Methods for treating neurological disorders using alpha 1A-AR partial agonists

Abstract

In various aspects and embodiments, compositions and methods are provided for and for treating a disease or disorder in a patient, for example, a disease or disorder affecting the patient's brain.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Patent No. 62 / 926,392, filed October 25, 2019, the entire contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present disclosure in various aspects and embodiments relates to compositions and methods for treating a brain-related disease or disorder in a patient. [Background technology]

[0003] Background information PCT Patent Application Publication No. WO2008 / 112773 states, "This application is directed to the use of droxidopa, alone or in combination with one or more additional ingredients, for the treatment of conditions such as neuromediated orthostatic hypotension."

[0004] U.S. Patent No. 5,952,362 (Patent Document 2) discloses "various 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenyl alkylsulfonamides and ureas" and claims the use of alpha-amyloids in the treatment of various disease states such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, aging, Alzheimer's disease, attention deficit and cognitive disorders, and eating disorders such as obesity, bulimia, and anorexia. 1A / 1L The '362 patent discloses the compound N-[6-chloro-3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-methylphenyl]methanesulfonamide hydrochloride. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2008 / 112773 [Patent Document 2] U.S. Patent No. 5,952,362 Summary of the Invention

[0006] Current treatments for nOH (e.g., the indirect sympathomimetic droxidopa / norterra, or the nonselective α1-AR agonist midodrine) often pose a risk of supine hypertension. Therefore, as discussed in more detail elsewhere herein, selective α1-AR agonists are needed. 1A -AR partial agonists were used to 1A It alleviates the symptoms of nOH by moderately activating smooth muscle in venous branches through -AR receptors, while also promoting the activation of arteriolar smooth muscle (mainly α 1B -AR function and α 1D It is one objective of at least some of the methods disclosed herein to preserve vasoconstriction (vasoconstriction-associated vasoconstriction-restriction function) and therefore attenuate the increase in peripheral vascular resistance (no increase in "afterload") that leads to supine hypertension caused by other nOH treatments.

[0007] Thus, in a first aspect, a method for treating nOH is provided, comprising identifying a patient diagnosed with or in need of treatment for nOH and administering to the patient a 1A and administering an -AR partial agonist. In some embodiments, patients diagnosed with nOH meet at least one of the following diagnostic criteria: (1) a decrease in SBP of ≥ 30 mmHg (or ≥ 20 mmHg, or ≥ 25 mmHg, or ≥ 35 mmHg) within 5 minutes of standing, (2) impaired autonomic reflexes as determined by the absence of BP overshoot during phase IV of the Valsalva maneuver, (3) experiencing dizziness, lightheadedness, or syncope upon standing, and (4) the absence of other identifiable causes of autonomic dysfunction. In some embodiments, patients diagnosed with nOH meet at least two, or at least three, or all four of the diagnostic criteria.

[0008] In another embodiment, the method comprises identifying a patient diagnosed with or in need of treatment for nOH and administering α 1A and administering an α-AR partial agonist to the patient, wherein the patient's peripheral vascular resistance is not significantly elevated (no increase in "afterload"). In a related aspect, the method includes identifying a patient diagnosed with or in need of treatment for nOH, administering an α-AR partial agonist to the patient, and administering an α-AR partial agonist to the patient, wherein the patient's peripheral vascular resistance is not significantly elevated (no increase in "afterload"). 1A and administering an α-AR partial agonist to the patient, wherein the patient's supine systolic blood pressure is greater than or equal to α 1A - Not increase by more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the patient's blood pressure before administration of the AR partial agonist.

[0009] The term "partial agonist," as used herein, refers to a ligand that acts as an agonist at a receptor but does not reach the system's maximum response capacity even with full receptor occupancy; i.e., a partial agonist results in submaximal activation even when occupying the total receptor population and therefore fails to produce a maximal response regardless of the concentration applied. In some embodiments, a partial agonist exhibits a maximum efficacy that is less than 1%, or 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85% of the corresponding full agonist at the same receptor.

[0010] As used herein, "α 1A The term "α-AR partial agonist" refers to 1A - means a ligand that is a partial agonist of the α-AR receptor. 1ASpecific examples of α-AR partial agonists include RO1151240 (dabzalgurone) and Compound-B. In some embodiments, 1A -AR partial agonists are α 1A - exhibits a maximum efficacy (or intrinsic activity "IA") that is less than 10%, or less than 15%, or less than 20%, or less than 25%, or less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or between 15-75%, or between 20-65%, or between 20-60%, or between 20-55%, or between 20-50%, or between 20-45%, or between 25-60%, or between 25-55%, or between 25-35%, or between 30-40%, or between 40-50%, or between 45-55% of the intrinsic activity of the corresponding full agonist at the AR receptor (α 1A Examples of full agonists of the -AR receptor include noradrenaline and amidefrin. In certain related embodiments, in some embodiments, 1A An α-AR partial agonist exhibits a maximum efficacy (or intrinsic activity "IA") of less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, but more than 5%, or more than 10%, or more than 15%, or more than 20%. Blue et al., BJU International, (2004) 93:162-170 (incorporated herein by reference in its entirety) describes partial agonism, particularly α-AR partial agonism. 1A The present invention provides compositions and methods that can be used to determine partial agonism of the α-AR receptor, and exemplary α 1A In certain embodiments, α-AR partial agonists are 1AAn α-AR partial agonist has less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the activity of a full agonist using the InsPs accumulation assay described in Blue et al. (e.g., the intrinsic activity of RO 115-1240 (dabzalgulone) free base is 0.31 and the intrinsic activity of RO 115-1240 (dabzalgulone) HCl salt is 0.27 compared to noradrenaline in the InsPs accumulation assay; see Table 1 in Blue et al.). In some embodiments, an α-AR partial agonist 1A An α-AR partial agonist has less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the activity of a full agonist using the FLIPR assay described in Blue et al. (See, e.g., Table 1 of Blue et al., which shows an intrinsic activity of 0.51 for RO 115-1240 (dabzalgurone) HCl base compared to noradrenaline in the FLIPR assay). In many embodiments, an α-AR partial agonist has less than 35%, or less than 40%, or less than 45%, or less than 55%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the activity of a full agonist. 1A -AR partial agonists have a higher α-AR activity compared to full agonists 1A As used herein, α 1A The term -AR partial agonist, in some embodiments, contemplates any pharmaceutically acceptable salt, or prodrug thereof.

