particularly fasudil, can be used to treat agitation / anxiety in dementia patients, particularly Alzheimer's disease patients. Fasudil treatment of Alzheimer's disease patients resulted in an improvement in agitation that was orders of magnitude greater than that observed with other potential therapeutic agents.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This is an international application under the Patent Cooperation Treaty, which claims priority to U.S. Provisional Patent Application No. 63 / 283,696, filed November 29, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Agitation is common in patients with Alzheimer's disease (AD) and other dementias. Agitation in these patients may manifest as verbal or physical agitation, irritability, anxious affect, disinhibited behaviors such as aggression, behavioral responses to delusions and hallucinations, and sleep and / or eating disorders. Agitation may be triggered by changes in routine, environment, or caregivers, discomfort (hunger, pain, drowsiness), fear, anxiety, fatigue, medications, or by navigating a confusing world. Patients experience increased agitation with increasing severity of dementia. Charernboon and Phanasathit observed high frequencies of agitation, aggression, abnormal behavior, and sleep problems in AD patients and found that the frequency of symptoms increased with disease severity. (Charernboon and Phanasathit 2014).

[0003] Agitation and / or aggression are estimated to affect up to approximately 80% of dementia patients (Ryu 2005; Tractenberg 2003). Agitation in AD and dementia patients leads to stress for caregivers, increased morbidity and mortality for patients, and earlier admission to nursing homes. Agitation and irritability are particularly threatening to the health and quality of life of dementia patients. For example, common paranoid delusions in dementia patients with agitation include believing there is an intruder in the house, personal belongings have been lost or stolen, someone is impersonating a family member, or that a spouse is cheating.

[0004] Current treatments for AD include nonpharmacological and pharmacological approaches, as appropriate. Nonpharmacological, behavioral approaches are challenging, time-consuming to implement, and not beneficial for nursing homes with low staff-to-resident ratios. Other nonpharmacological approaches include aromatherapy, lighting interventions, and environmental music therapy. Many patients do not respond to nonpharmacological approaches and often require pharmacotherapy. Currently, there are no FDA-approved pharmacological treatments for Alzheimer's agitation, and thus clinicians use antipsychotics, sedative / hypnotics, anxiolytics, and antidepressants off-label to attempt to control symptoms. Common medications used to treat agitation include beta-blockers such as propranolol and pindolol, anxiety medications such as buspirone, anticonvulsants such as valproate and lamotrigine, antipsychotics such as haloperidol and other high-potency dopamine blockers, and atypical antipsychotics. In AD, for example, pharmacological treatment often involves the use of atypical antipsychotics, whose modest efficacy outweighs safety and efficacy concerns that have led to a "black box" warning by the U.S. Food and Drug Administration (FDA). The use of these antipsychotics carries an increased risk of death and potentially life-threatening side effects, especially at higher doses (Maust 2015). Other adverse effects of antipsychotic use include increased cerebrovascular events, gait abnormalities, falls, and metabolic syndrome.

[0005] The U.S. Food and Drug Administration (FDA) recently approved pimavanserin for dementia-associated psychosis in Parkinson's disease, and the drug is currently in clinical trials to treat both psychosis and agitation in patients with AD, and is being tested for dementia-associated psychosis in multiple types of neurodegenerative disorders. Pimavanserin is a selective 5-HT2A receptor inverse agonist.

[0006] There is a continuing need for lower risk pharmacological agents to treat agitation and anxiety in patients with AD and other dementias, as well as in other diseases where agitation and anxiety are symptoms. Summary of the Invention

[0007] In one embodiment, a method is provided for treating agitation in a patient in need thereof with an effective amount of fasudil.

[0008] In one embodiment, a method of treating a patient having agitation-related dementia is provided, comprising treating said patient with a therapeutically effective amount of fasudil.

[0009] In some embodiments, the dementia results from, for example, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia, mixed dementia, dementia not otherwise specified, normal pressure hydrocephalus (NPH), and head injury, among others.

[0010] In a preferred embodiment, the dementia is Alzheimer's disease (AD), which is the most common cause of dementia, accounting for 60-80% of cases. (Alzheimer's Association. Alzheimers Dement 2016;12(4):459-509).

[0011] A preferred aspect of the present invention contemplates a method for treating a patient with agitation due to cortical dementia, comprising treating said patient with a therapeutically effective amount of fasudil.In a particular aspect of this embodiment, cortical dementia is proteinopathy-related dementia.Examples of cortical dementia are Alzheimer's disease (AD), vascular dementia, Lewy body dementia (LBD), frontotemporal dementia, frontotemporal lobe dementia (FTD) and primary progressive aphasia (PPA).

[0012] In another embodiment, the patient being treated for agitation has subcortical dementia. Examples of subcortical dementia are Binswanger's disease (BD; patchy dementia), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS).

[0013] In another embodiment, the patient treated with fasudil for agitation has agitation associated with disinhibitory symptoms of attention deficit hyperactivity disorder, conduct disorder, oppositional defiant disorder, Tourette's syndrome, Lesch-Nyhan syndrome, or post-traumatic stress disorder.

[0014] In certain embodiments, the fasudil administered to a patient with agitation is fasudil hydrochloride hemihydrate.

[0015] In one embodiment, fasudil is administered to a patient at a dosage of about 90-240 mg / day as an immediate release formulation.

[0016] In another embodiment, fasudil is administered to a patient in a sustained release formulation, wherein the maximum plasma concentration and the plasma area under the curve over 24 hours do not exceed by more than 15% those obtained using a dosing regimen of 90 to 240 mg / day as an immediate release formulation.

