Treating extrapyramidal syndrome using trapidil

Abstract

To provide methods for treatment of extrapyramidal syndromes.SOLUTION: Disclosed herein are methods for the treatment of extrapyramidal syndromes (for example, dyskinesia, dystonia, akathisia, or drug-induced Parkinsonism) in a subject in need thereof, including the step for the administration to the subject of a therapeutic effective amount of trapidil, a derivative, a metabolite, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] <Cross reference> This invention claims the benefit of U.S. Provisional Patent Application No. 62 / 317,983, filed April 4, 2016, which is incorporated herein by reference.

[0002] <Statement regarding federally funded research> This invention was made with U.S. Government support under Contract No. R43GM121117 awarded by the National Institutes of Health. Summary of the Invention

[0003] In certain embodiments, disclosed herein are methods, pharmaceutical combinations, dosage forms, and kits for treating extrapyramidal syndrome. In some cases, the treatment involves the use of a therapeutically effective amount of trapidil. In other cases, the treatment involves the use of a therapeutically effective amount of a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof of trapidil.

[0004] Disclosed herein, in certain embodiments, are methods for treating an extrapyramidal syndrome in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, the subject is administered a therapeutically effective amount of trapidil, a derivative, metabolite, or pharmaceutically acceptable salt thereof. In some embodiments, the extrapyramidal syndrome comprises dyskinesia, dystonia, akathisia, or drug-induced parkinsonism. In some embodiments, the dyskinesia is tardive dyskinesia (TD). In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). In some embodiments, the dyskinesia is biphasic dyskinesia or peak-dose dyskinesia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal or "rebound" akathisia. 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 includes AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565. In some embodiments, the metabolite comprises 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 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, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered orally. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered intravenously or subcutaneously. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is clonazepam, ginkgo biloba, clozapine, risperidone, quetiapine, vitamin E, levodopa, benzodiazepines, botulinum toxin, reserpine, tetrabenazine, propranolol, or a dopamine-depleting agent. agents), ondansetron, zotepine, aripiprazole, zopiclone, zonisamide, trihexyphenidyl (Broflex), biperiden, procyclidine, diazepam, baclofen, tizanidine, carbamazepine, gabapentin, lorazepam, mianserin, cyproheptadine, mirtazapine, benztropine, trihexyphenidyl, carbidopa, ropinirole, pramipexole, bromocriptine, selegiline, rasagiline, ziprasidone, olanzapine, amantadine, valbenazine, dutetrabenazine, or diphenhydramine. In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered before the administration of the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered after the administration of the additional therapeutic agent. In some embodiments, the subject has been diagnosed with an extrapyramidal syndrome.In some embodiments, the subject exhibits at least one marker associated with extrapyramidal syndrome. In some embodiments, the at least one marker is selected from FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some embodiments, the at least one marker is upregulated. In some embodiments, the at least one upregulated marker is selected from FOSL2, JUN, SREBF1, CEBPB, UBC, and ERK. In some embodiments, the at least one marker is downregulated. In some embodiments, the at least one marker is selected from MYC and BCL2. In some embodiments, trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof, modulates at least one marker associated with extrapyramidal syndrome. In some embodiments, the subject is not diagnosed with extrapyramidal syndrome. In some embodiments, the subject is a human.