[0011] In some embodiments, α 1A -AR partial agonists are selective α 1AAs used herein, a "selective α-AR partial agonist" is a 1A -AR partial agonist" is an α 1A It exhibits partial agonism at the α1-AR receptor, but not at other α1-AR subtypes (e.g., α 1B -AR or α 1D Blue et al., BJU International, (2004) 93:162-170 (incorporated herein by reference in its entirety) discusses selective agonism (and selective partial agonism), and in particular α 1A The present invention provides compositions and methods that can be used to determine selective agonism (and selective partial agonism) of α-AR receptors, 1A As used herein, a selective α-AR partial agonist demonstrates exemplary selectivity. 1A -AR agonist or selective α 1A α-AR partial agonists (e.g., using the method described by Blue et al.) 1B -AR or α 1D -AR-expressing CHO cells)α 1B -AR or α 1D In some embodiments, a selective α-AR receptor, as used herein, does not exhibit agonist activity against other receptors, including the α-AR receptor. 1A -AR agonist or selective α 1A -AR partial agonist has an α of less than 8.0, or less than 7.5, or less than 7.0, or less than 6.5, or less than 6.0, or less than 5.5, or less than 5, or less than 4.5, or less than 4, or less than 3.5, or between 2.5 and 6, or between 3 and 5.5, or between 3 and 5.0, or between 3 and 5 1B -AR and α 1D -pEC for AR receptors 50 In some embodiments, the selective α as used herein 1A -AR agonist or selective α 1AAn α-AR partial agonist has an α-AR activity of less than 7.0, or less than 6.5, or less than 6.0, or less than 5.5, or less than 5, or less than 4.5, or less than 4, or less than 3.5, or between 2.5 and 6, or between 3 and 5.5, or between 3 and 5.0, or between 3 and 5, using the InsPs accumulation assay described by Blue et al. 1B -AR and α 1D -pEC for AR receptors 50 (e.g., α in InsPs accumulation assays) 1B -AR and α 1D pEC >4.0 for RO 115-1240 (dabzalgulone) free base and HCl salt at the -AR receptor 50 (See Table 1 of Blue et al., which shows the results of the selective α 1A -AR agonist or selective α 1A An α-AR partial agonist has an α-AR partial agonist (α-AR) of less than 7.0, or less than 6.5, or less than 6.0, or less than 5.5, or less than 5, or less than 4.5, or less than 4, or less than 3.5, or between 2.5 and 6, or between 3 and 5.5, or between 3 and 5.0, or between 3 and 5, using the FLIPR assay described by Blue et al. 1B -AR and α 1D -pEC for AR receptors 50 (e.g., α in FLIPR accumulation assays) 1B -AR and α 1D pEC >5.0 for RO 115-1240 (dabzalgulone) free base and HCl salt at the -AR receptor 50 (See Table 1 of Blue et al., which shows the results of the selective α 1A -AR agonist or selective α 1A -AR partial agonists are α 1B -AR and α 1D pEC of non-selective agonists such as noradrenaline for the -AR receptor 50α is less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of 1B -AR and α 1D -pEC for AR receptors 50 In some embodiments, the selective α as used herein 1A -AR agonist or selective α 1A -AR partial agonists were tested using the InsPs accumulation assay described by Blue et al. 1B -AR and α 1D pEC of non-selective agonists such as noradrenaline for the -AR receptor 50 α is less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of 1B -AR and α 1D -pEC for AR receptors 50 In some embodiments, the selective α as used herein 1A -AR agonist or selective α 1A -AR partial agonists have an α-AR activity of less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% using the FLIPR assay described by Blue et al. 1B -AR and α 1D -pEC for AR receptors 50 In some embodiments, the selective α as used herein 1A -AR agonist or selective α 1A The α-AR partial agonist may be administered at a concentration of 30 μMol / L or less, 50 μMol / L or less, 75 μMol / L or less, or 100 μMol / L or less (e.g., using the method described in Blue et al.). 1B -AR or α 1D -AR-expressing CHO cells)α 1B -AR or α 1D In some embodiments, the selective α 1A-AR agonist or selective α 1A -AR partial agonists have pK i In some embodiments, the selective α 1A -AR agonist or selective α 1A -AR partial agonists have pK i α is higher than 5.0, or higher than 5.5, or higher than 6.0, or higher than 7.0, or higher than 8.0, or higher than 9.0 1B -AR receptor also has α 1D It does not bind to the -AR receptor.

[0012] The term "dabzalgulone," or "RO1151240," or "Ro 115-1240," as used herein, refers to a compound having the following chemical structure: means the compound N-[6-chloro-3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-methylphenyl]methanesulfonamide having TIFF0007737367000001.tif33128 (see WO / 2017 / 147532).

[0013] In some embodiments, the term "dabzalgulone," or "RO1151240," or "Ro 115-1240," as used herein, refers to a pharmaceutically acceptable salt (such as the hydrochloride salt) or a prodrug thereof, or in other embodiments, the free base thereof. Blue et al., BJU International, (2004) 93:162-170, incorporated herein by reference in its entirety, describes α 1A Its partial agonist activity against the -AR and α 1A -Provides characteristics of dabzalgurone, including its specificity for AR.

[0014] The term "Compound-B" as used herein refers to the compound having the following chemical structure: The compound N-[2-chloro-4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-phenyl]-methanesulfonamide has the formula TIFF0007737367000002.tif39128.

[0015] In some embodiments, the term "Compound-B" as used herein is a pharmaceutically acceptable salt (such as a hydrochloride salt) or a prodrug thereof, and in other embodiments, the free base thereof.

[0016] The term neuro-orthostatic hypotension (nOH) as used herein refers to a condition in which a subject experiences a persistent drop in blood pressure when changing position or standing up from a supine or sitting position. Symptoms of nOH can include dizziness, lightheadedness, and / or a feeling of possible loss of consciousness, especially when suddenly standing up or changing position. nOH can be associated with various neurological disorders, such as Parkinson's disease, multiple system atrophy (MSA), and pure autonomic failure (PAH). More detailed information on the definition, diagnosis, and characteristics of nOH and its etiology is provided elsewhere herein.

[0017] In a further aspect, the present invention provides a method for identifying a patient diagnosed with or in need of treatment for a disease or condition associated with insufficient cerebral blood flow (CBF) and / or variations in CBF, and administering to the patient a 1A In a further aspect, a method is provided comprising identifying a patient diagnosed with or in need of treatment for a condition caused by insufficient cerebral blood flow (CBF) and / or fluctuations in CBF, and administering to the patient an α-AR partial agonist. 1Aand administering an -AR partial agonist. In some embodiments, the disease or condition associated with insufficient cerebral blood flow (CBF) and / or CBF fluctuations is selected from the group consisting of nOH, cognitive impairment, dementia with Lewy bodies, Parkinson's disease dementia, Alzheimer's disease, MSA, and PAH. In some embodiments, the patient treated by the methods disclosed herein is experiencing cognitive fluctuations, such as those associated with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD) (see Riley and Espay, Journal of Clinical Movement Disorders, (2018) 5:1).

[0018] In yet another aspect, the method comprises identifying a patient in need of treatment to increase cardiac output and / or to increase venous return, administering to the patient a 1A and administering a -AR partial agonist.