[0017] In certain embodiments, fasudil is administered to a patient twice daily (BID) or three times daily (TID).

[0018] In another specific embodiment, fasudil is administered to a patient at a dose of 90 mg TID.

[0019] In certain preferred embodiments, the methods of the present invention include methods of treating a patient with dementia-related agitation, the methods comprising treating said patient with a therapeutically effective amount of fasudil, wherein said patient has not been previously treated with fasudil for chronic stroke.

[0020] In another embodiment, the dementia patient being treated for agitation does not have or have a history of depression, anxiety, or schizophrenia.

[0021] In another embodiment, the dementia patient to be treated does not exhibit wandering behaviors such as aloofness, boundary deviations, or impaired wayfinding abilities.

[0022] In a further embodiment, the dementia patient being treated does not exhibit wandering behavior, loping, or excessive walking.

[0023] In certain preferred embodiments, treated patients have a measurable minimum amount of agitation before starting treatment.When measured by NPI-Q agitation / aggression domain, certain patients may have a minimum score of 4, and in full NPI, certain patients will typically have a minimum score of 6 in agitation / aggression domain.When assessed by CMAI-C, certain patients will have a threshold baseline minimum score of at least 5, generally at least 10 or 15, with a preferred minimum score of 20.Minimum scores of 16, 17, 18, 19, 21, 22, 23, 24, and 25 are also contemplated.

[0024] In some embodiments, improvement in agitation and / or aggression, and / or related symptoms in subjects with dementia such as AD due to treatment with fasudil may be measured by improvement in one or more of the Clinical Global Impression-Severity (CGI-S) scale for agitation, the Cohen-Mansfield Agitation Inventory Clinician Version (CMAI-C), Alzheimer's Disease Behavioral Pathology, and the Neuropsychiatric Index (NPI) including the Agitation subscale.

[0025] In one embodiment, improvement in agitation with Fasudil is assessed using the CMAI, hi one embodiment, improvement with Fasudil is at least 2.5 points, at least 5 points, at least 10 points, at least 12 points, at least 20 points, or at least 25 points.

[0026] In one embodiment, improvement of agitation with fasudil treatment is assessed using the NPI-Q and / or NPI4D scores. For the NPI-Q, a score of 0 is the absence of symptoms, and a score of 12 reflects daily occurrence of symptoms of marked severity.

[0027] In another embodiment, the patient's NPI4A score is reduced by at least 2.5 compared to the patient's baseline score prior to administration of fasudil.

[0028] In one embodiment, the patient's NP14A score is reduced by at least 3.0 compared to the patient's baseline score prior to administration of fasudil.

[0029] In other embodiments, treatment with fasudil reduces the patient's agitation by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to baseline, i.e., the amount of agitation prior to fasudil treatment.

[0030] In another embodiment, treatment with fasudil reduces the amount of agitation by 50% or more.

[0031] In certain embodiments, fasudil treatment reduces the number of occurrences of agitation, such as from multiple occurrences daily to one or zero occurrences per day, or from daily occurrences to non-daily occurrences.

[0032] In a further embodiment, treatment with fasudil reduces the number of days per week on which agitation occurs by at least 1 day per week, preferably at least 2 days per week, and more preferably at least 3 days per week.

[0033] In another embodiment, treatment with fasudil reduces the severity of agitation by reducing the number of episodes of verbal or physical aggression.

[0034] In another specific embodiment, fasudil treatment reduces the number of "sundowning" episodes per week or month. In a further embodiment, fasudil treatment reduces the duration or progression of evening agitation of sundowning. In a further embodiment, fasudil reduces the severity of behaviors associated with sundowning.

[0035] In another embodiment, treatment with fasudil reduces or halts the increase in agitation that occurs with the progression of dementia.

[0036] In another embodiment, treatment with fasudil reduces abnormal motor activity in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In a particular embodiment, treatment with fasudil reduces abnormal motor activity that occurs during sundowning or in the evening.

[0037] In another embodiment, treatment with fasudil reduces sleep disorders such as insomnia in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In certain embodiments, the weekly incidence of insomnia is reduced.

[0038] In another embodiment, treatment with fasudil reduces the incidence of delusional or hallucinatory behavior by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0039] In yet another embodiment, treatment with fasudil reduces anxiety in a dementia patient by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0040] In another embodiment, treatment with fasudil reduces disinhibition in a dementia patient by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0041] In further embodiments, treatment with fasudil reduces hostility and suspiciousness in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0042] In another embodiment, treatment with fasudil reduces eating or appetite disorders in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0043] In another embodiment, treatment with fasudil reduces caregiver burden associated with agitation by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0044] In one embodiment, the dementia patient with agitation is male. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The present invention is based on the discovery that rho kinase inhibitors, such as fasudil, can be used to treat agitation associated with dementia. Fasudil, an inhibitor of rho kinase, has been reported to have several potentially beneficial effects in CNS conditions, but

[0046] There is no level 1 evidence of treatment efficacy in either condition, meaning any potential medical applications remain speculative.

[0047] Greathouse et al., Behavioural Brain Research. 2019; 373:112083, report that depletion of rho kinase or treatment with fasudil induces anxiety-like behavior in mice. Six-month-old mice were administered 10 mg / kg fasudil or water by oral gavage once daily for 30 days. Behavior was assessed over the final 3 days of drug treatment by elevated plus maze and open field. Fasudil treatment significantly reduced the amount of time mice spent in the "open arms" portion of the maze, indicating anxiety. Genetic reduction of rho kinase inhibitors (heterozygotes for ROCK1 and ROCK2) showed the same behavior. It is generally understood that anxiety and agitation are strongly related and that agitation can be caused by anxiety. The present invention is based on the surprising discovery that despite the anxiogenic effects of fasudil in mice, fasudil can be successfully used to treat agitation.

