Treatment of cognitive impairment with trapidil

Abstract

Disclosed herein are methods, therapeutic combinations, and administration combinations for preventing or treating cognitive impairment by administering a therapeutically effective amount of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an additional therapeutic agent, such as an antidepressant, an antipsychotic, anxiolytic, a dopamine precursor, or a dopamine agonist.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 942,645, filed December 2, 2019, the entirety of which is incorporated herein by reference. Summary of the Invention

[0002] In certain embodiments, methods, pharmaceutical combinations, dosage forms, and kits are disclosed herein for the treatment of cognitive disorders or psychiatric disorders. In some embodiments, the psychiatric disorders include clinical depression, anxiety, apathy, loss of motivation, or psychosis. In some embodiments, the treatment comprises the use of a therapeutically effective amount of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts of trapidil. In some embodiments, a combination of administration is provided for the treatment of cognitive disorders or psychiatric disorders described herein, the combination of administration comprises trapidil and a dopamine agonist or dopamine precursor (e.g., levodopa).

[0003] Provided herein, in some embodiments, is a method of treating or preventing a cognitive disorder or psychiatric illness in a subject in need thereof, the method comprising administering a therapeutically effective dose of trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof to the subject. In some embodiments, the subject has been diagnosed with Parkinson's disease. In some embodiments, the cognitive disorder or psychiatric illness is not caused by Parkinson's disease. In some embodiments, the cognitive disorder or psychiatric illness is at least partially caused by Parkinson's disease. In some embodiments, the cognitive disorder or psychiatric illness is not caused by schizophrenia. In some embodiments, the cognitive disorder or psychiatric illness is at least partially caused by schizophrenia. In some embodiments, the method described herein further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a Parkinson's disease therapy. In some embodiments, the cognitive disorder is at least partially caused by a therapeutic agent. In some embodiments, the administration of trapidil treats or prevents a cognitive disorder at least partially caused by the additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a)-(e). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine. In some embodiments, the cognitive disorder is a neurodegenerative disorder.In some embodiments, the cognitive disorder is associated with an antagonist of N-methyl-D-aspartate receptor (NMDA-R). In some embodiments, the cognitive disorder is caused by abnormal dopaminergic signaling caused by neurodegeneration. In some embodiments, the psychiatric illness is anxiety, depression, apathy, loss of motivation, psychosis, or a combination thereof. In some embodiments, the cognitive disorder is cognitive dysfunction. In some embodiments, the cognitive dysfunction is mild cognitive impairment and / or dementia. In some embodiments, the cognitive dysfunction is caused by schizophrenia or attention-deficit / hyperactivity disorder. In some embodiments, the dementia is Alzheimer's disease, senile dementia, Parkinson's dementia, Lewy body dementia, semantic dementia, subcortical dementia, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudosenility, apraxia, agnosia, behavior / personality change, impaired judgment, amnesia, frontotemporal dementia, frontotemporal dementia parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive slippage, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline.In some embodiments, the cognitive impairment comprises a defect in any of the five cognitive domains: attention, working memory, executive function, visuospatial function, and memory.In some embodiments, the cognitive impairment is an executive function defect, attention difficulty, slowed thinking, word-finding difficulty, information learning or memory difficulty, or any combination thereof. In some embodiments, the subject suffers from Parkinson's disease.In some embodiments, the trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine.In some embodiments, the derivative comprises AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.In some embodiments, the metabolite comprises desethyl-trapidil, 5-piperidine-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidine-4'-olyl-7-[N-pent-4-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy derivative or ketopentyl derivative, piperidinol or piperidinone, TP1, or TP2. In some embodiments, the pharmaceutically acceptable salt comprises a salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid. In some embodiments, trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt is administered orally. In some embodiments, the trapidil, derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts thereof are administered intravenously or subcutaneously. In some embodiments, the trapidil, derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts thereof and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the trapidil, derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts thereof are administered prior to administration of the additional therapeutic agent or after administration of the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously. In some embodiments, the additional therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a)-(e). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine.In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or a pharma- ceutically acceptable salt thereof is administered to a subject three times daily.

[0004] Provided herein, in some embodiments, is a pharmaceutical combination for use in a method of treatment for the treatment of a cognitive disorder or related psychiatric illness in a subject in need thereof, said pharmaceutical combination comprising a therapeutic combination of trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and an additional therapeutic agent. In some embodiments, said subject has been diagnosed with Parkinson's disease. In some embodiments, said cognitive disorder or psychiatric illness is not caused by Parkinson's disease. In some embodiments, said cognitive disorder or psychiatric illness is at least partially caused by Parkinson's disease. In some embodiments, said cognitive disorder or psychiatric illness is not caused by schizophrenia. In some embodiments, said cognitive disorder or psychiatric illness is at least partially caused by schizophrenia. In some embodiments, said cognitive disorder is at least partially caused by the additional therapeutic agent. In some embodiments, administration of trapidil treats or prevents a cognitive disorder at least partially caused by the additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a)-(e). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine. In some embodiments, the cognitive disorder is a neurodegenerative disorder.In some embodiments, the cognitive impairment is associated with an antagonist of the N-methyl-D-aspartate receptor (NMDA-R). In some embodiments, the cognitive impairment is due to abnormal dopaminergic signaling caused by neurodegeneration. In some embodiments, the psychiatric illness comprises anxiety, depression, apathy, loss of motivation, or psychosis, or any combination thereof. In some embodiments, the cognitive impairment comprises cognitive impairment. In some embodiments, the cognitive impairment comprises mild cognitive impairment and / or dementia. In some embodiments, the cognitive impairment is due to schizophrenia or attention-deficit / hyperactivity disorder. In some embodiments, the dementia comprises senile dementia, Parkinson's disease dementia, Lewy body dementia, semantic dementia, subcortical dementia, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudosenility, apraxia, agnosia, behavior / personality change, impaired judgment, amnesia, frontotemporal dementia, frontotemporal dementia parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive slippage, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline.In some embodiments, the cognitive impairment comprises a defect in any of the five cognitive domains: attention, working memory, executive function, visuospatial function, and memory.In some embodiments, the cognitive impairment is an executive function defect, difficulty with attention, slowed thinking, difficulty with word finding, difficulty with learning or remembering information, or any combination thereof. In some embodiments, trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine. In some embodiments, the derivative includes AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.In some embodiments, the metabolites include desethyl-trapidil, 5-piperidine-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidine-4'-olyl-7-[N-pent-4-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy derivatives or ketopentyl derivatives, piperidinol or piperidinone, TP1, or TP2. In some embodiments, the pharmaceutically acceptable salts of trapidil include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered intravenously or subcutaneously. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts, and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered before or after the administration of the additional therapeutic agent. In some embodiments, the pharmaceutical combination further comprises at least one pharma- ceutically acceptable excipient, carrier, or diluent. In some embodiments, the pharmaceutical combination is a fixed-dose combination, and further comprises at least one pharma- ceutically acceptable excipient, carrier, or diluent. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered to the subject three times a day.

[0005] Provided herein, in some embodiments, is an administration combination for use in treating a cognitive disorder or psychiatric illness in a subject in need thereof, the administration combination comprising administering to the subject a therapeutically effective combination of trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and an additional therapeutic agent. In some embodiments, the subject has been diagnosed with Parkinson's disease. In some embodiments, the cognitive disorder or psychiatric illness is not caused by Parkinson's disease. In some embodiments, the cognitive disorder or psychiatric illness is at least partially caused by Parkinson's disease. In some embodiments, the cognitive disorder or psychiatric illness is not caused by schizophrenia. In some embodiments, the cognitive disorder or psychiatric illness is at least partially caused by schizophrenia. In some embodiments, the additional therapeutic agent is a Parkinson's disease therapy. In some embodiments, the cognitive disorder is at least partially caused by the additional therapeutic agent. In some embodiments, the administration of trapidil treats or prevents a cognitive disorder at least partially caused by the additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a)-(e). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine. In some embodiments, the cognitive disorder is a neurodegenerative disorder.In some embodiments, the cognitive disorder is associated with an antagonist of the N-methyl-D-aspartate receptor (NMDA-R). In some embodiments, the cognitive disorder is abnormal dopaminergic signaling caused by neurodegeneration. In some embodiments, the psychiatric illness comprises anxiety, depression, apathy, loss of motivation, or psychosis, or any combination thereof. In some embodiments, the cognitive disorder comprises cognitive impairment. In some embodiments, the cognitive impairment comprises mild cognitive impairment and / or dementia. In some embodiments, the cognitive impairment is due to schizophrenia or attention-deficit / hyperactivity disorder (ADHD). In some embodiments, the dementia comprises Alzheimer's disease, senile dementia, Parkinson's dementia, Lewy body dementia, semantic dementia, subcortical dementia, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudosenility, apraxia, agnosia, behavior / personality changes, impaired judgment, amnesia, frontotemporal dementia, frontotemporal dementia parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive slippage, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline.In some embodiments, the cognitive impairment comprises a defect in any of the five cognitive domains: attention, working memory, executive function, visuospatial function, and memory.In some embodiments, the cognitive impairment is an executive function defect, difficulty with attention, slowed thinking, difficulty with word finding, difficulty with learning or remembering information, or any combination thereof. In some embodiments, trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine. In some embodiments, the derivative includes AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.In some embodiments, the metabolite comprises desethyl-trapidil, 5-piperidine-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidine-4'-olyl-7-[N-pent-4-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy derivative or ketopentyl derivative, piperidinol or piperidinone, TP1, or TP2. In some embodiments, the pharmaceutically acceptable salt comprises a salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid. In some embodiments, trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt is administered orally. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered intravenously or subcutaneously. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and the additional therapeutic agent are administered in separate dosage forms or in a combined dosage form. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered before or after the administration of the additional therapeutic agent. In some embodiments, the aforementioned administration combination further comprises at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned administration combination is a fixed administration combination and further comprises at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned administration combination is administered to a subject three times a day.

[0006] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0007] The novel features of the aspects of the invention are set forth with particularity in the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings. [Figure 1] It illustrates that trapidil is able to increase expression in neurons expressing D1 receptors (*-p<0.05). [Diagram 2] Trapidil demonstrates the inability to activate, inhibit or modulate dopamine receptors (D1, D2s, D3, D4 and D5). [Diagram 3] We demonstrate that the Variable Delayed Response (VDR) task can delineate between normal primates and those following chronic low doses of MPTP, which models the cognitive deficits of Parkinson's disease. Compared to normal: ***p<0.01 [Figure 4] 1 illustrates that treatment of MPTP-lesioned primates with levodopa tended to decrease their ability to accurately complete the VDR task. *p<0.1 compared to vehicle. [Diagram 5] 14 illustrates that trapidil as monotherapy can improve performance in the VDR task in MPTP-lesioned primates, especially in the short delay period (DP1 and DP2). Compared to vehicle: **p<0.05, ***p<0.01 [Figure 6] We demonstrate that trapidil in combination with levodopa can also improve performance in the VDR task in MPTP-lesioned primates, especially in the short delay period (DP1 and DP2). Compared to vehicle: *p<0.1, **P<0.05, ***P<0.01; compared to L-DOPA 5 mg / kg: #p<0.1, ##p<0.05, ###p<0.01 [Figure 7]Figure 2 illustrates that trapidil improves the VDR task with or without levodopa during the short delay period. Compared to vehicle: *p<0.1, **P<0.05, ***P<0.01; compared to L-DOPA 5mg / kg: #p<0.1, ##p<0.05, ###p<0.01. Note: Trapidil monotherapy was not compared to L-DOPA 5mg / kg. [Figure 8] Figure 2 illustrates that trapidil significantly decreases reaction times in the VDR task in primates. Compared to vehicle: **p<0.5, ***p<0.01 [Figure 9A] Figures 9A-B illustrate that trapidil significantly reduces the deficits caused by phencyclidine in a mouse model of schizophrenia in the Y-maze spontaneous alternation test. Figure 9A shows that acute administration of PCP (7.5 mg / kg, IP) induced working memory deficits as detected by a decrease in the percentage of spontaneous alternation in mice, and that oral administration of trapidil was able to correct the deficits observed at several different doses. [Figure 9B] Figures 9A-B illustrate that trapidil significantly reduces the deficits caused by phencyclidine in a mouse model of schizophrenia in the Y-maze spontaneous alternation test. Figure 9B shows that trapidil administration does not significantly affect the number of entries, indicating the absence of confounding factors. Compared to vehicle: *p<0.1, **P<0.05, ***P<0.01; compared to phencyclidine treatment: #p<0.1, ##p<0.05, ###p<0.01 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] In many cases, cognitive impairment (e.g., cognitive dysfunction, cognitive deficit, cognitive disease) affects a subject's ability to make decisions, learn new things, concentrate, or remember. Cognitive impairment can range from mild to severe, affecting daily activities and may result in loss of ability to function independently. Cognitive impairments described herein are exacerbated by pre-existing illnesses, including neurological disorders such as Parkinson's disease and schizophrenia. Many individuals with cognitive impairments may also develop psychiatric illnesses, such as anxiety, clinical depression, apathy, and loss of motivation. The combination of cognitive impairment and psychiatric illness may result in confounding factors in patient outcomes.