[0019] In yet another embodiment, (1) administering to the patient α 1A (2) monitoring the patient's blood pressure, cardiac contractility and stroke volume, ejection fraction, and / or venous return; and (3) if the patient's supine systolic blood pressure rises above 150, or 155, or 175, or 180, or 185, or 190, or 195, or 200, or 210, or 215, or 220, or 225, then administering an α-AR partial agonist to the patient. 1A and reducing the dose of the -AR partial agonist.

[0020] In some embodiments, there is provided a method of treating a patient as contemplated herein, the method comprising administering to the patient a 1A In some embodiments, a method of treating a patient as contemplated herein is provided, comprising administering to the patient an α-AR partial agonist at a daily dose of about 0.5 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 20 mg, or about 25 mg.1A In some embodiments, a method of treating a patient as contemplated herein is provided, comprising administering to the patient an α-AR partial agonist at a daily dose of about 0.5 mg, or about 1 mg, or about 3 mg, or about 5 mg, or about 7 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg. 1A In some embodiments, a method of treating a patient as contemplated herein is provided, comprising administering to the patient an α-AR partial agonist at a dose of about 0.5 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 20 mg, or about 25 mg. 1A -AR partial agonist at a daily dose of about 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, or 5 μg / kg, or 10 μg / kg, or 15 μg / kg, or 20 μg / kg, or 25 μg / kg, or 30 μg / kg, or 35 μg / kg, or 40 μg / kg, or 45 μg / kg, or 50 μg / kg, or 60 μg / kg, or 75 μg / kg, or 100 μg / kg, or 200 μg / kg, or 250 μg / kg, or 500 μg / kg, or 750 μg / kg, or 1 mg / kg.

[0021] In some embodiments, there is provided a method of treating a patient as contemplated herein, the method comprising administering to the patient α 1A -AR partial agonist, wherein the patient is 1A In some embodiments, the dose of the α-AR partial agonist is taken once daily, twice daily, three times daily, or four times daily. 1A The first dose of the -AR partial agonist is taken immediately after the patient wakes up in the morning. 1A The first dose of the -AR partial agonist is taken before noon. 1A All doses of the -AR partial agonist are taken before sunset. In some embodiments, the α-AR partial agonist is administered at 200 mg / day for any particular day. 1AThe last dose of the -AR partial agonist is taken at least about 1 hour, or at least about 2 hours, or at least about 3 hours, or at least about 4 hours, or at least about 5 hours, or at least about 6 hours before the patient goes to sleep at night. In some embodiments, the patient receives α-AR partial agonist doses at intervals of about 4 hours, about 5 hours, or about 6 hours. 1A In some embodiments, the patient receives a dose of an α-AR partial agonist immediately after waking up. 1A In some embodiments, patients receive a daily dose of an α-AR partial agonist immediately after waking up. 1A In some embodiments, patients receive a first dose of an α-AR partial agonist immediately after waking up, followed by a second dose 4-6 hours later. 1A In certain embodiments, administration early in the day results in a significant reduction in α-AR partial agonist activity compared to supine systolic blood pressure. 1A -mitigating any possible negative effects of AR partial agonists.

[0022] In certain embodiments of the methods described herein, α 1A -AR partial agonists are used to treat symptomatic nOH caused by primary autonomic failure (including pure autonomic failure, multiple system atrophy, and Parkinson's disease) or autonomic neuropathy (including diabetic and non-diabetic autonomic neuropathy). In another embodiment, the patient of the method described herein has multiple system atrophy and / or the patient has Parkinson's disease.

[0023] In some embodiments of the method as described herein, the patient has pure autonomic failure (PAF). In some embodiments of the method as described herein, the patient has multiple system atrophy (MSA). In some embodiments of the method as described herein, the patient has symptomatic nOH caused by autonomic neuropathy.

[0024] In some embodiments of the methods as described herein, the patient exhibits one or more symptoms selected from the group consisting of slowness, tremor, or rigidity (stiffness), clumsiness or incoordination, dysphagia, hoarse and trembling voice, fainting or lightheadedness due to orthostatic hypotension, sudden urgency to urinate or difficulty emptying the bladder, rigidity, tremor, balance, coordination, and bladder control problems such as autonomic nervous system dysfunction, ataxia (balance and coordination problems), difficulty swallowing, abnormal speech or trembling voice, abnormal eye movements, orthostatic hypotension, dry mouth, rapid heartbeat, tunnel vision, difficulty swallowing, bowel incontinence, blurred vision, urinary incontinence, constipation, anhidrosis, and sexual dysfunction.

[0025] In some embodiments of the methods of aspects and embodiments provided herein, the patient is diagnosed with MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (wellness), or The patient is identified as having one or more diseases or disorders selected from the group consisting of: Streptococcus aureus (STA), Streptococcus faecalis (STF ... In some embodiments, the patient is diagnosed with MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome), or other conditions. The patient is identified as having a neurodegenerative disease, which is one or more selected from the group consisting of: HIV-1-associated encephalopathy syndrome, alcoholic dementia and thiamine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related disease (such as CJD), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder).