[0048] The term "agitation" as used in this disclosure includes the definition of agitation provided in Cummings et al., International Psychogeriatrics. 2015; 27(1):7-17. In general, Cummings et al. define agitation as: 1) occurring in patients with cognitive impairment or cognitive syndrome; 2) exhibiting behavior consistent with psychological distress (such as sudden changes in mood, anxiety, irritability, outbursts, etc.) that persists for at least 2 weeks or recurs frequently and is a change from the patient's usual behavior; 3) the behavior is severe enough to cause undue impairment; and 4) the agitation is not simply due to another disorder (psychiatric, suboptimal care status, medical, or drug-related).

[0049] Agitation also includes the "sunset syndrome," a behavioral disorder that peaks in the late afternoon or early evening. Sunset syndrome affects up to two-thirds of dementia patients and is closely associated with circadian rhythm disorders.

[0050] Several rating scales are used to assess agitation, including the Cohen-Mansfield Agitation Inventory (CMAI; Cohen-Mansfield 1986), the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD Frequency Rating Scale; Monteiro 2001), and the widely used Neuropsychiatric Inventory (NPI; de Medeiros 2010). The Agitated Behavior Scale (ABS) assesses the nature and degree of agitation during the acute phase of recovery from acquired brain injury.

[0051] The 29-item CMAI was designed to measure the type and frequency of agitated behaviors. It is the most commonly used assessment, the current "gold standard," and is considered the only outcome measure accepted to date by regulatory agencies to approve pharmaceutical interventions for agitation. The CMAI consists of 29 items that form four subscales: physically aggressive behaviors (e.g., hitting others), physically nonaggressive behaviors (e.g., pacing), verbally aggressive behaviors (e.g., swearing), and verbally nonaggressive behaviors (e.g., repetitive sentences). The CMAI incorporates both the frequency and severity of behaviors associated with agitation, allowing the quantification of agitated behaviors to be a continuous measure that is sensitive to change. The CMAI asks the assessor to rate the subject's behavior over the past two weeks.

[0052] The CMAI-C is a 37-item scale for systematically assessing agitation using 35 specific symptoms, times of day of behavior, and frequency of "other" behaviors. Subjects are rated on a 7-point scale ranging from never (0) to several times per hour (6) for how often they exhibit physically aggressive behaviors, physically nonaggressive behaviors, and verbal agitation behaviors. The CMAI-C also asks raters to rate the subject's behavior over the past two weeks.

[0053] The NPI is an assessment that evaluates 12 behavioral domains and responses to treatment in patients with dementia. The total NPI score is a composite of scores from the standard 12 NPI domains: delusions, hallucinations, agitation / aggression, dysphoria / depression, anxiety, euphoria / elation, apathy / disinterest, disinhibition, irritability / lability, abnormal motor behavior, nocturnal behavior disorder, and appetite / eating disorder. The manualized NPI interview includes a composite screening question for each symptom domain, followed by a list of domain-specific behavioral questions that are administered when a positive response to the screening question is elicited. Each of the 12 items is scored based on the product of its frequency (1–4, sometimes, frequently, and very frequently) and its severity (1–3, mild, moderate, and marked), resulting in a maximum total score of 144. (Cummings 1997) The frequency and severity rating scales define anchor points to enhance the reliability of caregiver responses. Caregiver distress is assessed on a scale anchored by scores ranging from 0 (not at all distressed) to 5 (extremely distressed) for each positive neuropsychiatric symptom domain.

[0054] The original NPI included 10 neuropsychiatric domains, with two others added later: nocturnal behavioral disturbances and appetite / feeding changes. Another recent modification of the original NPI is the addition of a caregiver distress scale to assess the psychological impact of the neuropsychiatric symptoms reported to be present (Kaufer 1998). The NPI-Q includes both of these additions.

[0055] The clinician-rated form of the NPI, the NPI-C, has a broader scope, including neuropsychiatric features of MCI and severe dementia, high interrater reliability, and strong convergent validity for depression (assessed with the Cornell Scale for Depression in Dementia [CSDD]), psychosis (assessed with the Brief Psychiatric Rating Scale [BPRS]), apathy (vs. the Apathy Rating Scale [AES]), and agitation / aggression (vs. the CMAI).

[0056] One subdomain of the NPI is NPI4A, which is a composite score that includes the NPI agitation / aggression, abnormal motor behavior, irritability / lability, and anxiety domains (Dennehy 2013).

[0057] Other rating scales are also used. The ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, or "CGIC") uses a worksheet-based interview structure that prompts the assessor to assess specific neuropsychiatric symptoms. The ADCS-CGIC assesses patients in five treatment domains: 1) cognition (immediate and delayed memory, conduct, attention, and executive function), 2) clinical global change, 3) activities of daily living, 4) behavioral symptoms (agitation and other noncognitive symptoms), and 5) cognition in severely impaired patients (Schneider 1997). The ADCS-CGIC focuses on the clinician's observations of changes in the patient's cognitive, functional, and behavioral abilities since the start of the study. Unlike the targeted symptom scales, it takes into account the subject's overall functioning in the cognitive, behavioral, and functional activity domains. Scoring is based on interviews with caregivers and examination of the patient by an independent assessor and does not refer to other information such as cognitive test results. The ADCS-CGIC measures baseline global severity, scored from 1 (normal, not sick at all) to 7 (most sick patients); It measures global change at follow-up scored from 1 (marked improvement) to 7 (marked deterioration) (4 indicating no change).