[0005] Disclosed herein, in certain embodiments, are methods for preventing extrapyramidal syndrome in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, the subject is administered a therapeutically effective amount of trapidil, a derivative, metabolite, or pharmaceutically acceptable salt thereof. In some embodiments, the extrapyramidal syndrome comprises dyskinesia, dystonia, akathisia, or drug-induced parkinsonism. In some embodiments, the dyskinesia is tardive dyskinesia (TD). In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). In some embodiments, the dyskinesia is biphasic dyskinesia or peak-dose dyskinesia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal or "rebound" akathisia. 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 includes AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565. In some embodiments, the metabolite comprises 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, a hydroxy derivative or a ketopentyl derivative, a piperidinol or a 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, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered intravenously or subcutaneously. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises clonazepam, ginkgo biloba, clozapine, risperidone, quetiapine, vitamin E, levodopa, benzodiazepine, botulinum toxin, reserpine, tetrabenazine, propranolol, a dopamine-depleting agent, ondansetron, zotepine, aripiprazole, zopiclone, zonisamide, trihexyphenidyl (Broflex), biperiden, procyclidine, diazepam, baclofen, tizanidine, carbamazepine, gabapentin, lorazepam, mianserin, cyproheptadine, mirtazapine, benztropine, trihexyphenidyl, carbidopa, ropinirole, pramipexole, bromocriptine, selegiline, rasagiline, ziprasidone, olanzapine, amantadine, valbenazine, deutetrabenazine, or diphenhydramine. In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered before administration of the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered after administration of the additional therapeutic agent. In some embodiments, the subject has been diagnosed with an extrapyramidal syndrome. In some embodiments, the subject exhibits at least one marker associated with an extrapyramidal syndrome.In some embodiments, the at least one marker is selected from FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some embodiments, at least one additional marker is upregulated. In some embodiments, the at least one upregulated marker is selected from FOSL2, JUN, SREBF1, CEBPB, UBC, and ERK. In some embodiments, the at least one additional marker is downregulated. In some embodiments, the at least one marker is selected from MYC and BCL2. In some embodiments, trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof, modulates at least one marker associated with an extrapyramidal syndrome. In some embodiments, the subject is not diagnosed with an extrapyramidal syndrome. In some embodiments, the subject is human.

[0006] In certain embodiments, disclosed herein are pharmaceutical combinations comprising a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and an additional therapeutic agent. 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 includes AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565. In some embodiments, the metabolite comprises 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 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, the additional therapeutic agent is clonazepam, ginkgo biloba, clozapine, risperidone, quetiapine, vitamin E, levodopa, benzodiazepines, In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered orally.In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered intravenously or subcutaneously. In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered before the administration of the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered after the administration of the additional therapeutic agent.

[0007] Disclosed herein, in certain embodiments, is a dosage combination for use in treating an extrapyramidal syndrome in a subject in need thereof, the dosage combination comprising administering to the subject a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and an additional therapeutic agent; wherein the therapeutically effective amount is an amount that treats the extrapyramidal syndrome in the subject in need thereof. In some embodiments, the extrapyramidal syndrome comprises dyskinesia, dystonia, akathisia, or drug-induced parkinsonism. In some embodiments, the dyskinesia is tardive dyskinesia (TD). In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). In some embodiments, the dyskinesia is biphasic dyskinesia or peak-dose dyskinesia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal or "rebound" akathisia. 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 includes AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565. In some embodiments, the metabolite comprises 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 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, the additional therapeutic agent comprises clonazepam, ginkgo biloba, clozapine, risperidone, quetiapine, vitamin E, levodopa, benzodiazepine, botulinum toxin, reserpine, tetrabenazine, propranolol, a dopamine-depleting agent, ondansetron, zotepine, aripiprazole, zopiclone, zonisamide, trihexyphenidyl (Broflex), biperiden, procyclidine, diazepam, baclofen, tizanidine, carbamazepine, gabapentin, lorazepam, mianserin, cyproheptadine, mirtazapine, benztropine, trihexyphenidyl, carbidopa, ropinirole, pramipexole, bromocriptine, selegiline, rasagiline, ziprasidone, olanzapine, amantadine, valbenazine, deutetrabenazine, or diphenhydramine. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered orally. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered intravenously or subcutaneously. In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered before the administration of the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered after the administration of the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered in a combined dosage form.In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and the additional therapeutic agent are administered in separate dosage forms. In some embodiments, the subject has been diagnosed with extrapyramidal syndrome. In some embodiments, the subject exhibits at least one marker associated with extrapyramidal syndrome. In some embodiments, the subject is human.

[0008] Disclosed herein, in certain embodiments, are kits comprising a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof; and an additional therapeutic agent. [Brief explanation of the drawings]