[0026] In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a child. In some embodiments, the patient is an adult. As used herein, a child refers to a human between about 5 and 20 years of age. As used herein, an adult refers to a human about 21 years of age or older. [The present invention 1001] identifying a patient diagnosed with or in need of treatment for nOH; and administering α 1A and administering an -AR partial agonist. [The present invention 1002] and (4) identifying a patient diagnosed with or in need of treatment for nOH, wherein the patient meets at least one of the following diagnostic criteria: (1) a decrease in SBP of >20-30 mmHg within 5 minutes of standing, (2) an impairment of autonomic reflexes as determined by the absence of BP overshoot during phase IV of the Valsalva maneuver, (3) experiencing dizziness, lightheadedness, or syncope upon standing, and (4) no other identifiable cause of autonomic dysfunction. 1A and administering an -AR partial agonist. [The present invention 1003] identifying a patient diagnosed with or in need of treatment for nOH; and administering α 1A and administering an -AR partial agonist, The patient's peripheral vascular resistance is 1A - the method, wherein the IL-1 receptor is not significantly increased after administration of an IL-1 receptor partial agonist. [The present invention 1004] identifying a patient diagnosed with or in need of treatment for nOH; and administering α 1A and administering an -AR partial agonist, The patient's supine systolic blood pressure is 1A the patient's blood pressure does not increase by more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the patient's blood pressure before administration of the -AR partial agonist. [The present invention 1005] identifying a patient diagnosed with or in need of treatment for nOH, wherein said nOH in said patient is associated with one or more of Parkinson's disease, multiple system atrophy, and pure autonomic failure; and administering α 1A and administering an -AR partial agonist. [The present invention 1006] 1. A method for treating a disease or condition associated with insufficient cerebral blood flow (CBF) and / or variations in CBF, comprising: Identifying a patient diagnosed with or in need of treatment for a disease or condition associated with insufficient cerebral blood flow (CBF) and / or variations in CBF; and administering to said patient a 1A and administering an -AR partial agonist. [The present invention 1007] 1. A method for treating a disease or condition associated with insufficient cerebral blood flow (CBF) and / or variations in CBF, comprising: 1. Identifying a patient diagnosed with or in need of treatment for a disease or condition associated with insufficient cerebral blood flow (CBF) and / or variations in CBF, wherein the patient has been diagnosed with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD), and administering α 1A and administering an -AR partial agonist. [The present invention 1008] Identifying a patient experiencing cognitive fluctuations and diagnosed with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD) and administering alpha 1A and administering an -AR partial agonist. [The present invention 1009] identifying a patient in need of treatment to increase cardiac output and / or increase venous return; and administering to said patient a 1A - a method of treating a patient comprising administering an AR partial agonist. [The present invention 1010] The α 1A -AR partial agonist selective α 1A -Any method of the preceding invention, wherein the compound is an -AR partial agonist. [The present invention 1011] The α 1A -AR partial agonist, α 1A Any of the preceding methods of the invention, wherein the agonist exhibits a maximum efficacy that is less than 10%, or less than 15%, or less than 20%, or less than 25%, or less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or between 15 and 75%, or between 20 and 65%, or between 25 and 60%, or between 25 and 55%, or between 25 and 35%, or between 30 and 40%, or between 40 and 50%, or between 45 and 55% of the intrinsic activity of the corresponding full agonist at the -AR receptor. [The present invention 1012] The α 1A Any of the prior methods of the invention, wherein the -AR partial agonist exhibits a maximal efficacy that is less than 10%, or less than 15%, or less than 20%, or less than 25%, or less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or between 15 and 75%, or between 20 and 65%, or between 25 and 60%, or between 25 and 55%, or between 25 and 35%, or between 30 and 40%, or between 40 and 50%, or between 45 and 55% of the intrinsic activity of noradrenaline. [The present invention 1013] The α 1A -AR partial agonist, α 1B -AR and α 1D pEC of non-selective agonists for the -AR receptor 50 α is less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of 1B -AR and α 1D -pEC for AR receptors 50 any method of the preceding invention, comprising: [The present invention 1014] The α 1A -AR partial agonist, α 1B -AR and α 1D pEC of noradrenaline at -AR receptors 50 α is less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of 1B -AR and α 1D -pEC for AR receptors 50 any method of the preceding invention, comprising: [The present invention 1015] The patient's supine systolic blood pressure is 1A Any of the prior methods of the present invention, wherein the blood pressure of said patient does not increase by more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the patient's blood pressure before administration of the -AR partial agonist. [The present invention 1016] (1) α to the patient 1A (2) monitoring the patient's blood pressure and / or venous return; and (3) if the patient's supine systolic blood pressure rises above 150, or 155, or 175, or 180, or 185, or 190, or 195, or 200, or 210, or 215, or 220, or 225, then administering an α-AR partial agonist to the patient. 1A - reducing the dose of the AR partial agonist. [The present invention 1017] The patient receives a dose of the α1A Any of the prior methods of the present invention, wherein the -AR partial agonist is taken once a day, or twice a day, or three times a day, or four times a day. [The present invention 1018] The patient receives the first daily dose of the α 1A - Any of the methods of the preceding invention, wherein an AR partial agonist is administered. [The present invention 1019] The α 1A Any of the prior methods of the invention, wherein the -AR partial agonist is dabzalgulone. [The present invention 1020] The α 1A Any of the prior methods of the invention, wherein the -AR partial agonist is RO1151240 (dabzalgurone). [The present invention 1021] The α 1A Any of the prior methods of the present invention, wherein the -AR partial agonist is Compound-B. DETAILED DESCRIPTION OF THE INVENTION

[0027] Detailed Description of Specific Embodiments Some aspects and embodiments of the present disclosure are based, at least in part, on the use of relatively low doses of α 1A -α by AR partial agonist 1A The present invention is based on the discovery that partial agonism of the α-AR receptor can increase cardiac output resulting from improved venous return and myocardial contractility without a concomitant substantial increase in arteriolar vascular resistance, thus resulting in increased blood flow to various parts of the body, including the brain. Therefore, it is possible to identify patients with nOH or with diseases or disorders associated with insufficient cerebral blood flow (CBF) and / or CBF fluctuations, and administer α-AR therapy to these patients. 1A Compositions and methods are provided herein that include administering an -AR partial agonist.

[0028] While not wishing to be bound by any one particular theory in this regard, α 1A α-AR receptors are found preferentially on venous branches and on ventricular cardiomyocytes. 1AActivation of α1-AR receptors activates smooth muscle in venous branches, reducing venous capacitance and promoting blood return to the heart. It also activates myocardial cells, increasing pumping action, making it a cardiac agent with physiological inotropic effects. Increased venous return increases preload, thus increasing cardiac filling capacity, and the inotropic effect enhances ejection function. Both of these combine to deliver additional stroke volume to the arteries, resulting in relief of nOH symptoms. However, unlike the indirect sympathomimetic droxidopa / nortera, or the nonselective α1-AR agonist midline, α1-AR receptors do not have a direct effect on the cardiac function. 1A In certain embodiments, the -AR partial agonist inhibits arteriolar smooth muscle (primarily α 1B -AR and α 1D The cardiac output will be increased to a greater extent than the cardiac output (which functions via vasopressin-AR function), and peripheral vascular resistance will not be significantly increased (reduced "afterload" increase). Therefore, BP elevation will be less pronounced (especially in the supine position), and the increased cardiac output will readily perfuse the organs and brain.

[0029] Accordingly, the present disclosure includes methods and compositions for treating diseases, disorders, or conditions associated with or caused by impairment (or relative reduction) in one or both of (a) cardiac output and (b) venous return.

[0030] In certain aspects and embodiments of the present disclosure, the compositions and methods result in improved cognition in patients, increased brain metabolic activity, and / or improved inflammation control. In some embodiments, the methods described herein result in improved cognition, as demonstrated, for example, by improvements in the patient's cognitive test or model, memory test, mental state, brain function, diagnostic indicators of mental conditions, contextual learning test, or the like. Such cognitive tests, diagnoses, and models are well known in the art. In various aspects and embodiments, any of many accepted contextual learning tests for animals or humans can be used to assess baseline cognitive function and / or measure or quantify improvement in cognitive function. In some embodiments, the compositions and methods described herein can result in improvements in one or more tests, diagnoses, and models, such as: Similarly, increased cerebral metabolic activity and improved inflammation control can be imaged, in certain embodiments, through specialized methodologies including MRI (using arterial spin labeling [ASL] and which is blood oxygenation level dependent [BOLD]) and positron emission tomography approaches such as FDG-PET, and through sampling of cerebrospinal fluid (CSF) which allows for measurement of inflammatory cytokines and markers of glial cell activation.