[0058] The BEHAVE-AD (caregiver version) and experience version (E-BEHAVE AD) are reliable and valid 12-item clinician interview assessment instruments developed to assess behavioral pathology in Alzheimer's disease and related dementias. It rates 12 symptoms as 0 to 3 (not present to severely present), resulting in a maximum total score of 36. The Neurobehavioral Rating Scale (NBRS) is a 27-item observer-rated scale that measures a broad range of cognitive and noncognitive symptoms, including disinhibition (i.e., the ability to inhibit inappropriate behavior) and agitation. It has six levels ranging from "not present" to extremely severe. NBRS target symptoms include aggression, agitation, hostility, delusions, hallucinations, and suspiciousness.

[0059] ROCK inhibitors The method of the present invention contemplates the administration of the rho kinase (ROCK) inhibitor fasudil in the treatment of a disease or condition. 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 of the kinase domain is much higher (92%) (Jacobs 2006; Yamaguchi 2006). Both ROCK isoforms are serine / threonine kinases and have similar structures.

[0060] The method of the present 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 of the kinase domain is much higher (92%) (Jacobs 2006; Yamaguchi 2006). Both ROCK isoforms are serine / threonine kinases and have similar structures.

[0061] Several pharmacological ROCK inhibitors are known (Feng, LoGrasso, Defert, & Li, 2015). Isoquinoline derivatives are a preferred class of ROCK inhibitors. The isoquinoline derivative fasudil was the first small molecule ROCK inhibitor developed by Asahi Kasei Corporation (Tokyo, Japan). The characteristic chemical structure of fasudil consists of an isoquinoline ring linked to a homopiperazine ring via a sulfonyl group. Fasudil is a potent inhibitor of both ROCK isoforms. [ka]

[0062] In vivo, fasudil undergoes hepatic metabolism to its active metabolite hydroxyfasudil (also known as M3).Other examples of isoquinoline-derived ROCK inhibitors include dimethylfasudil and ripasudil.

[0063] Other preferred ROCK inhibitors are based on 4-aminopyridine structure. They were first developed by Yoshitomi Pharmaceutical (Uehata et al., 1997) and are exemplified by Y-27632. Still other preferred ROCK inhibitors include indazole, pyrimidine, pyrrolopyridine, pyrazole, benzimidazole, benzothiazole, benzothiophene, benzamide, aminofurazan, quinazoline, and boron derivatives (Feng et al., 2015). Exemplary ROCK inhibitors are shown below. [ka]

[0064] ROCK inhibitors according to the present invention may have more selective activity against either ROCK1 or ROCK2, and usually have various 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.

[0065] Fasudil is a preferred ROCK inhibitor for treating agitation according to the present invention. The isoquinoline derivative fasudil was the first small molecule ROCK inhibitor developed by Asahi Kasei Corporation (Tokyo, Japan). The characteristic chemical structure of fasudil consists of an isoquinoline ring linked 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 isoquinoline-derived ROCK inhibitors include dimethylfasudil and ripasudil.

[0066] Fasudil may be present as a free base or a salt, and may be in the form of a hydrate, such as a hemihydrate. As used herein, it will be understood that the methods for identifying the active moiety of a ROCK inhibitor apply equally to its free acid or free base, salts, hydrates, polymorphs, and prodrug derivatives. [ka] Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine monohydrochloride hemihydrate

[0067] Fasudil is a selective inhibitor of protein kinases such as ROCK, PKC, and MLCK, and treatment results in potent relaxation of vascular smooth muscle, leading to enhanced 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 enhancing vascular smooth muscle contraction. Furthermore, there is evidence that fasudil increases endothelial nitric oxide synthase (eNOS) expression by stabilizing eNOS mRNA, which contributes to increased levels of the potent vasodilator nitric oxide (NO), thereby enhancing vasodilation (Chen 2013).

[0068] Fasudil has a short half-life of about 25 minutes, but is substantially converted in vivo to its 1-hydroxy (M3) metabolite. M3 has effects similar to its fasudil parent molecule, with slightly enhanced activity and a half-life of about 8 hours (Shibuya 2001). Thus, M3 is likely responsible for most of the molecule's in vivo pharmacological activity.

[0069] The present invention includes pharma- ceutically acceptable salts and hydrates of Fasudil. Salts that can be formed through reaction with inorganic and organic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, maleic acid, oxalic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid, or para-toluenesulfonic acid.

[0070] Treatment method The present invention contemplates the treatment of agitation in dementia patients, particularly in AD patients. In one embodiment, fasudil is administered to dementia patients exhibiting agitation.

[0071] In certain embodiments, the baseline CMAI-C scores for aggressive behavior, non-aggressive agitated behavior, and verbal agitated behavior are about 13-15.

[0072] In another specific embodiment, the patient has a minimum NPI-Q agitation / aggression domain score of 4 or greater, or an NPI agitation / aggression domain score of 6 or greater, prior to administration of the first dose of fasudil.

[0073] In some embodiments, reduction in agitation is assessed using one or more of the following: NPI-Q, CMAI-C, ADCS-CGIC, BEHAVE-AD, ABS, and NBRS, or, where appropriate, the agitation / aggression subscale thereof.