[0009] Cognitive disorders and mental illnesses affect millions of people in the United States. It is estimated that 16 million Americans are living with cognitive impairment, with most of these patients being over the age of 65. The number of individuals living with cognitive impairment is expected to increase with the aging population. This impending increase will place a significant burden on the healthcare system. Nearly 80% of patients with pre-existing conditions such as Parkinson's disease will develop some form of cognitive impairment. Nearly one in five U.S. adults is living with a mental illness (51.5 million Americans in 2019).

[0010] Cognitive impairment may also be drug-induced. For example, many Parkinson's patients given high levels of levodopa (the gold standard of care for treating motor symptoms of Parkinson's disease) may be at increased risk of developing cognitive impairment. Administration of levodopa produces sustained dopaminergic stimulation of dopamine receptors in the striatum. Initially, cognitive impairment in Parkinson's patients responds well to dopaminergic stimulation by levodopa (e.g., is alleviated or prevented). However, overactivation of dopamine receptors caused by increasing doses of levodopa may worsen cognitive impairment in Parkinson's patients over time. In addition, excessive dopaminergic stimulation may have side effects that follow a "U-shaped" curve, with too little or too much dopamine causing cognitive impairment in Parkinson's patients. To address the loss of response to levodopa in Parkinson's patients, doses may be increased throughout the patient's life, potentially for many years. In patients with early-onset Parkinson's disease, the development of cognitive impairment or psychiatric illness resulting from the treatment regimen may be unavoidable.

[0011] Thus, there is a need for effective therapeutic strategies to treat cognitive disorders and / or psychiatric illnesses. This need is especially acute for patients who suffer from diseases in which cognitive deficits are part of the symptoms, or who suffer from pre-existing diseases that increase the likelihood of developing cognitive disorders or psychiatric illnesses (e.g., schizophrenia, Parkinson's disease), or in which gold standard therapies exacerbate (or in some cases cause) the cognitive disorders or psychiatric illnesses in the first place.

[0012] Trapidil is a vasodilator and antiplatelet drug used for the treatment of ischemic coronary heart, liver and kidney disease. Trapidil is a reported potentiator of protein kinase A regulatory subunit 2 (PRKAR2A and PRKAR2B). The reported mechanism of action of trapidil is not shared with known therapeutic agents used to treat cognitive disorders or psychiatric illnesses, such as cognition enhancers (acetylcholinesterase inhibitors), antipsychotics, antidepressants, and anxiolytics.

[0013] Surprisingly, the inventors of the present disclosure have determined by single-cell deconvolution computational analysis that trapidil, although not a known dopamine 1 receptor agonist, modulates neurons expressing dopamine 1 receptors in Parkinson's disease animal models. As shown in Example 1, trapidil induces large gene expression changes in neurons expressing dopamine 1 receptors but not in neurons expressing dopamine 2 receptors. Such selective changes in gene expression are similar to dopamine 1 agonists. In some embodiments, a therapeutically effective dose of trapidil is administered to a subject to activate neurons expressing dopamine 1 receptors and / or modulate neurons expressing dopamine 1 receptors. In some embodiments, activating and / or modulating neurons expressing dopamine 1 receptors (e.g., induced by administering a therapeutically effective amount of trapidil) prevents abnormal dopamine signaling. In some embodiments, activating and / or modulating neurons expressing dopamine 1 receptors (e.g., induced by administering a therapeutically effective amount of trapidil) treats or prevents cognitive impairment and / or psychiatric illness in a subject, e.g., a subject suffering from Parkinson's disease. In some embodiments, the cognitive impairment is caused, at least in part, by levodopa, or another dopamine precursor or dopamine agonist, administered to treat the subject's Parkinson's disease.

[0014] The present inventors have found that administering trapidil alone or in combination with levodopa increases cognitive function in non-human primate studies. In addition, it has been observed that animals administered trapidil show improved total reaction time and response accuracy. This decrease in reaction time suggests improved motivation and / or processing speed. Without being bound to any particular theory, it is believed that the observed increase in motivation may correct the psychiatric illness of amotivation. Amotivation is one of many psychiatric illnesses that are highly correlated with cognitive impairment, such as those common among Parkinson's disease patients, and can serve as a predictor of potential cognitive decline in these patients.

[0015] The present inventors also show herein that administration of trapidil also ameliorates cognitive deficits observed in mouse models of schizophrenia: mice treated with trapidil exhibit improved percentages of spontaneous alternation tests in the Y-maze, suggesting improved working memory.

[0016] Disclosed herein, in some embodiments, is a method for treating or preventing cognitive impairment or psychiatric illness with trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts. In some embodiments, the subject suffers from Parkinson's disease. In some embodiments, the cognitive impairment or psychiatric disorder is not caused by or associated with Parkinson's disease. In some embodiments, the subject suffers from schizophrenia. Also disclosed herein is a pharmaceutical combination or administration combination comprising trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a)-(e). In some embodiments, the additional therapeutic agent is a dopamine precursor (e.g., levodopa). In some embodiments, the additional therapeutic agent is a combination therapy of a dopamine precursor (e.g., levodopa) and an adjunctive therapy (e.g., carbidopa). In some embodiments, the additional therapeutic agent is a dopamine agonist (e.g., rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, or apomorphine). In some embodiments, the pharmaceutical combination is therapeutically effective for treating or preventing cognitive impairment or psychiatric illness in a subject. In some embodiments, the pharmaceutical combination further comprises at least one pharma- ceutically acceptable excipient, carrier, or diluent. In some embodiments, the pharmaceutical combination is a fixed-dose combination.

[0017] I. Treatment method Disclosed herein, in some embodiments, is a method for treating or preventing cognitive impairment or psychiatric illness using a therapeutic agent or combination of therapeutic agents described herein. In some embodiments, the therapeutic agent is trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof. In some embodiments, the subject suffers from Parkinson's disease or schizophrenia. In some embodiments, the subject suffers from drug-induced cognitive impairment, such as cognitive dysfunction. In some embodiments, the drug causing the cognitive dysfunction is a dopamine precursor (e.g., levodopa) or a dopamine agonist. In some embodiments, the subject suffers from schizophrenia. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a dopamine precursor (e.g., levodopa). In some embodiments, the additional therapeutic agent is a combination therapy of a dopamine precursor (e.g., levodopa) and an adjunctive therapy (e.g., carbidopa). In some embodiments, the additional therapeutic agent is a dopamine agonist (e.g., rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, or apomorphine). In some embodiments, the pharmaceutical combination is therapeutically effective for treating or preventing cognitive impairment or psychiatric illness in a subject. In some embodiments, the subject is a human. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and the additional therapeutic agent (e.g., levodopa) are administered together (e.g., in a combined dosage form) or separately. In some embodiments, a dose of up to 200 milligrams of trapidil is administered to the subject.

[0018] A. Diseases and illnesses 1. Cognitive impairment Cognitive impairment includes a category of mental health disorders that primarily affect cognitive abilities such as learning, memory, perception, or problem solving. In some embodiments, cognitive impairment includes cognitive impairments such as mild cognitive impairment (e.g., a stage between expected cognitive decline due to normal aging and dementia) and / or dementia. Non-limiting examples of dementia include Alzheimer's disease, Parkinson's disease dementia, senile dementia, and Lewy body dementia. In some embodiments, cognitive impairment (e.g., mild cognitive impairment) includes deficits in any of the following five cognitive domains: attention, working memory, executive function, visuospatial function, and memory. In some embodiments, attention deficits affect a subject's ability to focus and concentrate. In some embodiments, executive function deficits affect a subject's ability to multitask or problem solve. In some embodiments, visuospatial deficits affect a subject's ability to stereoscopically grasp information, such as an inability to judge distances or form a mental map for a route. In some embodiments, the cognitive impairment (e.g., mild cognitive impairment) is deficits in executive function, difficulty with attention, slowed thinking, difficulty finding words, and / or difficulty learning or remembering information.

[0019] In some embodiments, the cognitive impairment is associated with or caused by a therapeutic agent for treating a disease or condition other than cognitive impairment or mental illness (e.g., Parkinson's disease). In some embodiments, the therapeutic agent causing or associated with cognitive impairment or mental illness is a dopamine precursor or dopamine agonist. In some embodiments, the therapeutic agent causing or associated with cognitive impairment or mental illness is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, bromocriptine, lisuride, apomorphine, levodopa, entacapone, tolcapone, selegiline and / or rasagiline. In some embodiments, the drug causing or associated with cognitive impairment or mental illness is an N-methyl-D-aspartate receptor antagonist.

[0020] In some embodiments, the cognitive impairment comprises Parkinson's disease dementia, semantic dementia, subcortical dementia, postoperative cognitive impairment, memory loss, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudosenility, apraxia, agnosia, behavior / personality changes, impaired judgment, amnesia, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 parkinsonism, cognitive vulnerability, cognitive slippage, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline. In some embodiments, the cognitive impairment is due to schizophrenia or attention-deficit / hyperactivity disorder. In some embodiments, the cognitive impairment is not caused by Parkinson's disease.

[0021] 2. Mental illness Psychiatric illnesses described herein include psychiatric illnesses that affect a subject's emotions or mental state (e.g., the way a person thinks, feels, or behaves). In some embodiments, psychiatric illnesses described herein include anxiety, depression, apathy, loss of motivation, or psychosis, or any combination thereof. In some embodiments, the psychiatric illness includes a mental disorder such as schizophrenia or bipolar disorder. In some embodiments, the psychiatric illness is clinically diagnosed. In some embodiments, the psychiatric illness is not caused by Parkinson's disease.

[0022] B. Target The subject disclosed herein is a mammal, such as, for example, a human, a mouse, a rat, a guinea pig, a rabbit, a non-human primate, or a livestock animal. In some embodiments, the subject is a human. In some embodiments, the subject is a patient who has been diagnosed with a disease or disorder disclosed herein. In some embodiments, the subject has not been diagnosed with a disease or disorder. In some embodiments, the disease or disorder is a cognitive impairment or psychiatric disorder described herein.