[0009] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0010] [Figure 1] Figure 1 shows the ability of trapidil to ameliorate or reverse expression changes in key genes associated with extrapyramidal syndrome caused by haloperidol, a potent first-generation antipsychotic. * indicates that the changes caused by trapidil were significant at FDR < 0.05. [Figure 2] Figure 1 shows the ability of trapidil to ameliorate or reverse expression changes in key genes associated with extrapyramidal syndrome caused by risperidone, a second-generation antipsychotic. * indicates that the changes caused by trapidil were significant at FDR < 0.05. [Figure 3] Figure 1 shows propensity scores for extrapyramidal syndrome calculated from changes in gene expression following administration of various compounds in vitro. Trapidil dose-dependently reduces gene expression patterns associated with extrapyramidal syndrome induced by first-generation antipsychotics and second-generation antipsychotics (haloperidol and risperidone). [Figure 4] These results show the similarity of gene expression changes caused by compound administration in vitro to those observed in the rat striatum during levodopa administration in a model of levodopa-induced dyskinesia. Trapidil dose-dependently alters dopamine gene expression patterns that are distinct from the observed transcriptomic signature of dyskinesia. [Figure 5] 1 illustrates a study design to evaluate the efficacy of trapidil in the prevention and / or treatment of haloperidol-induced dyskinesia. DETAILED DESCRIPTION OF THE INVENTION

[0011] Drugs are administered to treat and alleviate medical conditions. Adverse drug reactions (ADRs) are negative side effects of drugs. In some cases, ADRs are classified into six types: 1) dose-related, 2) non-dose-related, 3) dose- and time-related, 4) time-related, 5) withdrawal, and 6) treatment failure. In some cases, ADRs result in clinical and economic burdens. According to the Food and Drug Administration's (FDA) Large-Scale Adverse Event Case Report Database, ADRs account for 100,000 deaths annually in the United States. For example, ADRs are responsible for approximately 6.5% of hospitalizations. Furthermore, ADRs and drug safety issues account for approximately 28% of failed phase 2 and 3 clinical trials. In some cases, ADRs are also the cause of drug withdrawal; for example, ADRs of Vioxx by Merck and Co. and Lipobay by Bayer AG Additional management include, for example, changes in the dosing regimen or its effects or specific treatment.

[0012] Extrapyramidal syndromes, their disorders, symptoms, or side effects, are a specific set of ADRs that are drug-induced movement disorders. Depending on the drug used, extrapyramidal syndromes affect up to approximately 30-40% of patients taking the medication. In some cases, extrapyramidal syndromes further affect the patient's quality of life, lead to therapeutic non-compliance, and in rare cases, lead to death.

[0013] In some cases, computational analysis has correlated extrapyramidal syndromes or drug-induced movement disorders with increased activity of the ERK pathway (also known as the MAPK pathway or Ras-Raf-MEK-ERK pathway). For example, computational analysis has shown increased expression of genes regulated by or interacting with the proteins JUN, FOS, UBC, SREBF1, CEBPB, and / or MYC. In some cases, these proteins are directly upregulated by ERK signaling proteins. In addition, inflammatory markers such as IL-6, IL-12, and TNF-α have been detected by computational analysis. Furthermore, increased ERK activity and inflammation have been observed in levodopa-induced dyskinesia and tardive dyskinesia. For example, upregulation of FOS and FOS-related protein (FRA), which is regulated by ERK / MAPK, has been associated with levodopa-induced dyskinesia (Thanvi, et al., “Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment,” Postgrad Med J. 83(980): 384-388(2007)).

[0014] In some instances, computational analyses have shown trapidil to modulate the expression (e.g., gene expression) of signaling proteins JUN, UBC, and / or ERK. In some cases, trapidil has also been correlated with decreased expression of genes that interact with inflammatory markers, such as TNF-α, IL-1α, and / or IL-1b, where IL-1b has been shown to be associated with levodopa-induced dyskinesia.

[0015] In certain embodiments, disclosed herein is a method for treating an ADR in a subject in need thereof. In some cases, the ADR is an extrapyramidal syndrome. In some cases, disclosed herein is a method for treating an extrapyramidal syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt.

[0016] Disclosed herein, in certain embodiments, is a method for preventing extrapyramidal syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0017] Disclosed herein, in certain embodiments, is a pharmaceutical combination comprising a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and an additional therapeutic agent.

[0018] Disclosed herein, in certain embodiments, is a dosage combination for use in treating an extrapyramidal syndrome in a subject in need thereof, the dosage combination comprising administering to the subject a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and an additional therapeutic agent; wherein the therapeutically effective amount is an amount that treats the extrapyramidal syndrome in the subject in need thereof.

[0019] Disclosed herein, in certain embodiments, are kits that include a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and an additional therapeutic agent.

[0020] <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 exemplary and illustrative only and are not restrictive of the claimed subject matter.