[0031] Orthostatic hypotension (OH), also known as postural hypotension, is a form of hypotension that occurs when a person stands up. In medical terms, OH is defined as a drop in systolic blood pressure of at least 20 or 30 mmHg or a drop in diastolic blood pressure of at least 10 mmHg within 3 minutes of changing posture from supine to upright (Neurology 1996;46:1470). OH can produce a variety of symptoms, including dizziness, lightheadedness, and fainting (syncope), as well as discomfort in the upper chest and shoulder area ("coat hanger" pain). Due to these symptoms, OH often inhibits or even prevents daily activities that require standing and walking. In addition, OH is associated with increased morbidity and mortality. See, e.g., Jones et al, Expert Review of Cardiovascular Therapy, 2015;13:11, 1263-1276; Kuritzky et al., Postgrad. Med. 2015;127(7):702-715; and Low et al, J. Clin. Neurol., 2015;11(3):220-226.

[0032] The underlying causes of OH can be broadly divided into neurogenic and non-neurogenic categories. Neurogenic orthostatic hypotension (nOH) is a form of OH caused by peripheral or central nervous system disorders, such as primary autonomic failure (including pure autonomic failure, multiple system atrophy, and Parkinson's disease) and autonomic neuropathy (dysautonomia) (including diabetic and non-diabetic autonomic neuropathy) (Arbique et al., JAMDA 15 (2014) 234-239). Such disorders can cause a deficiency or dysregulation of norepinephrine, the primary neurotransmitter that regulates blood pressure in response to postural changes (Loavenbruck et al., Curr. Med. Res. Opin., 2015;31:2095-2104). As a result, the autonomic nervous system is unable to adequately regulate blood pressure during postural changes, and patients experience a significant drop in blood pressure that can result in, for example, dizziness, lightheadedness, or fainting.

[0033] Thus, management of the nOH condition most fundamentally requires increasing cerebral blood flow (CBF) in conjunction with the otherwise pathological drop in blood pressure upon postural change from supine to standing in a patient. In various aspects and embodiments of the compositions and methods provided herein, α 1A An -AR partial agonist is administered to patients with nOH, and the action of the partial agonist results in less frequent and less severe signs and symptoms associated with nOH, including lightheadedness / dizziness, pre-fainting symptoms, fainting / loss of consciousness, and "coat hanger pain." By maintaining better CBF, in some embodiments, patients will also maintain improved cognitive function, particularly cognitive function prone to "fluctuations," typically seen in the Parkinsonian syndrome (or "synucleinopathies") family of conditions often associated with nOH. A description of symptoms / tests / screening and some treatments for nOH can be found in Eschlbock et al., J Neural Tansm, (2017) 124:1567-1605 and Gibbons et al., J Neurol, (2017) 264:1567-1582.

[0034] One goal of certain more traditional nOH treatments is to increase norepinephrine levels in patients. One method of increasing norepinephrine levels is to administer a drug that produces norepinephrine. For example, droxidopa (L-threo-3-4-dihydroxyphenylserine) is an amino acid that is converted to norepinephrine by decarboxylation in both the central and peripheral nervous systems, thereby increasing norepinephrine levels (Kaufmann et al., Circulation, 2003;108:724-728; Kaufmann, Clin. Auton. Res. (2008) 18 [Suppl 1]:19-24); and Isaacson et al., Vascular Health and Risk Management, 2014, 10:169-176). Droxidopa is approved in the United States for the treatment of orthostatic dizziness, lightheadedness, or a "feeling of fainting" in adult patients with symptomatic nOH caused by primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy. The main side effect of droxidopa is supine hypertension, and this serious side effect warrants a black box warning in the drug's prescribing information.

[0035] Alternatively, norepinephrine levels can be increased in patients by inhibiting the norepinephrine transporter responsible for norepinephrine reuptake. For example, atomoxetine is a selective norepinephrine reuptake inhibitor approved in the United States for the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine has been shown to increase blood pressure in patients with central autonomic failure (Ramirez et al., Hypertension, 2014;64:1235-40, and Shibao et al., Hypertension, 2007;50:47-53). However, atomoxetine is primarily metabolized via the CYP2D6 enzyme pathway, and therefore its pharmacokinetic properties vary depending on whether the patient has reduced CYP2D6 activity (poor metabolizers) or normal CYP2D6 activity (extensive metabolizers) (Ring et al., Drug Metabolism and Distribution, 2002, 30:319-323). The prescribing information for atomoxetine also includes several warnings about possible drug-drug interactions. Additionally, when used to treat ADHD, atomoxetine is associated with several gastrointestinal adverse effects, including dry mouth and nausea. Atomoxetine is not approved for the treatment of nOH.

[0036] Other medications historically used to treat nOH include the α1-adrenergic receptor full agonist, midrin (and its active nonselective agonist metabolite, desglymidrin), the synthetic mineralocorticoid, fludrocortisone, and the cholinesterase inhibitor, pyridostigmine. Side effects of these medications can include supine hypertension, paresthesia (including scalp tingling), piloerection (goosebumps), and urinary urgency or retention for midrin; hypokalemia, headache, peripheral edema, heart failure, and supine hypertension for fludrocortisone; and abdominal discomfort and urgency for pyridostigmine.

[0037] In some embodiments, nOH can be diagnosed by a patient reporting signs and symptoms of nOH, including, for example, shaking, lightheadedness / dizziness, prefainting symptoms, fainting / loss of consciousness, and "coat hanger pain." Neurally mediated hypotension can be diagnosed, in some embodiments, by using the so-called "tilt table test," which reveals a drop in blood pressure and may reveal a decrease in heart rate when a subject is moved to a nearly upright position. In some cases, neurally mediated hypotension (NMH) is diagnosed by a drop in blood pressure alone. In other cases, such a diagnosis is made only when the drop in blood pressure is also accompanied by a drop in heart rate. The tilt table test measures heart rate and blood pressure while lying down (at rest) and then standing at a 70-degree angle for 45 minutes. The patient is lowered while a drug such as isoproterenol is administered via IV to increase the heart rate by approximately 10% above the resting heart rate, and then the patient is returned to the 70-degree angle for 15 minutes. The medication is increased to further increase the heart rate, and the patient is returned to an upright position for 10 minutes. Preferably, the testing environment is quiet and non-stimulating to eliminate distractions. Patients may be required to fast after midnight before the test (to reduce the incidence of nausea and vomiting). Patients are strapped to a table to avoid injury in the event of syncope and to reduce the human tendency to compensate for blood pooling in the legs by "frantic movement." The patient's vital signs are monitored throughout the tilt table test, and the test is determined to have a positive result for NMH if there is a "significant" decrease in blood pressure and a decrease in heart rate. As mentioned above, some physicians consider a decrease in blood pressure alone to be a positive diagnosis.