[0023] In some embodiments, the subject suffers from Parkinson's disease. In some embodiments, the subject does not suffer from Parkinson's disease. In some embodiments, the subject has been diagnosed with Parkinson's disease. The four main motor symptoms of Parkinson's disease are tremor, rigidity, bradykinesia (slow movement) and postural instability (balance problems). Observing two or more of these symptoms in a subject is a suitable method for diagnosing Parkinson's disease. Suitable methods also include performing certain single photon emission computed tomography (SPECT) scans (e.g., dopamine transporter scans (DaTscans)).

[0024] In some embodiments, the subject suffers from schizophrenia. In some embodiments, the subject does not suffer from schizophrenia. In some embodiments, the subject has been diagnosed with schizophrenia. Schizophrenia may be diagnosed if the subject exhibits at least two of the following symptoms for one month: delusions, hallucinations, disorganized speech and behavior, catatonic confusion, or bizarre / hyperactive behavior.

[0025] C. Therapeutic Agents 1. Trapidil compounds Disclosed herein in some embodiments is a therapeutic agent comprising trapidil useful for treating a disease or illness described herein, such as a cognitive impairment or disorder or a psychiatric illness in a subject disclosed herein. In some embodiments, the subject suffers from Parkinson's disease. In some embodiments, the therapeutic agent comprises an additional therapeutic agent, such as a dopamine precursor (e.g., levodopa). Also provided in some embodiments is a pharmaceutical composition comprising trapidil and, optionally, an additional therapeutic agent (e.g., levodopa).

[0026] Trapidil, a triazolopyrimidine, belongs to the class of antianginal and vasodilator drugs. As demonstrated in Example 1, trapidil has been shown to modulate gene expression in neurons expressing dopamine 1 receptors.

[0027] Trapidil has the IUPAC name N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine and the following chemical structure:

[0028] [ka]

[0029] In some embodiments, Trapidil is also named AR12008, Avantrin, Trapymin, Trapymine, Trapidilum, Angichromen, Estelinol, Karnachol, Perucarate, Rocornal, Trapidil Towa Pharmaceuticals, and Travisco. In further instances, Trapidil is referred to herein as SB-0107.

[0030] In some embodiments, trapidil derivatives include, but are not limited to, AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.

[0031] In some embodiments, the trapidil derivative includes, but is not limited to, AR12455

[0032] [ka]

[0033] , AR12456

[0034] [ka]

[0035] , AR12460

[0036] [ka]

[0037] , AR12463

[0038] [ka]

[0039] , AR12464

[0040] [ka]

[0041] , AR12465

[0042] [ka]

[0043] , AR12565

[0044] [ka]

[0045] , or 5-piperidino-7-(N-(n-amyl)-N-(β-hydroxyethyl)-amino)-s-triazolo(1,5-a)pyrimidine

[0046] [ka] Includes.

[0047] In some embodiments, AR12455 is 5-n-butylamino-7-[N-(n-hexyl)-N-(β-hydroxyethyl)-amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12456 is 5-diethylamino-7-[N-(n-hexyl)-N-(β-hydroxyethyl)amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12460 is 2-((5-(diethylamino)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(hexyl)amino)ethan-1-ol. In some embodiments, AR12463 is 5-morpholino-7-[N-amyl-N-(β-hydroxyethyl)aminol-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12464 is 5-morpholino 7-[N-(n-butyl)-N-(β-hydroxyethyl)amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12465 is 5-piperidino-7-[N-hexyl-N-(β-hydroxyethyl)amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12565 is 2-((5-(diethylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl)(phenethyl)amino)ethan-1-ol.

[0048] In some embodiments, the trapidil metabolites include, but are not limited to, desethyl-trapidil, 5-piperidine-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidine-4'-olyl-7-[N-pent-4-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy derivatives or ketopentyl derivatives, piperidinol or piperidinone, TP-1

[0049] [ka]

[0050] or TP-2

[0051] [ka] Includes.

[0052] In some embodiments, pharma- ceutically acceptable salts of trapidil include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid.

[0053] In some embodiments, the trapidil is the trapidil disclosed in US Pat. No. 6,015,578, European Patent No. 0301423, or International Publication No. WO1993 / 009781.

[0054] In some embodiments, the trapidil is a trapidil derivative disclosed in Heinroth-Hoffmann et al. (1990) "Influence of trapidil and trapidil Derivatives on the Content of Cyclic Nucleotides in Human Intima Cells Cultured from Atherosclerotic Plaques," Drug Development Research, 19(3), 321-327, Heinroth et al. (1983) "Influence of trapidil derivatives on arachidonic acid- and prostaglandin endoperoxide analogue-induced platelet aggregation and thromboxane A2 formation," Biomedica biochimica acta, 43(8-9), S389-92, or Krause et al. (1985) Advances in Pharmacological Research and Practice: Proceedings of the 4th Congress of the Hungarian Pharmacological Society, Budapest, pages 139-142.

[0055] In some embodiments, the trapidil is a trapidil metabolite disclosed in Thurmann et al. (1997) "Pharmacokinetics of the PDGF-antagonist trapidil in patients with and without renal impairment," Clinical nephrology, 47(2), 99-105, or Pfeifer et al. (1990) "Biotransformation of the trapidil (rocornal) derivative AR 12463 in the rat," Die Pharmazie, 45(8), 609-614.

[0056] In some embodiments, the trapidil is a trapidil salt disclosed in US Pat. No. 6,369,065.

[0057] Also disclosed herein, in some embodiments, is a method of treating a patient by modulating neurons expressing dopamine 1 by administration of a therapeutically effective dose of trapidil, a derivative, metabolite, prodrug, analog, or a pharma- ceutically acceptable salt thereof.

[0058] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered orally, parenterally (e.g., intravenously, subcutaneously, intramuscularly), intranasally, buccally, topically, rectally, or transdermally. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered orally. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered parenterally (e.g., intravenously, subcutaneously, intramuscularly). In other cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered transdermally.