[0074] In certain embodiments of the invention, the CMAI-C score for agitation / aggression in fasudil-treated patients is reduced by at least 5 points from baseline in dementia patients treated with fasudil. In other embodiments, the CMAI-C score for agitation / aggression is reduced by at least 10 points, at least 12 points, at least 15 points, at least 20 points, or at least 25 points from baseline after treatment with fasudil. It is specifically contemplated that improvement in CMAI-C may be driven by one or more domains of the CMAI-C, including the verbally aggressive, verbally non-aggressive, physically aggressive, and physically non-aggressive domains.

[0075] In another embodiment, the CGIC score for agitation in fasudil-treated patients is improved by at least 0.5 in patients treated with fasudil compared to untreated subjects or subjects receiving a placebo.

[0076] In another embodiment, the patient's NPI4A score is reduced by at least 2.5 compared to the patient's baseline score prior to administration of fasudil.

[0077] In one embodiment, the patient's NP14A score is reduced by at least 3.0 compared to the patient's baseline score prior to administration of fasudil.

[0078] In one particular embodiment, treatment with fasudil reduces the patient's agitation by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to baseline, i.e., the amount of agitation prior to fasudil treatment.

[0079] In another embodiment, treatment with fasudil reduces the amount of agitation by 50% or more.

[0080] In certain embodiments, fasudil treatment reduces the number of occurrences of agitation, such as from multiple occurrences daily to one or zero occurrences per day, or from daily occurrences to non-daily occurrences.

[0081] In a further embodiment, treatment with fasudil reduces the number of days per week on which agitation 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 embodiment, treatment with fasudil reduces the severity of agitation by reducing the number of episodes of verbal or physical aggression.

[0083] In another specific embodiment, fasudil treatment reduces the number of "sundowning" episodes per week or month. In a further embodiment, fasudil treatment reduces the duration or progression of evening agitation of sundowning. In a further embodiment, fasudil reduces the severity of behaviors associated with sundowning.

[0084] In another embodiment, treatment with fasudil reduces abnormal motor activity in dementia patients 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 another embodiment, treatment with fasudil reduces abnormal motor activity that occurs during sundowning or in the evening. In one embodiment, the reduction in abnormal motor activity can be measured using electronic movement and / or activity tracking devices, including fitness trackers such as Fitbits. Fitness trackers can be used alone or in combination with GPS devices to measure location.

[0085] In another embodiment, treatment with fasudil reduces sleep disorders such as insomnia in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In certain embodiments, the weekly incidence of insomnia is reduced.

[0086] In another embodiment, treatment with fasudil reduces the incidence of delusional or hallucinatory behavior by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0087] In yet another embodiment, treatment with fasudil reduces anxiety in a dementia patient by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0088] In another embodiment, treatment with fasudil reduces disinhibition in a dementia patient by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0089] In further embodiments, treatment with fasudil reduces hostility and suspiciousness in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0090] In another embodiment, treatment with fasudil reduces eating or appetite disorders in dementia patients by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0091] In another embodiment, treatment with fasudil reduces caregiver burden associated with agitation by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0092] In one embodiment, the dementia patient with agitation is male.

[0093] Dosage and Administration According to the treatment methods of the present invention, an effective amount of fasudil or a pharma- ceutically acceptable salt thereof (such as fasudil hydrochloride hemihydrate) for one or more daily administrations may comprise from about 10 mg to about 1000 mg.

[0094] For example, fasudil hydrochloride hemihydrate is suitably administered in a daily dose 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.

[0095] One preferred dosing regimen involves treatment with 25, 30 or 40 mg of fasudil hydrochloride hemihydrate three times a day for a total daily dose of 75-120 mg using an oral immediate release formulation. Most preferred dosing exceeds the 70 mg daily dose, with the most preferred range of daily dosing being 90-180 mg, administered in three equal doses over the course of the day.

[0096] A particularly preferred daily dose is 90 mg / day, with 30 mg immediate release tablets administered three times a day. Most preferably, Fasudil is administered orally as described above using an immediate release formulation. In another embodiment, Fasudil is administered at a dose of 180 mg / day, with 60 mg immediate release tablets administered twice a day.

[0097] Another embodiment includes treatment with 90-180 mg of fasudil hydrochloride hemihydrate once daily in sustained release dosage form, with treatment with a total daily dose of 90 mg of fasudil hydrochloride hemihydrate once daily in sustained release dosage form being preferred.

[0098] In one embodiment, fasudil is administered to a patient at a dosage of about 90-240 mg / day as an immediate release formulation.

[0099] In another embodiment, fasudil is administered to a patient in a sustained release formulation, wherein the maximum plasma concentration and the plasma area under the curve over 24 hours do not exceed by more than 15% those obtained using a dosing regimen of 90 to 240 mg / day as an immediate release formulation.

[0100] It is understood that the dose ranges described herein provide a guide for administration.Certain patient subgroups, such as renal impairment patients and / or older patients (e.g., 65 years 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 may require lower doses to reduce Cmax or delay time to Cmax (increase Tmax).

[0101] Additionally, elderly patients, typically those with dementia, may require a lower dose at the beginning, gradually increasing to the recommended dose after a few days or weeks. In another embodiment, elderly patients may require a lower dose during the treatment period. Elderly population includes "elderly" aged 65-74 years, "elderly" aged 75-84 years, and "frail elderly" aged 85 years or older. For example, a starting dose of 30 mg per day for 2 weeks, followed by 60 mg per day for 4 weeks, then 90 mg per day. Titration may be warranted up to about 180 mg per day.

[0102] The method of administering the composition according to the present invention generally continues for at least 1 day.Some preferred methods treat 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 depends on the condition of the patient and their response to treatment.

[0103] Patients treatable according to the present invention typically score low on rating scales designed to measure, or that contain subscales for, agitation.