[0038] In one embodiment, α 1A -AR partial agonists are used to treat symptomatic nOH caused by primary autonomic failure (including pure autonomic failure, multiple system atrophy, and Parkinson's disease) or autonomic neuropathy (including diabetic and non-diabetic autonomic neuropathy). 1AThe -AR partial agonist is used to treat symptomatic nOH caused by primary autonomic failure. In this embodiment, the patient may be diagnosed with pure autonomic failure, multiple system atrophy, and / or Parkinson's disease. In one embodiment, the patient has pure autonomic failure. In another embodiment, the patient has multiple system atrophy. And in another embodiment, the patient has Parkinson's disease. Primary autonomic failure (also called primary autonomic dysreflexia) is a category of autonomic dysreflexia, i.e., a condition in which the autonomic nervous system does not function properly. In primary autonomic failure, autonomic dysfunction occurs as a primary condition, as opposed to a secondary condition resulting from another disease, such as diabetes. For example, autonomic failure is typically classified as "primary" when it results from a chronic condition characterized by degeneration of the autonomic nervous system, or when autonomic failure is the primary symptom and its cause is unknown. Conditions classified as primary autonomic failure include pure autonomic failure, multiple system atrophy, and Parkinson's disease.

[0039] Pure autonomic failure (PAF), also known as Bradbury-Eggleston syndrome or idiopathic orthostatic hypotension, is a degenerative disorder of the autonomic nervous system. The primary symptom of PAF is orthostatic hypotension. Other symptoms may include decreased sweating, heat intolerance, urinary retention, bladder spasms (potentially leading to incontinence), erectile dysfunction, fecal incontinence or constipation, and pupillary abnormalities. The cause of PAF is not fully understood, but cell loss within the intermediolateral columns of the spinal cord has been documented in patients with PAF. Additionally, PAF may be associated with abnormal accumulation of α-synuclein.

[0040] Parkinson's disease (PD) is a chronic and progressive movement disorder. While the cause is unknown, PD involves the malfunction and death of neurons in a region of the midbrain called the substantia nigra. These neurons produce dopamine, which plays a key role in movement and coordination. As PD progresses, the amount of dopamine produced in the brain decreases, leading to problems with motor control and coordination. Symptoms include tremor, rigidity, slowness of movement, and postural instability. However, some PD patients also experience non-motor symptoms, including orthostatic hypotension due to changes in the autonomic nervous system (PD-plus symptoms). In addition, some patients with PD symptoms have a condition known as Parkinson's-plus syndrome (or multiple system degenerative disorder). Parkinson's-plus syndrome is a group of neurodegenerative disorders that produce the classic symptoms of PD (tremor, rigidity, akinesia / bradycardia, and postural instability) with additional features that distinguish it from simple idiopathic PD. Clinical features that distinguish Parkinson's-plus syndrome from idiopathic PD include symmetric onset, absent or irregular resting tremor, and reduced response to dopaminergic medications (including levodopa). Additional features include bradycardia, early-onset postural instability, increased axial muscle rigidity, autonomic dysfunction, allotropic limb syndrome, supranuclear gaze palsy, apraxia, cerebellar involvement involving pyramidal cells, and in some cases, significant cognitive impairment.

[0041] Multiple system atrophy (MSA), also known as Shy-Drager syndrome, is a progressive neurodegenerative disorder characterized by a combination of symptoms affecting both the autonomic nervous system and movement. Early symptoms of MSA are often difficult to distinguish from those of Parkinson's disease and include slowness, tremor, or rigidity, clumsiness or incoordination, speech impairment, a hoarse, trembling voice, orthostatic hypotension causing fainting or lightheadedness, and bladder control problems, such as sudden urgency to urinate or difficulty emptying the bladder. MSA is divided into two distinct types, depending on the most prominent symptoms at the time an individual is evaluated: parkinsonian-type (MSA-P), with key features similar to Parkinson's disease (such as slow movements, rigidity, and tremors) along with problems with balance, coordination, and autonomic nervous system dysfunction; and cerebellar-type (MSA-C), with key symptoms characterized by ataxia (balance and coordination problems), difficulty swallowing, abnormal or trembling speech, and abnormal eye movements. The cause of MSA is unknown. A distinctive feature of MSA is the accumulation of the protein α-synuclein within neuroglia, cells that support nerve cells in the brain. These α-synuclein deposits occur specifically in oligodendrocytes, a type of cell that makes myelin (the coating on nerve cells that allows electrical signals to be conducted rapidly). Recent studies have indicated that a prion form of the α-synuclein protein may be the cause of the disease (Prusiner et al., PNAS, (2015) 112:E5308-17).

[0042] In one embodiment, α 1A-AR partial agonists are used to treat symptomatic nOH caused by autonomic neuropathy. Autonomic neuropathy, or dysautonomia, refers to a variety of conditions in which the autonomic nervous system (ANS) does not function properly. Autonomic neuropathy is a type of neuropathy that affects the nerves that carry information from the brain and spinal cord to the heart, bladder, intestines, sweat glands, pupils, and blood vessels. Key symptoms of autonomic neuropathy, which may vary between individuals, include orthostatic hypotension, dry mouth, rapid heart rate, tunnel vision, difficulty swallowing, bowel incontinence, blurred vision, urinary incontinence, constipation, anhidrosis, and sexual dysfunction. Autonomic neuropathy can result from a genetic or degenerative neurological disorder (primary dysautonomia) or can result from damage to the autonomic nervous system from an acquired disorder (secondary dysautonomia).

[0043] Riley and Espay, Journal of Clinical Movement Disorders, (2018) 5:1, described patients with Parkinson's disease dementia (PDD) who experienced cognitive fluctuations that correlated with the patient's blood pressure. Thus, in some aspects and embodiments, identifying a patient diagnosed with or in need of treatment for a disease or condition associated with insufficient cerebral blood flow (CBF) and / or fluctuations in CBF and administering alpha-amylindrical steroids to the patient is useful. 1A and administering an -AR partial agonist to a subject in need thereof. Patients treated by the methods disclosed herein are experiencing cognitive changes, for example, cognitive changes associated with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD).

[0044] In various embodiments, there are many contextual learning tests that are recognized and / or accepted in the art, and can be used in conjunction with the compositions and methods disclosed herein to assess baseline cognitive function and / or measure or quantify the improvement of cognitive function in human subjects.For example, the contextual learning test used can be based on single-task learning, multi-task learning, or spatial contextual memory.The contextual learning test assessment based on spatial contextual memory can be advantageous, for example, when assessing how well an individual can navigate a shopping mall, a neighborhood, or city transport or subway system, and when assessing any improvement in the ability to perform these tasks that results from the treatment methods described herein.

[0045] An example of a simple spatial context learning test is contextual cueing, where humans learn to repeatedly use spatial configurations to facilitate target search. A higher-order spatial context learning test is sequence learning, where humans learn to use subtle sequence regularities to respond more quickly and accurately to a sequence of events. For example, see JH Howard Jr., et al., Neuropsychology, Vol. 18(1), January 2004, 124-134.

[0046] In some embodiments, cognition may be assessed using the Mini-Mental State Examination (MMSE) and / or the Montreal Cognitive Assessment (MOCA).