[0059] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are orally administered. In some embodiments, the oral dose ranges from about 10 mg per day to about 3000 mg per day. In some embodiments, the oral dose ranges from about 10 mg per day to about 2900 mg per day, from about 10 mg per day to about 2800 mg per day, from about 10 mg per day to about 2700 mg per day, from about 10 mg per day to about 2600 mg per day, from about 10 mg per day to about 2500 mg per day, from about 10 mg per day to about 2400 mg per day, from about 10 mg per day to about 2300 mg per day, from about 10 mg per day to about 2500 mg per day, from about 10 mg per day to about 2600 mg per day, from about 10 mg per day to about 2700 mg per day, from about 10 mg per day to about 2800 mg per day, from about 10 mg per day to about 29 ... mg to about 2200 mg per day, about 10 mg per day to about 2100 mg per day, about 10 mg per day to about 2000 mg per day, about 10 mg per day to about 1900 mg per day, about 10 mg per day to about 1800 mg per day, about 10 mg per day to about 1700 mg per day, about 10 mg per day to about 1600 mg per day, about 10 mg per day to about 1500 mg per day, about 10 mg per day from about 10 mg per day to about 1400 mg per day, from about 10 mg per day to about 1300 mg per day, from about 10 mg per day to about 1200 mg per day, from about 10 mg per day to about 1100 mg per day, from about 10 mg per day to about 1000 mg per day, from about 10 mg per day to about 950 mg per day, from about 10 mg per day to about 900 mg per day, from about 10 mg per day to about 850 mg per day, from about 10 mg per day to about 1000 mg per day from about 10 mg per day to about 800 mg per day, from about 10 mg per day to about 750 mg per day, from about 10 mg per day to about 700 mg per day, from about 10 mg per day to about 650 mg per day, from about 10 mg per day to about 600 mg per day, from about 10 mg per day to about 550 mg per day, from about 10 mg per day to about 500 mg per day, from about 10 mg per day to about 450 mg per day, from about 10 mg per day to about 400 mg per day,from about 10 mg per day to about 350 mg per day, from about 10 mg per day to about 300 mg per day, from about 10 mg per day to about 250 mg per day, from about 10 mg per day to about 200 mg per day, from about 10 mg per day to about 150 mg per day, from about 10 mg per day to about 100 mg per day, from about 50 mg per day to about 3000 mg per day, from about 100 mg per day to about 3000 mg per day, from about 150 mg per day to about 3000 mg per day, from about 2 from about 3000 mg per day, from about 300 mg per day to about 3000 mg per day, from about 400 mg per day to about 3000 mg per day, from about 500 mg per day to about 3000 mg per day, from about 600 mg per day to about 3000 mg per day, from about 700 mg per day to about 3000 mg per day, from about 800 mg per day to about 3000 mg per day, from about 900 mg per day to about 3000 mg per day, from about 1000 mg per day to about 3000 mg per day, from about 1100 mg per day to about 3000 mg per day, from about 1200 mg per day to about 3000 mg per day, from about 1300 mg per day to about 3000 mg per day, from about 1400 mg per day to about 3000 mg per day, from about 1500 mg per day to about 3000 mg per day, from about 1600 mg per day to about 3000 mg per day, from about 1700 mg per day to about 3000 mg per day, from about 1800 mg per day to about 3000 mg per day, from about 1900 mg per day to about 3000 mg per day up to about 3000 mg per day, from about 2000 mg per day to about 3000 mg per day, from about 2100 mg per day to about 3000 mg per day, from about 2200 mg per day to about 3000 mg per day, from about 2300 mg per day to about 3000 mg per day, from about 2400 mg per day to about 3000 mg per day, from about 2500 mg per day to about 3000 mg per day, from about 2600 mg per day to about 3000 mg per day, from about 2700 mg per day to about 3000 mg per day,From about 2800 mg per day to about 3000 mg per day, from about 2900 mg per day to about 3000 mg per day, from about 50 mg per day to about 2800 mg per day, from about 100 mg per day to about 2800 mg per day, from about 150 mg per day to about 2800 mg per day, from about 200 mg per day to about 2800 mg per day, from about 300 mg per day to about 2800 mg per day, from about 400 mg per day to about 2800 mg per day, from about 500 mg per day to about 2800 mg per day g, from about 600 mg per day to about 2800 mg per day, from about 700 mg per day to about 2800 mg per day, from about 800 mg per day to about 2800 mg per day, from about 900 mg per day to about 2800 mg per day, from about 1000 mg per day to about 2800 mg per day, from about 1100 mg per day to about 2800 mg per day, from about 1200 mg per day to about 2800 mg per day, from about 1300 mg per day to about 2800 mg per day, from about 1400 mg per day to about 2800 mg per day from about 1500mg per day to about 2800mg per day, from about 1600mg per day to about 2800mg per day, from about 1700mg per day to about 2800mg per day, from about 1800mg per day to about 2800mg per day, from about 1900mg per day to about 2800mg per day, from about 2000mg per day to about 2800mg per day, from about 2100mg per day to about 2800mg per day, from about 2200mg per day to about 2800mg per day, 2300mg to about 2800mg per day, about 2400mg per day to about 2800mg per day, about 2500mg per day to about 2800mg per day, about 2600mg per day to about 2800mg per day, about 2700mg per day to about 2800mg per day, about 50mg per day to about 2500mg per day, about 100mg per day to about 2500mg per day, about 150mg per day to about 2500mg per day, about 200mg per day to about 2500mg per day,from about 300 mg per day to about 2500 mg per day, from about 400 mg per day to about 2500 mg per day, from about 500 mg per day to about 2500 mg per day, from about 600 mg per day to about 2500 mg per day, from about 700 mg per day to about 2500 mg per day, from about 800 mg per day to about 2500 mg per day, from about 900 mg per day to about 2500 mg per day, from about 1000 mg per day to about 2500 mg per day, from about 1100 mg per day to about 2500 mg per day mg, from about 1200 mg per day to about 2500 mg per day, from about 1300 mg per day to about 2500 mg per day, from about 1400 mg per day to about 2500 mg per day, from about 1500 mg per day to about 2500 mg per day, from about 1600 mg per day to about 2500 mg per day, from about 1700 mg per day to about 2500 mg per day, from about 1800 mg per day to about 2500 mg per day, from about 1900 mg per day to about 2500 mg per day, from about 2000 mg per day from about 2100mg per day to about 2500mg per day, from about 2200mg per day to about 2500mg per day, from about 2300mg per day to about 2500mg per day, from about 2400mg per day to about 2500mg per day, from about 50mg per day to about 2200mg per day, from about 100mg per day to about 2200mg per day, from about 150mg per day to about 2200mg per day, from about 200mg per day to about 2200mg per day, from about 300 mg to about 2200 mg per day, from about 400 mg per day to about 2200 mg per day, from about 500 mg per day to about 2200 mg per day, from about 600 mg per day to about 2200 mg per day, from about 700 mg per day to about 2200 mg per day, from about 800 mg per day to about 2200 mg per day, from about 900 mg per day to about 2200 mg per day, from about 1000 mg per day to about 2200 mg per day, from about 1100 mg per day to about 2200 mg per day,from about 1200 mg per day to about 2200 mg per day, from about 1300 mg per day to about 2200 mg per day, from about 1400 mg per day to about 2200 mg per day, from about 1500 mg per day to about 2200 mg per day, from about 1600 mg per day to about 2200 mg per day, from about 1700 mg per day to about 2200 mg per day, from about 1800 mg per day to about 2200 mg per day, from about 1900 mg per day to about 2200 mg per day, from about 2000 mg per day to about 2200 mg per day from about 2100 mg per day to about 2200 mg per day, from about 50 mg per day to about 2000 mg per day, from about 100 mg per day to about 2000 mg per day, from about 150 mg per day to about 2000 mg per day, from about 200 mg per day to about 2000 mg per day, from about 300 mg per day to about 2000 mg per day, from about 400 mg per day to about 2000 mg per day, from about 500 mg per day to about 2000 mg per day, from about 600 mg per day to about 1 ... up to about 2000 mg per day, from about 700 mg per day to about 2000 mg per day, from about 800 mg per day to about 2000 mg per day, from about 900 mg per day to about 2000 mg per day, from about 1000 mg per day to about 2000 mg per day, from about 1100 mg per day to about 2000 mg per day, from about 1200 mg per day to about 2000 mg per day, from about 1300 mg per day to about 2000 mg per day, from about 1400 mg per day to about 2000 mg per day, 1500mg to about 2000mg per day, about 1600mg per day to about 2000mg per day, about 1700mg per day to about 2000mg per day, about 1800mg per day to about 2000mg per day, about 1900mg per day to about 2000mg per day, about 50mg per day to about 1800mg per day, about 100mg per day to about 1800mg per day, about 150mg per day to about 1800mg per day, about 200mg per day to about 1800mg per day,from about 300 mg per day to about 1800 mg per day, from about 400 mg per day to about 1800 mg per day, from about 500 mg per day to about 1800 mg per day, from about 600 mg per day to about 1800 mg per day, from about 700 mg per day to about 1800 mg per day, from about 800 mg per day to about 1800 mg per day, about 1800mg per day, about 900mg per day to about 1800mg per day, about 1000mg per day to about 1800mg per day, about 1100mg per day to about 1800mg per day, about 1200mg per day to about 1800mg per day, about 1300mg per day to about 1800mg per day, about 1400mg per day to about 1800mg per day, about 1500mg per day to about 1800mg per day, about 1600mg per day to about 1800mg per day, about 1700mg per day to about 1800mg per day, about 1800mg per day to about 1800mg per day, about 1900mg per day to about 1800mg per day, about 2000mg per day to about 2000mg per day, about 2100mg per day to about 2100mg per day, about 2200mg per day to about 2200mg per day, about 2300mg per day to about 2300mg per day, about 2400mg per day to about 2400mg per day, about 2500mg per day to about 2500mg per day, about 2600mg per day to about 2600mg per day, about 2700mg per day to about 2700mg per day, about 2800mg per day to about 2800mg per day, about 2900mg per day to about 2900mg per day, about 3000mg per day to about 3000mg per day, about 3100mg per day to about 3100mg per day, about 3200mg per day to about 3200mg per day, about 3300mg per day to about 3300mg per day, about 0 mg to about 1800 mg per day, about 50 mg per day to about 1500 mg per day, about 100 mg per day to about 1500 mg per day, about 150 mg per day to about 1500 mg per day, about 200 mg per day to about 1500 mg per day, about 300 mg per day to about 1500 mg per day, about 400 mg per day to about 1500 mg per day, about 500 mg per day to about 1500 mg per day, about 600 mg per day to about 1500 mg per day, about 700 mg per day to about 1500 mg per day, about 800 mg per day to about 1500 mg per day, about 900 mg per day to about 1500 mg per day, about 1000 mg per day to about 1500 mg per day, about 15 ... 00mg to about 1500mg per day, about 800mg per day to about 1500mg per day, about 900mg per day to about 1500mg per day, about 1000mg per day to about 1500mg per day, about 1100mg per day to about 1500mg per day, about 1200mg per day to about 1500mg per day, about 1300mg per day to about 1500mg per day, about 1400mg per day to about 1500mg per day, about 50mg per day to about 1200mg per day, from about 100 mg per day to about 1200 mg per day, from about 150 mg per day to about 1200 mg per day, from about 200 mg per day to about 1200 mg per day, from about 300 mg per day to about 1200 mg per day, from about 400 mg per day to about 1200 mg per day, from about 500 mg per day to about 1200 mg per day, from about 600 mg per day to about 1200 mg per day, from about 700 mg per day to about 1200 mg per day, from about 800 mg per day to about 1200 mg per day,from about 900 mg per day to about 1200 mg per day, from about 1000 mg per day to about 1200 mg per day, from about 1100 mg per day to about 1200 mg per day, from about 50 mg per day to about 1000 mg per day, from about 100 mg per day to about 1000 mg per day, from about 150 mg per day to about 1000 mg per day, from about 200 mg per day to about 1000 mg per day, from about 300 mg per day to about 1000 mg per day, from about 400 mg per day to about 10 00mg per day, about 500mg per day to about 1000mg per day, about 600mg per day to about 1000mg per day, about 700mg per day to about 1000mg per day, about 800mg per day to about 1000mg per day, about 900mg per day to about 1000mg per day, about 50mg per day to about 800mg per day, about 100mg per day to about 800mg per day, about 150mg per day to about 800mg per day, about 200mg per day to about 800mg, about 300mg per day to about 800mg per day, about 400mg per day to about 800mg per day, about 500mg per day to about 800mg per day, about 600mg per day to about 800mg per day, about 700mg per day to about 800mg per day, about 50mg per day to about 600mg per day, about 100mg per day to about 600mg per day, about 150mg per day to about 600mg per day, about 200mg per day to about 600mg per day g, from about 300 mg per day to about 600 mg per day, from about 400 mg per day to about 600 mg per day, from about 500 mg per day to about 600 mg per day, from about 50 mg per day to about 500 mg per day, from about 100 mg per day to about 500 mg per day, from about 150 mg per day to about 500 mg per day, from about 200 mg per day to about 500 mg per day, from about 300 mg per day to about 500 mg per day, from about 400 mg per day to about 500 mg per day,From about 50 mg per day to about 400 mg per day, from about 100 mg per day to about 300 mg per day, from about 100 mg per day to about 200 mg per day, from about 200 mg per day to about 500 mg per day, from about 300 mg per day to about 500 mg per day, or from about 400 mg per day to about 500 mg per day.

[0060] In some embodiments, the oral dose is about 10 mg per day, about 15 mg per day, about 20 mg per day, about 30 mg per day, about 40 mg per day, about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 450 mg per day, about 500 mg per day, about 550 mg per day, about 600 mg per day, about 650 mg per day, about 700 mg per day, about 750 mg per day, about 800 mg per day, about 850 mg per day, about 900 mg per day, about 1000 mg per day, about 150 ...1000 mg per day, about 1500 mg per day, about 1000 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg per day, about 1500 mg about 950 mg per day, about 1000 mg per day, about 1100 mg per day, about 1200 mg per day, about 1300 mg per day, about 1400 mg per day, about 1500 mg per day, about 1600 mg per day, about 1700 mg per day, about 1800 mg per day, about 1900 mg per day, about 2000 mg per day, about 2100 mg per day, about 2200 mg per day, about 2300 mg per day, about 2400 mg per day, about 2500 mg per day, about 2600 mg per day, about 2700 mg per day, about 2800 mg per day, about 2900 mg per day, or about 3000 mg per day.

[0061] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered in a single dose. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered in multiple doses per day, for example, 2, 3, 4, 5, 6, or more doses. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered intravenously or subcutaneously. In such cases, the intravenous or subcutaneous dose ranges from about 1 mg / kg body weight to about 10 mg / kg body weight, from about 2 mg / kg body weight to about 10 mg / kg body weight, or from about 4 mg / kg body weight to about 8 mg / kg body weight.

[0062] 2. Combination therapy In certain embodiments, disclosed herein is a method for treating or preventing cognitive impairment in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and an additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered simultaneously with trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some embodiments, the additional therapeutic agent is administered before or after trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some embodiments, the combination of trapidil and the additional therapeutic agent is therapeutically effective for treating or preventing cognitive impairment or psychiatric illness in a subject in need thereof.

[0063] In some embodiments, administration of trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof potentiates the additional therapeutic agent, such that subclinical doses of the additional therapeutic agent are required to treat the cognitive disorder or psychiatric illness, hi some embodiments, said additional therapeutic agent is levodopa.

[0064] In some embodiments, the additional therapeutic agent comprises an antidepressant. Non-limiting examples of antidepressants include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, Selfemra, Prozac Weekly), fluvoxamine (Luvox), paroxetine (Paxil, Paxil CR, Pexeva), sertraline (Zoloft), vortioxetine (formerly known as Brintellix, Trintellix), and vilazodone (Viibryd). In some embodiments, trapidil, its derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt is administered in combination with an antidepressant.

[0065] In some embodiments, the additional therapeutic agent comprises an antipsychotic drug. Non-limiting examples of antipsychotic drugs include aripiprazole (Abilify), asenapine (Saphris), cariprazine (Vraylar), clozapine (Clozaril), lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon). In some embodiments, the antipsychotic drug comprises chlorpromazine, fluphenazine, haloperidol, perphenazine, or any combination thereof. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered in combination with the antipsychotic drug.

[0066] In some embodiments, the additional therapeutic agent comprises an anti-anxiety agent. Non-limiting examples of anti-anxiety agents include alprazolam (Xanax), chlordiazepoxide (Librium), clonazepam (Klonopin), diazepam (Valium), and lorazepam (Ativan). In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered in combination with an anti-anxiety agent.

[0067] In some embodiments, the additional therapeutic agent comprises a dopamine precursor or a dopamine agonist. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered in combination with a dopamine precursor. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharma- ceutically acceptable salts are administered in combination with a dopamine agonist.

[0068] In some embodiments, the dopamine precursor comprises levodopa. In some embodiments, the dopamine precursor is a combination of levodopa and carbidopa. In some embodiments, the dopamine precursor is a combination of levodopa and benserazide. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof is administered in combination with levodopa and / or carbidopa. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma-ceutically acceptable salt thereof is administered in combination with levodopa and / or benserazide.

[0069] In some embodiments, the additional therapeutic agent is a dopamine agonist, including pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, bromocriptine, lisuride, apomorphine, levodopa, entacapone, selegiline, rasagiline, and / or tolcapone. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof is administered in combination with pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, bromocriptine, lisuride, apomorphine, levodopa, entacapone, selegiline, rasagiline, and / or tolcapone.