[0021] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must 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," as well as other forms such as "include," "includes," and "included," is open-ended.

[0022] As used herein, ranges and amounts can 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.

[0023] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0024] As used herein, the terms "drug," "pharmaceutical," "small molecule drug," "biologic," "biopharmaceutical," and "therapeutic agent" are used interchangeably to refer to exogenous compounds administered to a patient for therapeutic purposes, with or without adverse drug reactions (ADRs). These compounds may be obtained by the patient with a prescription from a healthcare professional or without a prescription for over-the-counter products.

[0025] As used herein, "adverse drug reaction," "ADR," "adverse drug event," "adverse event," and "side effect" are used interchangeably to refer to unintended and damaging consequences of a drug. In some cases, an ADR is a single disease, symptom, sign, or diagnosis. For example, nausea is an ADR. In some cases, an ADR is a single set of closely related diseases, symptoms, signs, or diagnoses. For example, the set of nausea and vomiting is an ADR.

[0026] As used herein, "derivative" refers to a compound derived from or obtained from a compound disclosed herein. In some cases, the derivative acts to improve its solubility, absorption, biological half-life, etc., or to reduce the toxicity of the molecule, eliminate or reduce undesirable side effects of the molecule, etc.

[0027] In some cases, derivatives of the compounds described herein include compounds that are isotopically labeled (e.g., with a radioisotope) or by other means, including, but not limited to, the use of chromophoric or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The 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 by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include, for example, 2 H, 3 H, 13 C. 14 C. 15N, 18 O. 17 O. 35 S, 18 F, 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. In some cases, isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds into which radioactive isotopes such as 3C are incorporated are useful in drug and / or substrate tissue distribution assays.

[0028] In some embodiments, derivatives of the compounds described herein are deuterated versions of the compounds. In some cases, deuterated versions of the compounds contain at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more deuterium substituents. In some cases, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0029] In some cases, derivatives of the compounds described herein include AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565.

[0030] As used herein, a "metabolite" of a compound disclosed herein refers to an intermediate or product of that compound that is formed when the compound is metabolized. In additional embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof, thereby producing a metabolite, which is then used to provide a desired effect, including a desired therapeutic effect. In some cases, a metabolite of a compound disclosed herein is an active metabolite. 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 transformed by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes). Thus, in some cases, enzymes effect specific structural modifications to a compound.

[0031] In some embodiments, moieties on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals reduces, minimizes, or eliminates this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuterated alkyl groups.

[0032] In some cases, 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.

[0033] In some embodiments, metabolites of the compounds disclosed herein are optionally identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0034] 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, in some situations, they are easier to administer than the parent drug. In some cases, a prodrug is bioavailable by oral administration while the parent drug is not. In some cases, a prodrug has improved solubility in pharmaceutical compositions over the parent drug. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to a biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharmaceutically, or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified so that it can be regenerated upon in vivo administration. In some cases, a prodrug is designed to alter the metabolic stability or transport properties of a drug to mask side effects or toxicity, improve the flavor of a drug, or alter other characteristics or properties of a drug. In some cases, prodrugs are designed as reversible drug derivatives to be used as modifiers to enhance drug delivery to site-specific tissues.With knowledge of pharmacodynamic processes and in vivo drug metabolism, those skilled in the art can design prodrugs of pharmaceutically active compounds once they know them. (See, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992) The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401; Saulnier et al., (1994) Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

[0035] As used herein, "analog" refers to a compound that is structurally and functionally similar to or mimics the effects of a compound disclosed herein. In some cases, an analog mimics the biological effect of a compound disclosed herein. In other cases, an analog mimics the physical effect of a compound disclosed herein.

[0036] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein that has no lasting adverse effects on the 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, hydroboric 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. Salts of acidic amino acids include, for example, aspartic acid and glutamic acid.

[0037] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms.In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and are formed during the crystallization process with a pharmaceutically acceptable solvent, such as water or ethanol.When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed.Solvates of the compounds described herein are suitably prepared or formed during the process described herein.In addition, the compounds provided herein optionally exist in both solvated and unsolvated forms.

[0038] The methods and formulations described herein include the use of N-oxides (where appropriate), or pharmaceutically acceptable salts, of the compounds described herein, as well as active metabolites of these compounds that possess the same type of activity.