[0047] Arizona Cognitive Test Battery (ACTB). A testing protocol that can be used in various embodiments is the Arizona Cognitive Test Battery (ACTB). See Edgin, J., et al. J. Neurodevelop. Disord. (2010) 2:149-164. The ACTB was developed specifically to assess the cognitive phenotype in DS and includes a variety of tests with varying task demands and associations with brain function. More specifically, tests are included for 1) benchmarks such as the KBIT II verbal subscale and KBIT II nonverbal subscale IQ tests, 2) hippocampal function, 3) prefrontal cortex function, 4) cerebellar function, 5) finger sequencing task, 6) NEPSY visual-motor accuracy, and 7) simple reaction time.

[0048] The domains / exams assessed according to ACTB, exam descriptions, and correlations of key competencies are provided below. TIFF0007737367000003.tif181155

[0049] With respect to the agents described herein, the terms "modulate" and "modulation" refer to the upregulation (i.e., activation or stimulation) or downregulation (i.e., inhibition or suppression) of a response. A "modulator" is a modulating agent, compound, or molecule, and may be, for example, an agonist, antagonist, activator, stimulator, suppressor, or inhibitor. The terms "inhibit," "reduce," and eliminate, as used herein, refer to any inhibition, reduction, decrease, suppression, downregulation, or prevention of expression, activity, or symptoms, including partial or complete inhibition of activity or symptoms. Partial inhibition may refer to a level of expression, activity, or symptom that is, for example, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of the uninhibited expression, activity, or symptom. The terms "eliminate" or "eradicate" refer to a complete reduction in activity or symptom.

[0050] As used herein, the term "disorder" or "disease" refers to any disturbance or abnormality of function, i.e., a morbid physical or mental condition. See Dorland's Illustrated Medical Dictionary, (WB Saunders Co. 27th ed. 1988).

[0051] As used herein, the term "treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., slowing, halting, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset, development, or progression of the disease or disorder.

[0052] In some embodiments, contemplated methods may include, for example, administering a prodrug of a compound described herein or a pharmaceutical composition thereof. The term "prodrug" refers to a compound that is transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Transformation can occur by various mechanisms (e.g., esterase, amidase, phosphatase, oxidative and / or reductive metabolism, etc.) in various locations (e.g., within the intestinal lumen, or during transport through the intestine, blood, or liver). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). In some embodiments, the prodrug structure is constructed according to the disclosure of U.S. Pat. No. 9,849,134, the entire contents of which are incorporated herein by reference.

[0053] For example, if a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound, contains a carboxylic acid functional group, the prodrug may be 1~8 ) alkyl, (C 2~12 ) alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N--(C 1~2 ) alkylamino-(C 2~3 ) alkyl (β-dimethylaminoethyl, etc.), carbamoyl-(C 1~2 ) alkyl, N,N-di(C 1~2) alkylcarbamoyl-(C 1~2 ) alkyl and piperidino-, pyrrolidino- or morpholino (C 2~3 ) alkyl and the like.

[0054] Similarly, if a compound of the present disclosure contains an alcohol functional group, the prodrug may be 1~6 ) alkylcarbonyloxymethyl, 1-((C 1~6 ) alkylcarbonyloxy) ethyl, 1-methyl-1-((C 1~6 ) alkylcarbonyloxy) ethyl, (C 1~6 )alkoxycarbonyloxy)methyl, N--(C 1~6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) alkylcarbonyl, α-amino (C 1~4 ) alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl α-aminoalkylcarbonyl, each α-aminoalkylcarbonyl group being a group selected from the group consisting of the naturally occurring L-amino acids, P(O)(OH), —P(O)(O(C 1~6 ) alkyl) 2 or glycosyl (the radical resulting from removal of the hemiacetal hydroxyl group of a carbohydrate).

[0055] When the compounds of the present disclosure incorporate an amine functional group, prodrugs can be formed, for example, by creating amides or carbamates, N-alkylcarbonyloxyalkyl derivatives, (oxodioxolenyl)methyl derivatives, N-Mannich bases, imines, or enamines.In addition, secondary amines can be metabolically cleaved to generate bioactive primary amines, or tertiary amines can be metabolically cleaved to generate bioactive primary or secondary amines.See, for example, Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0056] As used herein, a "therapeutically effective amount" refers to an amount of a compound or composition (as described herein) that causes at least one desired change in a cell, cell population, tissue, individual, patient, or the like. In some embodiments, a therapeutically effective amount as used herein refers to an amount of a compound or composition (as described herein) that prevents or provides a clinically significant change (e.g., a reduction of at least about 30 percent, at least about 50 percent, or at least about 90 percent) in a disease or condition or one or more characteristics of a disease or condition described herein.

[0057] Dosage, Administration, and Pharmaceutical Formulations The term "pharmaceutically acceptable salt" refers to an acid addition salt that is commonly used in human or veterinary medicine and is deemed safe for use. Examples of the present disclosure include, but are not limited to, salts obtained from the following acids: acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, isethionic acid, lactic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid. Any hydrates of such salts are also included in this definition. Thus, for example, both fumarate and hemifumarate salts are specifically contemplated, along with their hydrates. For example, fumarate dihydrate may be specifically mentioned.

[0058] In some embodiments, the pharmaceutical preparation may be in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or any appropriate number of these in packaged dosage form. The composition may also contain other compatible therapeutic agents, if desired. A preferred pharmaceutical preparation can deliver the compound of the present disclosure in a sustained-release formulation.

[0059] For binders, compositions, or compounds according to the present disclosure, the dosage form may optionally be a liquid dosage form. Solutions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose or an emulsifier such as polysorbate. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Formulations optionally contain excipients, including, but not limited to, buffers, antioxidants, stabilizers, carriers, diluents, and pH-adjusting agents. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl, or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum; albumin. , proteins such as gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine, monosaccharide bases including glucose, mannose, or dextrin, disaccharide bases, and other carbohydrates, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose, or sorbitol, salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), and / or non-ionic surfactants such as TWEEN, PLURONICS, or polyethylene glycol (PEG).

[0060] In certain embodiments, the agents according to the methods provided herein are administered subcutaneously (sc), intravenously (iv), intramuscularly (im), intranasally, or topically. Administration of the agents described herein can be, independently, 1 to 4 times daily, 1 to 4 times monthly, 1 to 6 times per year, or once every 2, 3, 4, or 5 years. Administration can be daily or for a duration of 1, 2, 3, 6 months, 1, 2, 3 years, or even for the lifespan of a human patient. Dosages can be administered as a single dose or divided into multiple doses. In some embodiments, the agent is administered about 1 to about 3 times (e.g., 1, 2, or 3 times). [Example]

[0061] The present disclosure is further described in the following examples, which are not intended to limit the scope of the disclosure.