[0070] In some embodiments, the additional therapeutic agent is administered orally, alone or in combination with trapidil. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously, alone or in combination with trapidil.

[0071] In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, is administered before the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, is administered after the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered in a combined dosage form. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered in separate dosage forms.

[0072] D. Therapeutic Drug Dosage Schedule In some embodiments, the therapeutic agent, combination therapy, or pharmaceutical composition described herein is administered according to a specific dosing schedule. In some embodiments, the pharmaceutical composition is administered once a day, twice a day, three times a day, or more. The pharmaceutical composition is administered daily, daily, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more. The pharmaceutical composition is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, or more.

[0073] In some embodiments, the trapidil and the additional therapeutic agent are administered simultaneously, sequentially, or at an interval of time. In some embodiments, the trapidil and the additional therapeutic agent are administered simultaneously. In some embodiments, the trapidil and the additional therapeutic agent are administered sequentially. In further cases, the trapidil and the additional therapeutic agent are administered at an interval of time (e.g., a first administration of a first pharmaceutical composition (e.g., trapidil) on day 1, followed by at least 1, 2, 3, 4, 5, or more days before administration of at least a second pharmaceutical composition (e.g., an additional therapeutic agent)).

[0074] If the patient's condition improves, at the physician's discretion, administration of the composition may continue or, alternatively, the dose of the composition being administered may be temporarily reduced or suspended for a specified period of time (i.e., a "drug holiday"). In some embodiments, the length of the drug holiday may range from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays can be from 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0075] Once the patient's condition (e.g., cognitive impairment or disorder) has improved, a maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on symptoms, to a level at which the improved disease, disorder, or condition is maintained.

[0076] In some embodiments, the amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the identity (e.g., body weight) of the subject or host in need of treatment, but will nevertheless be determined in a manner known and commonly used in the art depending on the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, and the subject or host being treated. In some embodiments, the desired dose is conventionally provided in a single dose or as divided doses, administered simultaneously (or over a short period of time) or at appropriate intervals, e.g., as two, three, four or more sub-doses per day.

[0077] Due to the large number of variables associated with any particular treatment regimen, the foregoing ranges are merely suggestive and significant deviations from these recommendations are not uncommon. Such dosages will vary depending on many variables, including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the particular subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0078] In some embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. Compounds that exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used in formulating a range of dosages for human use. The dosage of such compounds is preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. Dosages vary within this range depending on the dosage form used and the route of administration utilized.

[0079] II. Compositions and Formulations Disclosed herein, in some embodiments, is a pharmaceutical composition (or combination) comprising a therapeutic agent disclosed herein. In some embodiments, the pharmaceutical composition comprises trapidil, a derivative, metabolite, prodrug, analog, or pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition or combination further comprises an additional therapeutic agent. In some embodiments, said additional therapeutic agent is a dopamine precursor (e.g., levodopa). In some embodiments, said additional therapeutic agent is a combination therapy of a dopamine precursor (e.g., levodopa) and an adjunctive therapy (e.g., carbidopa). In some embodiments, said additional therapeutic agent is a dopamine agonist (e.g., rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, or apomorphine). In some embodiments, the pharmaceutical composition or combination is therapeutically effective for treating or preventing cognitive impairment or psychiatric illness in a subject. In some embodiments, the pharmaceutical composition or combination further comprises at least one pharma- ceutically acceptable excipient, carrier or diluent. In some embodiments, the pharmaceutical combination is a fixed dose combination. In some embodiments, the dosage of trapidil in the pharmaceutical composition or combination is about 200 milligrams or less.

[0080] A. Pharmaceutical Compositions and Formulations Disclosed herein in certain embodiments is a pharmaceutical composition or combination comprising a therapeutic agent described herein. In some embodiments, the therapeutic agent is trapidil. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a dopamine precursor (e.g., levodopa) or a dopamine agonist. In some embodiments, the pharmaceutical composition or combination is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents, that facilitate the processing of the active compound into a preparation that can be used pharmaceutically. The appropriate formulation depends on the route of administration selected. Any well-known techniques, carriers, and excipients are used as appropriate and as understood in the art. Summary summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the entireties of which are incorporated herein by reference.

[0081] Pharmaceutical composition, as used herein, refers to a mixture of the compounds described herein, such as trapidil and additional therapeutic agents, with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, viscosity agents, and / or excipients, for example, to treat Parkinson's disease. The aforementioned pharmaceutical composition or combination facilitates administration of the compound to an organism. In carrying out the methods of treatment or use provided herein, a therapeutically effective amount of the compounds described herein is administered as a pharmaceutical composition to a mammal suffering from the disease, disorder, or illness to be treated. Preferably, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0082] In certain embodiments, the composition or combination also includes one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane, and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. These acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition in an acceptable range.

[0083] In other embodiments, the composition or combination also includes one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0084] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., the compounds described herein and the auxiliary agent, are both administered to the patient simultaneously in the form of a single substance or dosage. The term "non-fixed combination" means that the active ingredients, e.g., the compounds described herein and the auxiliary agent, are administered to the patient simultaneously, in parallel, or sequentially as separate substances without any specific intervening time limit, and such administration provides the patient's body with effective levels of the two compounds. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0085] The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration.The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0086] In some embodiments, pharmaceutical compositions containing a compound described herein are manufactured in a conventional manner, such as by means of conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping or compressing processes, by way of example only.

[0087] In some embodiments, "defoamers" reduce foaming during processing that can lead to coagulation of the aqueous dispersion, air bubbles in the finished film, or generally interfere with processing. Typical defoamers include silicone emulsions or sorbitan sesquioleate.

[0088] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium bisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability as needed.

[0089] In certain embodiments, the compositions provided herein also include one or more preservatives to inhibit microbial activity.Suitable preservatives include mercury-containing substances such as merfen and thimerosal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0090] In further embodiments, the formulations described herein benefit from antioxidants, metal chelators, thiol-containing compounds and other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0091] B. Dosage form In some embodiments, the compositions or combinations described herein are formulated for administration to a subject via any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. In some embodiments, the compositions are formulated for administration in a combined dosage form. In some embodiments, the compositions are formulated for administration in separate dosage forms.

[0092] Additionally, the pharmaceutical compositions described herein, comprising trapidil and an additional therapeutic agent, may be formulated in any suitable dosage form for oral ingestion by a patient to be treated, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0093] Orally used pharmaceutical preparations can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and then processing the mixture of granules after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If desired, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added.

[0094] The dragee core is provided with a suitable coating.For this purpose, concentrated sugar solvents are used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and suitable organic solvents or solvent mixtures.Dyes or pigments are added to the tablets or dragee coatings to identify or characterize the dosage of various combinations of active compounds.

[0095] Orally used pharmaceutical preparations include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. All preparations for oral administration should be in dosages suitable for such administration.

[0096] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including suspension tablets, fast dissolving tablets, bite disintegrating tablets, fast disintegrating tablets, effervescent tablets, or caplets), a pill, a powder (including sterile packaged powders, dispensable powders, or effervescent powders), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a biodegradable dosage form, a controlled release formulation, a pulsed release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast dissolving tablet. In addition, the pharmaceutical formulations described herein may be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0097] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing the particles of trapidil and / or additional therapeutic agents with one or more pharmaceutical excipients to form a mixed composition body.When these mixed composition bodies are referred to as homogeneous, it means that the particles of trapidil and / or additional therapeutic agents are evenly distributed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.Individual unit dosages may further include a film coating that disintegrates when taken orally or when contacted with a diluent.These formulations can be manufactured by conventional pharmaceutical techniques.

[0098] Conventional pharmaceutical techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tabletting, extrusion, and the like.

[0099] In some embodiments, the pharmaceutical solid dosage forms described herein comprise a compound described herein and one or more additional pharma- ceutically acceptable additives, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, permeation enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In yet another aspect, a film coating is provided around the formulation of trapidil and / or additional therapeutic agent using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In another embodiment, some or all of the particles of trapidil and / or additional therapeutic agent are not microencapsulated and are not coated.

[0100] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0101] Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0102] In order to release the compound of trapidil and / or additional therapeutic agent from the solid dosage form matrix as efficiently as possible, especially when the dosage form is compressed with a binder, disintegrants are often used in the formulation. Disintegrants help the dosage form matrix to break down by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, cellulose such as wood products, methyl crystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Included are Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches, such as sodium starch glycolate, crosslinked polymers, such as crospovidone, which is a crosslinked polyvinylpyrrolidone, alginates, such as alginic acid, or salts of alginic acid, such as sodium alginate, clays (magnesium aluminum silicate), such as Veegum® HV, gums, such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins, such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0103] Binders provide adhesive properties to solid oral dosage formulations, for powder filled capsule formulations, aid in the formation of a plug that can be filled into soft or hard shell capsules, and for tablet formulations, help ensure that the tablet remains intact after compression and helps ensure that the mix is ​​uniform prior to the compression or filling process. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose stearate acetate (Aqoate®), cellulose acetate (e.g., cellulose acetate stearate acetate), cellulose acetate stearate acetate (Citrate® ... HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrin, cellulose, cellulose acetate, cellulose esters, cellulose glycerides, cellulose esters ... These include sugars such as trose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as gum arabic, tragacanth, and gum ghatti, mucilage from isapol bark, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0104] Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary depending on whether they are direct compression, wet granulation, roller compaction, or use other excipients such as fillers that can act as moderate binders themselves. Formulators in the art can determine the binder level for their formulation, but it is common for binder usage levels to be up to 70% in tablet formulations.

[0105] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax™, PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl stearate palmitate, glyceryl benzoate, magnesium, or sodium lauryl sulfate.

[0106] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and cyclodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0107] The term "water-insoluble diluent" includes calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline cellulose, and fine cellulose (e.g., about 0.45 g / cm 3These represent compounds typically used in the formulation of pharmaceuticals, such as cellulose acetate (e.g., Avicel, powdered cellulose having a density of 100 nm), as well as talc.

[0108] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0109] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like.

[0110] Suspension agents suitable for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., vinylpyrrolidone / vinyl acetate copolymer (S630), where the polyethylene glycol has a molecular weight of about 300 to about 6000, about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, ... Examples of suitable cellulose derivatives include cellulose acetate, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth, gum acacia, guar gum, xanthan including xanthan gum, sugars, cellulosics such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0111] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylhydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0112] It should be recognized that there is considerable overlap between the additives used in the solid dosage forms described herein.Therefore, the above-listed additives should be considered merely as illustrative and not limiting of the types of additives that can be included in the solid dosage forms described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0113] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0114] Compressed tablets are solid dosage forms prepared by compressing the mixture body of the formulation described above. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavorings. In other embodiments, compressed tablets include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of trapidil and / or additional therapeutic agents from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry® coating, or sugar coating). Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight. In other embodiments, compressed tablets include one or more excipients.

[0115] Capsules are prepared, for example, by placing a mixture of the formulation of trapidil and / or additional therapeutic agent described above inside the capsule. In some embodiments, the formulation (non-aqueous suspension and solvent) is placed in a soft gelatin capsule. In other embodiments, the formulation is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, where the capsule is swallowed whole or the capsule is opened and its contents are sprinkled on food before eating. In some embodiments, the therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0116] In various embodiments, particles of trapidil and / or additional therapeutic agent, and one or more excipients are dry mixed and compressed into a mass, such as a tablet, that has sufficient hardness to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluids.

[0117] In another aspect, the dosage form may comprise a microencapsulated formulation.In some embodiments, one or more other compatible materials are present in the microencapsulation material.Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials, such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0118] Materials useful for microencapsulation as described herein include materials compatible with trapidil and / or additional therapeutic agents that sufficiently isolate the trapidil or additional therapeutic agent compound from other incompatible excipients. Materials compatible with trapidil or additional therapeutic agent compound are materials that retard the release of trapidil or additional therapeutic agent compound in vivo.