[0039] 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 a situation characterized by the supervision (e.g., continuous or intermittent) of a health care worker (e.g., a physician, registered nurse, nurse practitioner, physician assistant, janitorial staff, or hospice staff).

[0040] <Extrapyramidal syndrome> Extrapyramidal syndromes include a class of movement disorders caused by drugs. In some embodiments, drug classes identified as causing extrapyramidal syndromes include, but are not limited to: 1) antipsychotics, 2) levodopa, 3) antidepressants, 4) anticholinergics, e.g., used for respiratory problems, bladder control problems, or Parkinson's disease, 5) antiemetics, 6) antianxiety medications, e.g., for anxiety disorders, 7) antiepileptics, 8) antiparkinsonian medications, 9) antimalarials, and 10) antihistamines.

[0041] In some embodiments, extrapyramidal syndromes, symptoms, disorders, or side effects thereof include movement disorders, dyskinesia, akathisia, tardive dyskinesia, psychomotor hyperactivity, abnormal involuntary movements, acute dyskinesia, jerkiness, spasmodic movements, oromotor impairment, orolingual dyskinesia, protracted tongue, facial jerks, trembling attacks, motor restlessness, compulsive hyperkinesia, levodopa-induced dyskinesia, neuroleptic-induced dyskinesia, dystonia, drug-induced parkinsonism, pseudoparkinsonism, bradykinesia, tremor, rigidity, and lip smacking.

[0042] Disclosed herein, in some embodiments, is a method of treating extrapyramidal syndrome caused by an antipsychotic, levodopa, antidepressant, anticholinergic, antiemetic, anxiolytic, antiepileptic, antiparkinsonian, antimalarial, or antihistamine in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In additional embodiments, disclosed herein are methods of treating a subject exhibiting one or more extrapyramidal symptoms, such as movement disorders, dyskinesia, akathisia, tardive dyskinesia, psychomotor hyperactivity, abnormal involuntary movements, acute dyskinesia, jerking movements, spasmodic movements, impaired oromonia, orolingual dyskinesia, protracted tongue, facial spasms, trembling attacks, motor restlessness, compulsive hyperkinesia, levodopa-induced dyskinesia, neuroleptic-induced dyskinesia, dystonia, drug-induced parkinsonism, pseudoparkinsonism, bradykinesia, tremor, rigidity, and lip smacking, with a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0043] <Dyskinesia> In some embodiments, the extrapyramidal syndrome is dyskinesia. In some embodiments, the dyskinesia is tardive dyskinesia (TD), levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak-dose dyskinesia. In some embodiments, the dyskinesia is tardive dyskinesia (TD). In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). In some embodiments, the dyskinesia is biphasic dyskinesia. In some embodiments, the dyskinesia is peak-dose dyskinesia.

[0044] In some embodiments, dyskinesia is an extrapyramidal syndrome, which is a drug-induced movement disorder. Dyskinesia refers to a category of movement disorders characterized by involuntary muscle movements, including movements similar to tics or chorea and a reduction in voluntary movements. Dyskinesias range from, for example, slight tremors in the hands to uncontrollable movements of the upper or lower body. Dyskinesias are symptoms of several medical disorders, which are differentiated by their underlying causes.

[0045] In some embodiments, the dyskinesia is tardive dyskinesia (TD). Tardive dyskinesia refers to a type of dyskinesia that results in repetitive, involuntary, purposeless body movements, including, but not limited to, facial grimacing, tongue movements, lip smacking, lip puckering, lip pursing, or excessive eye blinking. The involuntary movements have a slow or delayed onset. In some embodiments, this syndrome occurs in children and infants as a result of long-term or high-dose use of antipsychotics or as a side effect from the use of medications for gastrointestinal disorders. In some cases, TD is caused by antipsychotics, levodopa, antidepressants, anticholinergics, antiemetics, antiepileptics, antimalarials, and antihistamines.

[0046] In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). Levodopa-induced dyskinesia refers to a form of dyskinesia associated with levodopa, which is used to treat the motor symptoms of Parkinson's disease. LID is often accompanied by hyperkinesia, including chorea, dystonia, and athetosis.

[0047] In some embodiments, the dyskinesia is biphasic dyskinesia. Biphasic dyskinesia refers to a type of levodopa-induced dyskinesia that occurs when plasma levodopa levels are rising or falling but not at peak levels. Biphasic dyskinesia occurs primarily in the lower limbs and is often dystonic or ballistic. This form of dyskinesia does not respond to a reduction in levodopa dosage.