[0062] Example 1: Treatment of patients with nOH Patients aged 40 to 80 years diagnosed with symptomatic orthostatic hypotension due to pure autonomic failure, multiple system atrophy, or Parkinson's disease (i.e., PD plus symptoms) are enrolled. At presentation, autonomic function testing is performed to confirm the diagnosis of autonomic dysfunction, including sinus arrhythmia, and the Valsalva maneuver. Patients must (1) demonstrate a ≥30 mmHg decrease in SBP within 5 minutes of standing, (2) demonstrate impaired autonomic reflexes as determined by the absence of BP overshoot during phase IV of the Valsalva maneuver, (3) experience dizziness, lightheadedness, or syncope upon standing, and (4) have no other identifiable causes of autonomic dysfunction.

[0063] Patients are given 5 mg of dabzalglon oral tablets and are instructed to take one tablet immediately upon waking in the morning and a second tablet four to six hours later each day.

[0064] Some patients will return for a follow-up visit one week after treatment. Symptoms of nOH are expected to improve compared to the first visit before double Zaglon treatment. At the follow-up visit, supine systolic blood pressure (SSBP) may be measured. It is expected that patients taking double Zaglon will not experience a substantial increase in SSBP and / or that the increase in SSBP will be less than that observed in patients taking midrine or droxidopa for nOH.

[0065] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, or limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., should be read expansively and without limitation. In addition, the terms and expressions employed herein are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the shown and described features or portions thereof, but it is recognized that various modifications are possible within the scope of the claims.

[0066] While the present disclosure has been particularly shown and described with reference to certain embodiments, some of which are preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

[0067] Various embodiments of the present disclosure may be characterized by potential claims, which are recited in the paragraphs following this paragraph (and before the actual claims provided at the end of this application). These potential claims form part of the specification of this application. Accordingly, the subject matter of the following potential claims may be presented as actual claims in a subsequent proceeding involving this application or any application claiming priority from this application. The inclusion of such potential claims should not be interpreted as meaning that the actual claims do not encompass the subject matter of the potential claims. Accordingly, a decision not to present these potential claims in a subsequent proceeding should not be interpreted as donating the subject matter to the public.

[0068] The embodiments of the present disclosure described above are intended to be merely exemplary, and numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present disclosure as defined in any appended claims.

[0069] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0070] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

1. Therapeutic effective dose of α １Ａ A pharmaceutical composition for use in a method for treating neuro-orthostatic hypotension (nOH), comprising an -AR partial agonist, The method comprises: Identifying a patient diagnosed with or in need of treatment for nOH; administering to the patient a therapeutically effective amount of the α １Ａ - administering an AR partial agonist; Including, The α 1A -AR partial agonist is RO1151240 (dabzalgulone); The pharmaceutical composition.

2. 10. The pharmaceutical composition of claim 1, wherein the patient meets at least one or more of the following diagnostic criteria: (1) exhibiting a fall in SBP of >20-30 mmHg within 5 minutes of standing, (2) exhibiting impaired autonomic reflexes as determined by the absence of BP overshoot during phase IV of the Valsalva maneuver, (3) experiencing dizziness, lightheadedness, or syncope upon standing, and (4) having no other identifiable cause of autonomic dysfunction.

3. The patient's peripheral vascular resistance is １Ａ The pharmaceutical composition of claim 1, wherein the level of vasopressin-1 receptor agonist is not significantly increased after administration of an AR partial agonist.

4. The patient's supine systolic blood pressure is １Ａ 2. The pharmaceutical composition of claim 1, wherein the blood pressure of the patient does not increase by more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the blood pressure of the patient before administration of the -AR partial agonist.

5. 10. The pharmaceutical composition of claim 1, wherein the nOH in the patient is associated with one or more of Parkinson's disease, multiple system atrophy, and pure autonomic failure.

6. The α １Ａ -AR partial agonist selective α １Ａ The pharmaceutical composition according to any one of claims 1 to 5, which is an -AR partial agonist.

7. The α １Ａ -AR partial agonist is α １Ａ 7. The pharmaceutical composition of any one of claims 1 to 6, which exhibits a maximum efficacy that is less than 10%, or less than 15%, or less than 20%, or less than 25%, or less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the intrinsic activity of the corresponding full agonist of the -AR receptor.

8. The α １Ａ 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the -AR partial agonist exhibits a maximum efficacy that is less than 10%, or less than 15%, or less than 20%, or less than 25%, or less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the intrinsic activity of noradrenaline.

9. The α １Ａ -AR partial agonist is α １Ｂ -AR and α １Ｄ pEC of non-selective agonists for -AR receptors ５０ α is less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of １Ｂ -AR and α １Ｄ -pEC for AR receptors ５０ The pharmaceutical composition according to any one of claims 1 to 8, comprising:

10. The α １Ａ -AR partial agonist is α １Ｂ -AR and α １Ｄ pEC of noradrenaline on -AR receptors ５０ α is less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of １Ｂ -AR and α １Ｄ -pEC for AR receptors ５０ The pharmaceutical composition according to any one of claims 1 to 9, comprising:

11. The patient's supine systolic blood pressure is １Ａ 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the blood pressure of the patient does not increase by more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the blood pressure of the patient before administration of the -AR partial agonist.

12. The method further comprises: (1) administering to the patient α １Ａ (2) monitoring the patient's blood pressure and / or venous return; and (3) if the patient's supine systolic blood pressure rises above 150, or 155, or 175, or 180, or 185, or 190, or 195, or 200, or 210, or 215, or 220, or 225, １Ａ - reducing the dose of the AR partial agonist.

13. The patient receives a dose of the α １Ａ The pharmaceutical composition according to any one of claims 1 to 12, wherein the -AR partial agonist is taken once a day, or twice a day, or three times a day, or four times a day.

14. The patient receives the first daily dose of the α １Ａ The pharmaceutical composition according to any one of claims 1 to 13, wherein an AR partial agonist is administered.

15. The pharmaceutical composition of claim 1, wherein dabzalglon is administered at a dose selected from the group consisting of 0.5 mg, 1 mg, 3 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, and 25 mg.

16. A pharmaceutical composition as described in claim 1, wherein dabzalglon maintains blood flow to the brain.

17. A pharmaceutical composition as described in claim 1, wherein dabzalgulone increases preload and / or increases ventricular contractility.

18. The pharmaceutical composition of claim 1, which increases cardiac output without a concomitant substantial increase in arteriolar vascular resistance.

19. The pharmaceutical composition of claim 15, wherein the dose is 0.5 mg.

20. The pharmaceutical composition of claim 15, wherein the dose is 1 mg.

21. The pharmaceutical composition of claim 15, wherein the dose is 3 mg.

22. The pharmaceutical composition of claim 15, wherein the dose is 5 mg.

23. The pharmaceutical composition of claim 15, wherein the dose is 7 mg.

24. The pharmaceutical composition of claim 15, wherein the dose is 10 mg.

25. The pharmaceutical composition of claim 15, wherein the dose is 15 mg.

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