[0119] Exemplary microencapsulation materials useful for delaying the release of formulations comprising the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers, such as Methocel®-A, hydroxypropyl methylcellulose stearate acetate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, ethylcellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), such as Opadry®, AMB, hydroxyethylcellulose, e.g. Natrosol®, carboxymethylcellulose and salts of carboxymethylcellulose (CMC), e.g. Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers, e.g. Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers, and mixtures of cellulose ethers and acrylic polymers, e.g. Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, Seprafilm, such as a mixture of HPMC and stearic acid, cyclodextrin, and mixtures of these materials.

[0120] In yet another embodiment, plasticizers such as polyethylene glycol, e.g., PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, microencapsulation materials useful for delaying the release of pharmaceutical compositions are from the USP or National Formulary (NF). In yet another embodiment, the microencapsulation material is Klucel. In yet another embodiment, the microencapsulation material is Methocel.

[0121] The microencapsulated compound of either trapidil or additional therapeutic agent may be prepared by methods known to those skilled in the art. Such known methods include, for example, spray drying process, spinning disk dissolution process, hot melt process, spray chilling, fluidized bed, electrostatic deposition, centrifugal extrusion, spin suspension separation, polymerization at liquid-gas or solid-gas interface, extrusion by pressure, or spraying into a solvent extraction tank. In addition to these, various chemical techniques may also be used, such as complex coacervation, melt evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, submerged drying, and desolvation in liquid medium. Furthermore, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating may also be used.

[0122] In other embodiments, the solid dosage formulation of any compound of trapidil and / or additional therapeutic agent is plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0123] In other embodiments, the powder containing the formulation having any of the compounds of trapidil and / or additional therapeutic agents described herein may be formulated to include one or more pharmaceutical excipients and flavorings. Such powders may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a mixed composition body. Further embodiments also include a suspending agent and / or a wetting agent. This mixed body is uniformly subdivided into unit dose packages or multi-dose package units.

[0124] In yet another embodiment, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders that contain drugs in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acid and base react to liberate carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide may be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or greater.

[0125] In some embodiments, the solid dosage forms described herein may be formulated as enterically coated delayed release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize an enteric coating to affect release in the small intestine of the gastrointestinal system. The enterically coated dosage forms may be compressed, molded, or extruded tablets / forms (coated or uncoated) containing granules, powders, pellets, beads, or particles (coated or uncoated) of the active ingredient and / or other compositional ingredients. The enterically coated oral dosage forms may be capsules (coated or uncoated) containing pellets, beads, or granules of solid carriers, or compositions (coated or uncoated).

[0126] As used herein, the term "delayed release" refers to delivery that is achievable at a generally predictable location in the gastrointestinal tract that is distal to where release would have been achieved had the delayed release not been altered. In some embodiments, the method for delaying release is a coating. Any coating should be applied with sufficient thickness such that the entire coating does not dissolve in digestive fluids at a pH below about 5, but dissolves at a pH above about 5. It is anticipated that any anionic polymer that exhibits a pH-dependent solubility profile may be used as an enteric coating in the methods and compositions described herein to achieve delivery down the gastrointestinal system. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties include, but are not limited to, the following:

[0127] Shellac, also called purified lac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH >7.

[0128] Acrylic polymers. The performance of acrylic polymers (mainly solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble but permeable in the gastrointestinal system and are primarily used for colonic targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine.

[0129] Cellulose Derivatives. An example of a suitable cellulose derivative is ethyl cellulose, a reaction mixture of a partial acetate ester of cellulose and phthalic anhydride. Its performance may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a pseudolatex of spray-dried CAP that is water-based and has particles of <1 μm. Other ingredients in Aquateric may include Pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman), methylcellulose (Pharmacoat, Methocel), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCS), and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Its performance may vary based on the degree and type of substitution. For example, HPMCP such as grades HP-50, HP-55, HP-55S, HP-55F are suitable. The performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at pH above that. These polymers are polyvinyl acetate phthalates (PVAP), provided as granules or as fine powders for aqueous dispersion. PVAP dissolves at pH>5 and is much less permeable to water vapor and gastric juices.

[0130] In some embodiments, the coating may, and usually does, contain plasticizers, and possibly other coating excipients such as colorants, talc, and / or magnesium stearate, as are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxyl acrylic polymers usually contain 10-25% by weight of plasticizers, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spray coating or pan coating are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired localized delivery site in the gastrointestinal tract is reached.

[0131] In addition to plasticizers, colorants, detackifiers, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) may be added to the coating to solubilize or disperse the coating materials and to improve coating performance and the coating product.

[0132] In other embodiments, the formulations described herein, including trapidil and / or additional therapeutic agents, are delivered using a pulsatile dosage form. Pulsatile dosage forms can provide one or more immediate release pulses at a pre-determined time point after a controlled lag time or at a specific site. Many other types of controlled release systems known to those skilled in the art are suitable for use with the formulations described herein. Examples of such delivery systems include polymer-based systems such as polylactic acid, polyglycolic acid, polyanhydrides and polycaprolactones, non-polymer-based systems that are lipids, including porous matrices, sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as monoglycerides, diglycerides and triglycerides, hydrogel release systems, silastic systems, peptide-based systems, wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410; 5,977,175; 6,465,014; and 6,932,983.

[0133] In some embodiments, a pharmaceutical formulation is provided comprising particles of trapidil and / or an additional therapeutic agent as described herein and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which when mixed with water will give a substantially uniform suspension.

[0134] The dosage form of the liquid formulation for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharma-ceutically acceptable aqueous oral dispersion, emulsion, solution, elixir, gel, and syrup.See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition, the liquid dosage form may include additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) at least one preservative, (e) viscosity enhancers, (f) at least one sweetener, and (g) at least one flavoring agent.In some embodiments, the aqueous dispersion may further include a crystallization inhibitor.

[0135] The aqueous suspensions and dispersions described herein can remain homogeneous as defined by the USP Pharmacist's Pharmacopoeia (2005 Edition, Chapter 905) for at least 4 hours. For the determination of the homogeneity of the entire composition, homogeneity should be determined by a consistent sampling method. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, no agitation is required to maintain a homogeneous aqueous dispersion.

[0136] Examples of disintegrants used in aqueous suspensions and dispersions include, but are not limited to, starches, e.g., natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Included are Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches, such as sodium starch glycolate, crosslinked polymers, such as crospovidone, which is a crosslinked polyvinylpyrrolidone, alginates, such as alginic acid, or salts of alginic acid, such as sodium alginate, clays (magnesium aluminum silicate), such as Veegum® HV, gums, such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins, such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0137] In some embodiments, dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents, such as hydroxypropyl cellulose, hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose, hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose stearate acetate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymers (Plasdone®, e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymers with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which are tetrafunctional block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine, (BASF Chemicals, Inc.). Corporation, Parsippany, NJ).In other embodiments, the dispersing agent is selected from the group that does not include one of the following agents, including hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose stearate acetate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymers with ethylene oxide and formaldehyde, poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), or poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®).

[0138] Suitable wetting agents for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens, such as, for example, Tween 20 and Tween 80 (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowax 3350 and Carbowax 1450, and Carbopol 934 (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine, and the like.

[0139] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of paraoxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[0140] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, alginates, gum arabic, chitosan, and combinations thereof. The concentration of the viscosity enhancing agent depends on the agent selected and the viscosity desired.

[0141] Examples of sweeteners suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois cream, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhizin (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, Neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, sweet cherry, wintergreen, xylitol, or combinations of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion may include a sweetening or flavoring agent in a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion, hi another embodiment, the aqueous liquid dispersion may include a sweetening or flavoring agent in a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion.In yet another embodiment, the aqueous liquid dispersion may include a sweetening or flavoring agent in a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion.

[0142] In addition to the additives listed above, liquid formulations may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers.Exemplary emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, docusate sodium, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

[0143] In some embodiments, the pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). An emulsion is a dispersion of one immiscible phase in another phase, usually in the form of droplets. In general, emulsions are created by active mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously form emulsions when added to excess water without external mechanical dispersion or agitation. The advantage of SEDDS is that it requires only gentle mixing to distribute the droplets throughout the solution. In addition, water or an aqueous phase can be added immediately before administration, which ensures the stability of unstable or hydrophobic active ingredients. Thus, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can provide an improvement in the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms are known in the art and include, but are not limited to, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.

[0144] It should be recognized that there is overlap between the above-listed additives used in the aqueous dispersion or suspension described herein, because certain additives are often classified differently by different practitioners in the field or are generally used for any of several different actions.Therefore, the above-listed additives should be considered as merely exemplary and, without limitation, as the types of additives that can be included in the formulations described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0145] 1. Injectable preparations Formulations containing trapidil or a compound of an additional therapeutic agent suitable for intramuscular, subcutaneous, or intravenous injection may include sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders that are physiologically acceptable for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Formulations suitable for subcutaneous injection may also include additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0146] For intravenous injection, the compounds described herein may be formulated in aqueous solution, preferably in physiologically compatible buffer such as Hank's solution, Ringer's solution or physiological saline buffer.For transmucosal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art.For other parenteral injection, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffer or excipient.Such excipients are generally known in the art.

[0147] Parenteral injections may include bolus injection or continuous infusion. Preparations for injection may be provided in unit dosage form, for example in ampoules or multi-dose containers, with the addition of a preservative. The pharmaceutical compositions described herein are in a form suitable for parenteral injection, such as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may include formulatory agents, such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0148] 2. Further Formulations In certain embodiments, delivery systems for pharmaceutical compounds may be utilized, such as, for example, liposomes and emulsions. In certain embodiments, the compositions provided herein may also include a mucoadhesive polymer, for example, selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0149] In some embodiments, the compounds described herein may be administered topically and may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments, etc. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0150] In some embodiments, the compounds described herein are also formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, which contain synthetic polymers such as polyvinylpyrrolidone, PEG, and the like, in addition to traditional suppository bases such as cocoa butter or other glycerides. In suppository forms of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0151] III. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are merely exemplary and illustrative and are not restrictive of the claimed subject matter.

[0152] In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" is open-ended, as are other forms such as "include," "includes," and "included."

[0153] As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" also includes the exact amount. Thus, "about 5 μL" also means "about 5 μL" and "5 μL." In general, the term "about" includes amounts that are expected to be within experimental error.

[0154] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0155] As used herein, "drug," "pharmaceutical," "small molecule drug," "biological agent," "biopharmaceutical," and "therapeutic" are used interchangeably to refer to exogenous compounds administered to a patient for therapeutic purposes. These compounds may be obtained by the patient with a prescription from a medical professional or without a prescription for over-the-counter products.

[0156] As used herein, "cognitive disorder" refers to a disease that affects cognitive abilities that may have an underlying brain pathology. In some embodiments, the cognitive disorder is a single disease, symptom, sign, or diagnosis. In some embodiments, the cognitive disorder is a set of closely related diseases, symptoms, signs, or diagnoses.

[0157] As used herein, "cognitive dysfunction" refers to cognitive impairment that causes cognitive decline or impairment. In some embodiments, cognitive dysfunction comprises decline or impairment in one or more of five cognitive domains, including attention, working memory, executive function, visuospatial function, and memory.

[0158] As used herein, "cognition" refers to mental activities including, for example, working memory, executive function, visuospatial function, memory, association, concept formation, pattern recognition, language, attention, perception, behavior, problem solving, and mental imagery.

[0159] As used herein, "derivative" refers to a compound derived or obtained from a compound disclosed herein. In some embodiments, the derivative improves the solubility, absorption, biological half-life, etc., or reduces the toxicity of the molecule, or eliminates or reduces undesirable side effects of the molecule.