[0104] Combination therapy The methods of the present invention also contemplate administering a ROCK inhibitor, such as fasudil, together with other compounds used to treat dementia or other dementia symptoms. They may be administered in combination, in a single dosage form, in a common dosing regimen, or may be administered to the same patient at different times of the day using different dosing regimens.

[0105] In some embodiments, the patient is administered fasudil in combination with a cholinesterase inhibitor and another active agent approved to treat 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 agent is a combination of donepezil and memantine at a dose of 28 mg memantine and 10 mg donepezil.

[0106] In certain embodiments, the combination of fasudil and a cholinesterase inhibitor is administered to an agitated patient with proteinopathy-associated cortical dementia. In further embodiments, the combination of fasudil and a cholinesterase inhibitor is administered to an agitated patient with mixed dementia.

[0107] In yet a further embodiment, the combination of fasudil and a cholinesterase inhibitor is not administered to agitated patients with vascular cortical dementia only.

[0108] Dextromethorphan hydrobromide is a noncompetitive NMDA receptor antagonist that also has activity as a sigma-1 receptor agonist. The 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.

[0109] In one embodiment, treatment with fasudil reduces or eliminates the need for use of mood stabilizers, benzodiazepines, antipsychotics, anti-agitation stimulants, or sleep aids.

[0110] In further embodiments, the patient treated with fasudil is not being treated with active substances including mood stabilizers, benzodiazepines, antipsychotics, anti-agitation stimulants, or sleep aids. In certain embodiments, the patient treated with fasudil is not being treated with haloperidol, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, lumateperone, carbamazepine, gabapentin, or valproic acid.

[0111] In another embodiment, the patient is treated with the aforementioned active agent but still exhibits agitation that justifies treatment with Fasudil, hi one embodiment, Fasudil treatment allows the patient to discontinue treatment with one of the drugs.

[0112] In another specific embodiment, the patient treated with fasudil is not treated with an anxiolytic.Anxiolytics, including alprazolam (Xanax), buspirone (BuSpar), lorazepam (Ativan), and oxazepam (Serax), often cause drowsiness.Paradoxically, they can also worsen confusion and agitation.

[0113] In further embodiments, the patient treated with fasudil may be treated for depression. In certain embodiments, the patient is co-treated with fasudil and an antidepressant, such as citalopram or escitalopram or trazodone or other selective serotonin reuptake inhibitors. In a preferred embodiment, the co-treatment is citalopram at 20-40 mg / day.

[0114] In one embodiment, the patient being treated with fasudil is not being treated with an antidepressant.

[0115] In one embodiment, fasudil can be administered in combination with dextromethorphan and quinidine, hi another embodiment, fasudil can be administered in combination with prazosin.

[0116] Pharmaceutical Compositions Oral dosage forms. The pharmaceutical composition of ROCK inhibitor for oral administration may be in the form of a tablet or capsule, may be an immediate release formulation, or may be a controlled release formulation or a sustained release formulation, which may contain pharmaceutically acceptable additives such as cornstarch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose, and similar substances. The pharmaceutical composition containing ROCK inhibitor and / or its salt may contain one or more pharmaceutically acceptable additives known in the art. Formulations include oral films, oral disintegrating tablets, effervescent tablets, and granules or beads that can be sprinkled on food or mixed with liquid as a slurry, or poured directly into the mouth and washed down.

[0117] Pharmaceutical compositions containing ROCK inhibitors, their salts and hydrates can be prepared by any method known in the pharmaceutical art. In general, such preparation methods include the step of bringing into association the ROCK inhibitor or its pharma- ceutically acceptable salt with the carrier or excipient, and / or one or more other accessory ingredients, and then, as necessary and / or desired, shaping and / or packaging the product into a desired single-dose or multi-dose unit.

[0118] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as single unit doses and / or as a plurality of single unit doses.As used herein, a "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 would be administered to a subject, and / or a convenient fraction of such dosage, such as, for example, half or a third of such dosage.

[0119] The relative amounts of the active ingredient, pharma- ceutically acceptable excipients, and / or any additional components in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as on 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) active ingredient.

[0120] The pharma- ceutically acceptable additives used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils.Additives such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and aromatic agents may also be present in the compositions.

[0121] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may include 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.

[0122] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include granulating and / or dispersing agents.Exemplary granulating 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, sponge, cation exchange resins, calcium carbonate, silicate, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0123] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a binder. Exemplary binders include starch (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, bread worm gum, ghatti gum, mucilage of isapol skin, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM.RTM.), and larch arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0124] 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, antiprotozoal 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.

[0125] 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, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0126] In certain embodiments, the pharmaceutical composition used in the method of the present invention can include 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. Exemplary antimicrobial 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.

[0127] In certain embodiments, the pharmaceutical composition may include 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, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0128] 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 oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0129] In other embodiments, the pharmaceutical composition containing the ROCK inhibitor or its salt is administered as a liquid dosage form.Liquid dosage forms for oral and parenteral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active ingredients, liquid dosage forms may 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 (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0130] 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 pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) excipients or fillers (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, jasmine, etc.), (e) glycerol, (f) glycerol, (g) glycerol, (h) glycerol, (i) glycerol, (j) glycerol, (k) glycerol, (l ... (e) solution retarders (such as paraffin), (f) absorption enhancers (such as quaternary ammonium compounds), (g) wetting agents (such as 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 glycols, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0131] Some compositions of the present invention relate to sustained 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 exit of dissolved drug from the dose. Dissolution-controlled products control the dissolution rate of the drug by using a slowly solubilizing polymer or by microencapsulation of the drug, using a variable thickness to control the release. Erosion products control the release of the drug by the erosion rate of the carrier matrix. Osmotic pump systems release the drug based on the constant influx of water across a semipermeable membrane into a reservoir containing an osmotic agent. Ion exchange resins can be used to bind the drug so that when ingested, the release of the drug is determined by the ionic environment in the gastrointestinal tract.

[0132] Parenteral dosage forms. Fasudil can be administered in parenteral dosage forms. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or infusion techniques.

[0133] Pharmaceutical compositions or formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, sealed ampoules, and vials, and may be stored in a lyophilized (lyophilized) state requiring only the addition of the sterile liquid carrier, water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0134] Parenteral pharmaceutical formulations may further contain vegetable oils such as peanut oil, cottonseed oil, sesame oil, and other acceptable liquid carriers in amounts that do not alter the aqueous nature of the formulation, including organic solvents, PEGs, propylene glycol, glycerol, and surfactants. 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.

[0135] Parenteral formulations may further comprise at least one of any suitable auxiliary agent, including, but not limited to, diluents, crystal inhibitors, isotonicity agents, water structure forming or disrupting agents, polymers, ion pairing agents, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable auxiliary agents are preferred. Examples and methods of preparing such sterile solutions are well known in the art and are described in REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990); Handbook of Pharmaceutical Excipients, 9 th Pharmaceutical compositions and methods for treating pulmonary circulation disorders are described in well-known textbooks, such as, but not limited to, The Journal of Clinical Chemistry, vol. 10, no. 10, pp. 1111-1120, 2011. Pharmaceutical compositions and methods for treating pulmonary circulation disorders are described in ...

[0136] In one embodiment, the aqueous parenteral pharmaceutical formulation contains at least 50% water, preferably 70% or more water. The pharmaceutical composition may be prepared by dissolving or suspending the compound in the liquid carrier such that the final formulation contains about 0.005% to 30% by weight of the compound.

[0137] Also provided are routes of administration and effective dosages of aqueous parenteral pharmaceutical formulations containing Fasudil.For parenteral administration, sterile suspensions and solutions are preferred.When intravenous administration is preferred, isotonic preparations are used, which generally contain suitable preservatives.The pharmaceutical composition may be parenterally administered by injection of a pharmaceutical composition containing Fasudil dissolved in an inert liquid carrier.

[0138] The preferred route of parenteral administration is intravenous.The pharmaceutical preparations described herein may also be administered by injection.The pharmaceutical preparations described herein may also be administered by bolus dose, and may optionally be combined with administration by injection.The compounds described herein may be administered in combination with other pharmaceuticals in various protocols for the effective treatment of disease. EXAMPLES

[0139] Example 1 A clinical trial was conducted to determine the efficacy of oral fasudil in reducing agitation in patients with Alzheimer's disease (AD).

[0140] Nineteen patients with Alzheimer's dementia were recruited and treated with fasudil HCl hemihydrate for 6 to 12 weeks. All patients were treated with 90 mg per day (30 mg TID) for 6 weeks, and a subset of patients was treated with 180 mg per day (60 mg TID) for an additional 6 weeks. Both treatment regimens were well tolerated. Various assessments were performed at baseline and end of treatment, including the NPI-Q and CMAI.

[0141] Patients were selected based on a minimum threshold of agitation at baseline at the end of treatment (not all patients had a particular threshold of agitation at baseline, and the threshold provided a population with a larger deficit to show improvement in order to demonstrate the effect of treatment on agitation). Two baseline thresholds were set and two analyses were performed based on the two resulting groups. One threshold was based on the agitation / aggression domain of the NPI-Q, and the other was based on the CMAI score. The NPI-Q-based selection threshold resulted in a smaller patient population than the CMAI-based threshold, but the results were very similar when the groups were analyzed using the CMAI score (the gold standard agitation assessment required by the FDA).

[0142] Primary selection was based on an NPI-Q score of 4 or greater. This threshold resulted in 6 patients who had a mean CMAI score of 45.3 at baseline. All members of this subgroup were treated with fasudil at 90 mg per day (30 mg TID) for 6 weeks.

[0143] RESULTS:The six patients with an NPI-Q score of 4 or greater had a mean CMAI score of 45.3 at baseline and a mean of 23.0 at the end of treatment, a difference of 22.3. [Table 1]

[0144] The second selection required a CMAI score of 20 or more at baseline, which resulted in a subgroup of 13 patients with a mean baseline CMAI score of 34.4. All patients in the second subgroup were treated with fasudil at 90 mg per day (30 mg TID) for 6 weeks, and 3 of the 13 were treated with fasudil at 180 mg per day (60 mg TID) for an additional 6 weeks. All patients selected using an NPI-Q agitation / aggression domain score of 4 or more were also included in this subgroup.

[0145] The analysis looked at pre-treatment CMAI scores and compared them to the last day of treatment (6 weeks for 10 low-dose patients and 12 weeks for 3 high-dose patients).

[0146] RESULTS:The 13 patients with a CMAI score of 20 or more had a mean CMAI score of 34.4 before treatment and 21.8 at the end of treatment, a difference of 12.6. [Table 2]

[0147] The outcomes of patients in both groups are highly relevant. A change of less than 5 points on the CMAI was considered clinically meaningful, and these changes were several times larger. The NPI-Q threshold resulted in a more stringent selection and a more dramatic effect, but the CMAI threshold also resulted in meaningful changes, so either threshold can be considered in selecting patients for treatment.