[0160] In some embodiments, derivatives of the compounds described herein include compounds that are isotopically labeled (e.g., with radioisotopes) or by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures presented herein, except for the fact that one or more atoms are replaced with atoms that have different atomic masses or mass numbers than those normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, etc. In some embodiments, isotopically labeled compounds described herein, such as compounds that incorporate radioisotopes such as 3H and 14C, are useful for drug and / or substrate tissue distribution assays.

[0161] In some embodiments, the derivative of the compound described herein is a deuterated version of the compound.In some embodiments, the deuterated version of the compound comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more deuterium substitutions.In some embodiments, substitution with an isotope such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased half-life in vivo or reduced dosage requirements.

[0162] In some embodiments, derivatives of the compounds described herein include AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.

[0163] As used herein, the "metabolite" of a compound disclosed herein refers to intermediates and products of that compound that are formed when the compound is metabolized. In further embodiments, the compounds described herein are metabolized when administered to an organism in need, thereby producing metabolic products that are then used to produce a desired effect, including a desired therapeutic effect. In some embodiments, the metabolic products of the compounds disclosed herein are active metabolites. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the totality of processes by which a particular substance is altered by an organism, including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions. Thus, in some embodiments, enzymes produce specific structural modifications to the compound.

[0164] In some embodiments, the sites on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. The incorporation of suitable substituents on the organic radicals reduces, minimizes, or eliminates this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic rings to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuterium alkyl groups.

[0165] In some embodiments, exemplary metabolites disclosed herein include, but are not limited to, desethyl-trapidil, 5-piperidin-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-olyl-7-[N-pent-4-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy or ketopentyl derivatives, piperidinol or piperidinone, TP1 or TP2.

[0166] In some embodiments, metabolic products of the compounds disclosed herein are optionally identified either by administration of the compound to a host and analysis of tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0167] As used herein, a "prodrug" of a compound disclosed herein refers to an agent that is converted to a compound disclosed herein in vivo. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. In some embodiments, the prodrug is bioavailable by oral administration while the parent drug is not. In some embodiments, the prodrug has improved solubility in pharmaceutical compositions over the parent drug. In certain embodiments, the prodrug is chemically converted to a biologically, pharma- ceutical, or therapeutically active form of the compound upon administration in vivo. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharma- ceutical, or therapeutically active form of the compound. To generate a prodrug, a pharma- ceutical active compound is modified so that it is regenerated upon administration in vivo. In some embodiments, the prodrug is designed to alter the metabolic stability or transport properties of the drug to mask side effects or toxicity, improve the flavor of the drug, or change other characteristics or properties of the drug. In some embodiments, prodrugs are designed as reversible drug derivatives to be used as regulators to enhance drug delivery to site-specific tissues. Knowledge of pharmacodynamic processes and in vivo drug metabolism allows those skilled in the art to design prodrugs of pharmacologic compounds once they are known. (See, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401; Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

[0168] As used herein, "analog" refers to a compound that is structurally and functionally similar to or mimics the action of a compound disclosed herein. In some embodiments, an analog mimics the biological action of a compound disclosed herein. In other cases, an analog mimics the physical action of a compound disclosed herein.

[0169] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein that has no lasting deleterious effects on the overall health of the subject being treated or that does not abrogate the biological activity or properties of the compound and is relatively non-toxic. In some embodiments, "pharmaceutically acceptable salt" includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids. Salts of inorganic bases include, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium, magnesium or aluminum, and ammonia. Salts of organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. Salts of inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Salts of organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Salts of basic amino acids include, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

[0170] As used herein, "mental illness" refers to an illness that affects mood, thoughts, behavior, or a combination thereof. In some embodiments, the mental illness comprises clinical depression, anxiety, apathy, or loss of motivation. In some embodiments, the aforementioned mental illness is psychosis.

[0171] As used herein, "Parkinson's disease" refers to a brain disease that affects motor function. Significant symptoms of Parkinson's disease include: (i) trembling of the hands, arms, legs, jaw, or head, (ii) stiffness of the limbs and trunk, (iii) difficulty moving, and (iv) impaired balance and coordination.

[0172] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water or ethanol. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. The solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0173] The methods and formulations described herein also include the use of N-oxides (if appropriate), or pharma- ceutically acceptable salts, of the compounds described herein, as well as active metabolites of these compounds that have the same type of activity.

[0174] As used herein, the terms "individual," "subject," and "patient" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is non-human. None of the terms require or are limited to situations characterized by the supervision (e.g., continuous or intermittent) of a medical professional (e.g., a physician, registered nurse, nurse practitioner, physician assistant, janitorial staff, or hospice staff).

[0175] "Binders" provide adhesive properties and include, for example, alginic acid and its salts, cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), sugars such as microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose, natural or synthetic gums such as acacia, tragacanth, and ghatti gum, isapol bark (e.g., glyceryl stearate, sorbitol ... Examples of suitable antibacterial agents include mucus of husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0176] "Carriers" or "carrier materials" include excipients commonly used in pharmaceuticals and should be selected based on compatibility with the compounds disclosed herein, such as trapidil and additional therapeutic compound, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, etc. "Pharmaceutically compatible carrier materials" include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose complexes, sugars sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0177] "Dispersing agents" and / or "viscosity modifiers" include substances that control the diffusion and homogeneity of drugs through liquid media or granulation or compounding methods. In some embodiments, these agents also promote the effectiveness of the coating or erosion matrix. Exemplary diffusion enhancers / dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents, such as hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose stearate acetate (HPMCAS), amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which are tetrafunctional block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine, (BASF Corporation, Parsippany, NJ).), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of from about 300 to about 6000, from about 3350 to about 4000, or from about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate 80, sodium alginate, gums, e.g., tragacanth, gum arabic, guar gum, xanthan, including xanthan gum, sugars, cellulosics, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan, and combinations thereof. Plasticizers such as cellulose or triethylcellulose may also be used as dispersing agents. Particularly useful dispersing agents in liposomal and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate.

[0178] Combinations of one or more corrosion promoters with one or more diffusion promoters may also be used in the compositions of the present invention.

[0179] The term "diluent" refers to a chemical compound that is used to dilute the compound of interest before delivery. Diluents may also be used to stabilize the compound, as they can provide a more stable environment. Salts dissolved in buffers (which can also control or maintain pH) are utilized as diluents in the art, including, but not limited to, phosphate buffered saline solutions. In certain embodiments, diluents increase the bulk of the composition to facilitate compression or create sufficient bulk for homogeneous mixing for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®, calcium hydrogen phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray dried lactose, pregelatinized starch, compressible sugars such as Di-Pac® (Amstar), mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose stearate acetate, sucrose-based diluents, powdered sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, mannitol, sodium chloride, inositol, bentonite, and the like.

[0180] The term "disintegrate" includes both dissolution and dispersion of the dosage form when contacted with gastrointestinal fluids. A "disintegration agent or disintegrant" promotes the breakdown or disintegration of a substance. Examples of disintegrants include starches, such as natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Included are Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches, such as sodium starch glycolate, crosslinked polymers, such as crospovidone, which is a crosslinked polyvinylpyrrolidone, alginates, such as alginic acid, or salts of alginic acid, such as sodium alginate, clays (magnesium aluminum silicate), such as Veegum® HV, gums, such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins, such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0181] "Drug absorption" or "absorption" typically refers to the process of movement of a drug across a barrier from the site of administration of the drug to the blood vessel or site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.

[0182] An "enteric coating" is a material that remains substantially intact in the stomach but dissolves and releases a drug in the small intestine or colon. Generally, enteric coatings include polymeric materials that prevent release in the low pH environment of the stomach, but ionize at a higher pH, typically a pH of 6 to 7, and therefore dissolve sufficiently in the small intestine or colon to release the active agent therein.

[0183] "Erosion promoters" include substances that control the erosion of a particular substance in gastrointestinal fluids. Erosion promoters are generally known to those skilled in the art. Exemplary corrosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0184] "Bulking agents" include compounds such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, and polyethylene glycol.

[0185] "Flavoring agents" and / or "sweetening agents" useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois cream, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus , Cyclamate, Cyclamate, Dextrose, Eucalyptus, Eugenol, Fructose, Fruit Punch, Ginger, Glycyrrhetinate, Glycyrrhiza (Licorice) Syrup, Grape, Grapefruit, Honey, Isomalt, Lemon, Lime, Lemon Cream, Monoammonium Glycyrrhizinate (MagnaSweet®), Maltol, Mannitol, Maple, Marshmallow, Menthol, Mint Cream, Mixed Berry, Neohesperidin DC, Ne oteme, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharine, aspartame, acesulfame potassium, mannitol, talc, cylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, sweet cherry, wintergreen, xylitol, or combinations of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0186] "Lubricants" and "gliding agents" are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol such as Carbowax®, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid®, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

[0187] "Measurable serum concentration" or "measurable plasma concentration" describes the serum or plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per mL, dL, or L of serum absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng / ml or μg / ml.

[0188] "Pharmacodynamics" refers to the factors that determine the biological response observed relative to the concentration of a drug at a site of action.

[0189] "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of an adequate concentration of a drug at a site of action.

[0190] "Plasticizers" are compounds used to soften microencapsulation materials or film coatings to make them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethylcellulose, and triacetin. In some embodiments, plasticizers may also function as dispersing or wetting agents.

[0191] "Solubilizing agents" include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, docusate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.

[0192] "Stabilizers" include compounds such as any antioxidants, buffers, acids, preservatives, and the like.

[0193] As used herein, "steady state" is when the amount of drug administered equals the amount of drug eliminated within a single dosing interval resulting in a plateau or constant plasma drug exposure.

[0194] "Suspending agents" include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol has a molecular weight of about 300 to about 6000, about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose stearate acetate, poly sorbate 80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth, gum acacia, guar gum, xanthan including xanthan gum, sugars, cellulosics such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylate sorbitan monolaurate, polyethoxylate sorbitan monolaurate, povidone, and the like.

[0195] "Surfactants" include compounds such as sodium lauryl sulfate, docusate sodium, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate sorbitan monooleate polysorbate, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40. In some embodiments, surfactants are included to enhance physical stability or for other purposes.

[0196] "Viscosity enhancing agents" include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose stearate acetate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, and combinations thereof.

[0197] "Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene monolaurate, docusate sodium, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, Vitamin E TPGS, ammonium salts, and the like. EXAMPLES

[0198] IV. Working Examples The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0199] Example 1: Single-cell deconvolution of the effects of trapidil in the striatal bulk of Parkinson's rats demonstrates that it modulates neuronally expressed dopamine 1 receptors Male Sprague Dawley rats (n=25) were made parkinsonian through unilateral administration of 6-hydroxydopamine ("6-OHDA") in the medial forebrain bundle. After 2 weeks of recovery from surgery, rats were divided into three groups and received daily intraperitoneal administrations of either 1) levodopa (6 mg / kg) / benserazide (15 mg / kg) and vehicle (BID) (n=5), 2) levodopa (6 mg / kg) / benserazide (15 mg / kg) and trapidil (7.5 mg / kg, BID) (n=10), or 3) levodopa (6 mg / kg) / benserazide (15 mg / kg) and trapidil (15 mg / kg, BID) (n=10) for 2 weeks. On day 14, rats were sacrificed after the final drug administration and striatum ipsilateral to the lesion was harvested. RNA was extracted from the tissue mass. Preparation steps were completed for RNA-seq on an Illumina sequencer. Samples were sequenced, yielding an average of approximately 28 million reads per sample. After a quality control step, the reads for each sample were aligned to the Rattus norvegicus genome (using STAR), counted (using HTseq), and differential expression was calculated (using DESeq2).

[0200] Tissue body RNA-seq results were computationally deconvoluted into predicted effects on individual cell types using recently developed algorithms (Frishberg et al., Nature Methods 2019) and single-cell RNA-seq reference data from mouse striatum (Gokce et al., Cell Reports 2016). By deconvolving tissue body data into 11 cell types (including neurons expressing dopamine 1 or dopamine 2 receptors, astrocytes, oligodendrocytes, immune cells, and vascular cells), we assessed which cell types had gene expression changes due to trapidil. The only cell type expression significantly activated by trapidil was neurons expressing dopamine 1 receptors (Figure 1). Such changes in expression of dopamine 1 receptor-expressing neurons are consistent with dopamine agonists activating dopamine 1 receptors (Gerfen et al. Science 1990). This finding is surprising since trapidil is not an activator or inhibitor of dopamine receptors (Example 2).

[0201] Because cognitive impairment in Parkinson's disease may result from defects in dopaminergic signaling, trapidil may be therapeutically useful.

[0202] Example 2: Trapidil does not activate, inhibit, or modulate dopamine receptors Trapidil was tested at relevant physiological concentrations (up to 20 uM) in cell-based pharmacological assays for dopamine receptors (D1, D2s, D3, D4, and D5).No significant effects (thresholds set at 50% activation or 50% inhibition) were observed at any of the four concentrations used (Figure 2).

[0203] Example 3: Initial Dosage Levels of Trapidil for Non-Human Primate Studies Efficacy studies often produce uninterpretable data due to inappropriate dosing. Although human and rat plasma PK profiles of SB-0107 can be obtained, the dose-exposure relationship of trapidil in non-human primates cannot. Oral plasma levels of trapidil were characterized at four different doses, 3, 10, 15, and 20 mg / kg, in MPTP-lesioned non-human primates with Parkinson's disease. Blood was collected before and after drug compound administration (10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h) for analysis. Calculated pharmacokinetic parameters are shown in Table 1. Finally, oral doses of 10 mg / kg and 15 mg / kg were used in efficacy studies (Example 4).

[0204] [Table 1]

[0205] Example 4: Efficacy of Trapidil in Treating Cognitive Dysfunction in a Long-Term Low-Dose MPTP-Lesioned Non-Human Primate Model Trapidil was administered using the dosages determined from Example 3 to test its in vivo efficacy in treating cognitive impairment of Parkinson's disease in a chronic low-dose MPTP-lesioned non-human primate model.

[0206] Because animals develop mild cognitive impairment but no motor impairment due to chronic low doses of the toxin MPTP, it is possible to assess the same areas of cognitive impairment observed in patients, including attention, working memory, and executive function. The ability of trapidil to improve cognitive tests with and without low doses of levodopa (which have minimal effects on cognitive function) is tested and compared to high doses of levodopa (which begin to impair cognitive function).

[0207] Five male non-human primates were used, randomized to receive eight treatments in a partial Latin square design (Table 2). Animals were pre-trained to complete several cognitive tasks prior to lesion, including the variable delayed response (VDR). The VDR is a spatial working memory task in which NHPs are rewarded for recalling a location on a screen after a variable delay period (from 2 to 60 seconds, DP1-DP5). Shorter periods (i.e., DP1, DP2) require only an attentional component, whereas longer delay periods include additional memory components (i.e., D4, D5). This task was specifically chosen due to its cognitive domain (spatial working memory and attention) because these tasks are improved by dopamine 1 receptor agonism in models of cognitive impairment and are impaired by high doses of levodopa in models of cognitive impairment in Parkinson's disease patients.

[0208] [Table 2]

[0209] After chronic low-dose MPTP, five primates showed significant deficits in their ability to accurately complete the VDR task at all five delay periods (Figure 3), thus demonstrating cognitive deficits in the domains of spatial working memory, executive function, and attention. When animals were administered levodopa (5-20 mg / kg, groups 6-8), they tended to complete the VDR test with less accuracy, especially at the short delay periods (DP1 and DP2) (Figure 4).

[0210] Trapidil, at 10 mg / kg, can significantly improve the VDR response accuracy in two short delay periods (Figure 5). This means that it improves cognition in the domains of spatial working memory, executive function, and attention. Furthermore, the response accuracy in the treatment group with a combination of low dose levodopa (5 mg / kg) and trapidil further indicates that trapidil improves responses in the VDR task in the short delay periods (Figure 6). Finally, we show that trapidil significantly improves correct responses in DP1 and DP2 with or without levodopa (Figure 7). In Figures 5-7, "best dose" refers to the best one, either 10 mg / kg or 15 mg / kg, for each of the five primates in terms of response to treatment with trapidil.

[0211] Additionally, we investigated in more detail the improvement in delay periods DP1 and DP2 with trapidil 10 mg / kg monotherapy, since it had the strongest effect of any treatment. In particular, we observed a significant decrease in the primates' total reaction time (from the stimulus cue to the primate's response) with trapidil (10 mg / kg) (Figure 8). This decrease suggests an increase in motivation and encouragement, and in some cases may correct the associated psychiatric illness of amotivation in Parkinson's disease. Amotivation in Parkinson's disease has been shown to be highly correlated with cognitive impairment in Parkinson's disease, and amotivation is a predictor of potential cognitive decline. The extent of the decrease in reaction time is in line with the maximal decrease in reaction time with any dose of levodopa, a known drug with anti-amotivating effects. However, not only did the primates complete the task faster with trapidil, but they also did so in a more precise manner, unlike levodopa (Figure 7).

[0212] Example 5: Efficacy of trapidil in treating cognitive dysfunction in a mouse model of phencyclidine-induced schizophrenia Acute administration of phencyclidine (PCP) is a well-established model of schizophrenia in rodents to assess various types of deficits, including cognition. It is a common model for evaluating potential pharmacologic treatments for schizophrenia. Mice and rats exhibit cognitive deficits that can be detected using a variety of behavioral assessments, including the Y-maze spontaneous alternation test, an assessment of cognitive performance in working memory.

[0213] In a dose-finding study, C57BL / 6J mice were divided into several treatment groups (Table 3). Short-term administration of PCP (7.5 mg / kg, IP) induced deficits in working memory, as detected by a decrease in the percentage of spontaneous alternation (Figure 9A). Oral administration of trapidil was able to correct the deficits observed in the percentage of spontaneous alternation induced by several different doses of PCP. These results are consistent with the atypical antipsychotic clozapine (2.5 mg / kg, IP), used as a positive control. In addition, the total number of entries into the Y-maze was catalogued to assess confounding factors. Such confounding factors were not detected, since there was no significant difference in the number of entries between the PCP groups (Figure 9B).

[0214] [Table 3]

[0215] Example 6. Treatment of dementia with trapidil A patient diagnosed with dementia is administered a therapeutically effective dose of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil. In some embodiments, the therapeutically effective dose of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil is 200 milligrams or less, administered three times a day.

[0216] In some embodiments, the patient is also diagnosed with Parkinson's disease. In this example, the dementia is not caused by Parkinson's disease. In some embodiments, the patient is also administered a therapeutically effective dose of a dopamine precursor (e.g., levodopa) or a dopamine agonist, with or without adjunctive therapy (e.g., carbidopa), to treat Parkinson's disease. In some embodiments, the dose of levodopa is subclinical when administered in combination with a dose of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil.

[0217] In some embodiments, the patient is also diagnosed with schizophrenia. In some embodiments, the patient is also administered a therapeutically effective dose of an antipsychotic drug (e.g., aripiprazole) to treat schizophrenia. In some embodiments, the dose of aripiprazole is a subclinical dose when administered in combination with a dose of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil.

[0218] Example 7. Treatment of lethargy with trapidil A patient diagnosed with lethargy is administered a therapeutically effective dose of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil. In some embodiments, the therapeutically effective dose of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil is 200 milligrams or less administered three times a day.

[0219] In some embodiments, the patient is also diagnosed with Parkinson's disease. In this example, the apathy is not caused by Parkinson's disease. In some embodiments, the patient is also administered a therapeutically effective dose of a dopamine precursor (e.g., levodopa) or a dopamine agonist, with or without adjunctive therapy (e.g., carbidopa), to treat Parkinson's disease. In some embodiments, the dose of levodopa is subclinical when administered in combination with a dose of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil.

[0220] In some embodiments, the patient is also diagnosed with schizophrenia. In some embodiments, the patient is also administered a therapeutically effective dose of an antipsychotic drug (e.g., aripiprazole) to treat schizophrenia. In some embodiments, the dose of aripiprazole is subclinical when administered in combination with trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil.

[0221] Example 8. Treatment or prevention of drug-induced cognitive deficits in Parkinson's disease patients In Parkinson's disease patients, cognitive impairment is caused or aggravated by administration of clinical doses of levodopa and / or carbidopa for treating Parkinson's disease.To treat cognitive impairment, a therapeutically effective amount of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil is administered to the patient.After administration of a therapeutically effective amount of a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil, the patient's cognitive function improves.

[0222] In some embodiments, trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil potentiates the therapeutic action of levodopa and / or carbidopa for the treatment of Parkinson's disease in a patient, such that lower (subclinical) doses of levodopa and / or carbidopa are required over time to treat Parkinson's disease. Thus, administration of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharma- ceutically acceptable salt of trapidil is effective in preventing cognitive deficits in a patient caused or exacerbated by administration of clinical doses of levodopa and / or carbidopa.

Claims

1. 1. A medicament for treating or preventing cognitive impairment associated with Parkinson's disease, schizophrenia, or attention deficit hyperactivity disorder in a subject, the medicament comprising trapidil (N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine), deuterated trapidil, a pharma- ceutically acceptable salt of trapidil, or a pharma- ceutically acceptable salt of deuterated trapidil.

2. The drug is (a) an antidepressant, (b) an antipsychotic, (c) anxiolytics, (d) dopamine precursors, (e) a dopamine agonist, or (f) Any combination of (a) to (e) above. The method of claim 1 , wherein the method is administered with a further therapeutic agent comprising:

3. The subject is (a) an antidepressant, (b) an antipsychotic, (c) anxiolytics, (d) dopamine precursors, (e) a dopamine agonist, or (f) Any combination of (a) to (e) above. The method of claim 1, which is being treated with an additional therapeutic agent comprising:

4. The method of claim 2 or 3, wherein the dopamine precursor is levodopa.

5. The method of claim 1 , wherein the cognitive impairment is associated with Parkinson's disease.

6. The method of claim 1 , wherein the cognitive impairment is associated with schizophrenia.

7. The method of claim 1, wherein the cognitive impairment is associated with attention deficit hyperactivity disorder.

8. 2. The method of claim 1, wherein the pharma- ceutically acceptable salts include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid.

9. 2. The method of claim 1, wherein the trapidil, the deuterated trapidil, the pharma- ceutically acceptable salt of the trapidil, or the pharma- ceutically acceptable salt of the deuterated trapidil is formulated for oral, intravenous, or subcutaneous administration.

10. The method of claim 2 or 3, wherein the trapidil, the deuterated trapidil, the pharma- ceutically acceptable salt of the trapidil or the pharma- ceutically acceptable salt of the deuterated trapidil, and the additional therapeutic agent are administered simultaneously.

11. The method of claim 2 or 3, wherein the trapidil, the deuterated trapidil, the pharma- ceutically acceptable salt of the trapidil or the pharma- ceutically acceptable salt of the deuterated trapidil, and the additional therapeutic agent are administered sequentially.

12. 2. The method of claim 1, wherein the dose of said trapidil, said deuterated trapidil, said pharma- ceutically acceptable salt of said trapidil or said pharma- ceutically acceptable salt of said deuterated trapidil is comprised about 200 milligrams or less.

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