[0148] Finally, to examine the effect of changing the CMAI-C threshold, the cutoff was moved from 0 to 35, using 5-point increments. As the threshold increased, the magnitude of the observed effect also increased. It was concluded that, although higher thresholds were more powerful in detecting change, setting the CMAI-C threshold at least 5 produced meaningful results across populations. [Table 3]

[0149] References Charernboon T, Phanasathit M, Prevalence of neuropsychiatric symptoms in Alzheimer's disease: a cross-sectional descriptive study in Thailand. J Med Assoc Thai. 2014; 97, 560-565. 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. Cohen-Mansfield, Agitated behaviours in the elderly: II. Preliminary results in the cognitively deteriorated. JAGS. 1986; 34:722-7 Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997;48(Suppl 6):S10-6. Dennehy EB et al., Derivation of a brief measure of agitation and aggression in Alzheimer's disease. Int. Geriatr Psychiatry. 2013; 28(2): 182-9. de Medeiros K et al., The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int. Psychogeriatr. 2010; 22(6): 984-94. Feng Y, LoGrasso P, Defert O, Li R, Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J Med Chem. 2016; 59*6): 2269-2300. Greathouse et al., Fasudil or genetic depletion of ROCK1 or ROCK2 induces anxiety-like behaviors. Behavioural Brain Research. 2019; 373:112083. 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. Kaufer et al, Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease: The neuropsychiatric inventory caregiver distress scale. JAGS, 1998;46:210-215. Maust DT et al., Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015; 72(5): 438-45. Monteiro IM et al., Addition of a frequency-weighted score to the Behavioral Pathology in Alzheimer's Disease Rating Scale: the BEHAVE-AD-FW: methodology and reliability. Eur Psychiatry. 2001 Jan;16 Suppl 1:5s-24s. 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. Ryu et al., Persistence of and changes in neuropsychiatric symptoms in Alzheimer disease over 6 months: the LASER-AD study. Am. J. Geriatr. Psychiatry. 2005; 13(11):976-83. Shibuya M, Asano T, Sasaki Y. 2001. Effect of Fasudil HCl, a protein kinase inhibitor, on cerebral vasospasm. Acta Neurochir Suppl. 77:201-4. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. The Alzheimer's Disease Cooperative Study. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S22-32. Trachtenberg et al., Comorbidity of Psychopathological Domains in Community-Dwelling Persons With Alzheimer's Disease. J. Geriatr. Psychiatry. Neurol. 2003; 16(2):94-99. 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. 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.

[0150] The disclosure of each reference mentioned herein is incorporated herein by reference in its entirety.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of fasudil or hydroxyfasudil (M3) or a pharmaceutically acceptable salt thereof for treating agitation in a patient in need of such treatment.

2. The pharmaceutical composition described in claim 1, wherein the patient to be treated is suffering from dementia.

3. 3. The pharmaceutical composition of claim 1, wherein the dementia is selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia, and mixed dementia.

4. The pharmaceutical composition of claim 3, wherein the patient to be treated has Alzheimer's disease.

5. 2. The pharmaceutical composition of claim 1, wherein the agitation includes aggression, hostility, delusions, hallucinations, suspiciousness, insomnia, or abnormal motor behavior.

6. The pharmaceutical composition of claim 1, wherein the immediate release formulation is administered to a patient at a total daily dose of 90 mg to 240 mg of fasudil hydrochloride hemihydrate.

7. The pharmaceutical composition of claim 6, wherein a total daily dose of 90 mg of fasudil hydrochloride hemihydrate is administered to the patient at 30 mg TID.

8. The pharmaceutical composition of claim 2, wherein the patient to be treated has a minimum score of 20 or greater on the Cohen-Mansfield Agitation Inventory (CMAI-C).

9. The pharmaceutical composition described in claim 8, wherein the patient to be treated exhibits at least one of the following types of agitation as measured by the CMAI-C: physically aggressive, verbally aggressive, physically non-aggressive, and verbally non-aggressive.

10. The pharmaceutical composition of claim 8, wherein the treatment improves the CMAI-C by at least about 5 points from the patient's baseline score before treatment.

11. The pharmaceutical composition of claim 10, wherein the treatment improves the CMAI-C by at least about 12 points from the patient's baseline score before treatment.

12. The pharmaceutical composition of claim 1, wherein the patient to be treated has a Mini Neuropsychiatric Symptom Assessment Questionnaire agitation / aggression domain score of 4 or greater, or an NPI agitation / aggression domain score of 6 or greater.

13. The pharmaceutical composition of claim 12, wherein the treatment improves the NPI-Q agitation / aggression domain by at least about 1 point to at least about 3 points from the patient's baseline score before treatment.

14. The pharmaceutical composition of claim 1, wherein treatment reduces the number of incidents of agitation over a period of time.

15. The pharmaceutical composition of claim 14, wherein the treatment reduces the incidence of agitation per day.

16. The pharmaceutical composition of claim 14, wherein the treatment reduces the number of days per week on which agitation occurs.

17. The pharmaceutical composition of claim 14, wherein the treatment reduces the weekly number of occurrences, duration, or severity of evening agitation.

18. The pharmaceutical composition of claim 2, wherein the treatment delays the increase in agitation that occurs in dementia patients as the severity of dementia progresses.

19. The pharmaceutical composition of claim 1, wherein the patient being treated does not exhibit wandering behavior consisting of aloofness, boundary deviation, or impaired wayfinding ability.

20. The pharmaceutical composition of claim 1, wherein the patient being treated does not exhibit pacing, loitering, or excessive walking.

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