[0048] In some embodiments, the dyskinesia is peak-dose dyskinesia. Peak-dose dyskinesia refers to a form of levodopa-induced dyskinesia that correlates with peak plasma levels of levodopa. Peak-dose dyskinesia involves the head, trunk, and limbs, and sometimes respiratory muscles. Peak-dose dyskinesia corresponds to a reduction in levodopa dosage, but at the cost of worsening parkinsonism.

[0049] In some embodiments, disclosed herein are methods for treating dyskinesia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some embodiments, the dyskinesia is tardive dyskinesia (TD), levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak-dose dyskinesia. In some cases, disclosed herein are methods for treating tardive dyskinesia (TD) by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating levodopa-induced dyskinesia (LID) by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating diphasic dyskinesia with the administration of a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating peak dose dyskinesia with the administration of a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0050] <Dystonia> In some embodiments, the extrapyramidal syndrome is dystonia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the dystonia is generalized dystonia. In some embodiments, the dystonia is focal dystonia. In some embodiments, the dystonia is segmental dystonia. In some embodiments, the dystonia is acute dystonia.

[0051] In some embodiments, the extrapyramidal syndrome is dystonia. Dystonia refers to a movement disorder in which held muscle contractions cause twisting and repetitive movements or abnormal postures. In some cases, the movements resemble tremors. Dystonia is often initiated or exacerbated by voluntary movements, and symptoms "spill over" into adjacent muscles. In some embodiments, the dystonia is drug-induced dystonia. Dystonic reactions are characterized by intermittent spasmodic or held involuntary contractions of muscles in the face, neck, trunk, pelvis, limbs, and larynx.

[0052] In some embodiments, the dystonia is generalized dystonia, which refers to forms of dystonia that affect most or all of the body.

[0053] In some embodiments, the dystonia is focal dystonia. Focal dystonia refers to a form of dystonia that is localized to a particular part of the body. In some cases, the focal dystonia is multifocal dystonia, which involves two or more unrelated body parts.

[0054] In some embodiments, the dystonia is segmental dystonia. Segmental dystonia refers to a form of dystonia that affects two or more adjacent parts of the body.

[0055] In some embodiments, the dystonia is acute dystonia, which refers to a form of dystonia consisting of sustained, often painful muscle spasms that result in twisted, abnormal postures.

[0056] In some embodiments, disclosed herein are methods for treating dystonia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some cases, disclosed herein are methods for treating generalized dystonia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating focal dystonia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating segmental dystonia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods of treating acute dystonia with the administration of a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0057] <Akathisia> In some embodiments, the extrapyramidal syndrome is akathisia, as disclosed herein. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal or "rebound" akathisia. In some embodiments, the akathisia is acute akathisia. In some embodiments, the akathisia is chronic akathisia. In some embodiments, the akathisia is pseudoakathisia. In some embodiments, the akathisia is withdrawal or "rebound" akathisia.

[0058] In some embodiments, the extrapyramidal syndrome is akathisia. In some embodiments, akathisia is a movement disorder characterized by a sense of internal restlessness and a constant need to move, as well as movements such as rocking while standing or sitting, marching in place, and crossing and uncrossing legs while sitting. In some embodiments, the akathisia is drug-induced.

[0059] In some embodiments, the akathisia is acute akathisia. Acute akathisia refers to a form of akathisia that develops shortly after 1) initiation of medication or subsequent dosage increase, 2) switching to a stronger medication, or 3) withdrawal of the medication. In some cases, acute akathisia lasts less than 6 months and includes extreme discomfort, restlessness and complex perceptions, and semi-purposeful motor fidgetiness.

[0060] In some embodiments, akathisia is chronic akathisia.Chronic akathisia refers to the form of akathisia that continues for more than 6 months after the last increase in drug dosage.In some cases, chronic akathisia includes mild discomfort, restlessness, motor fidgetiness with stereotyped movements, and limb and orofacial dyskinesia.

[0061] In some embodiments, the akathisia is pseudoakathisia. In some cases, pseudoakathisia is a late symptom of chronic akathisia. Typical symptoms include motor signs with a subjective component, motor fidgets with stereotypic movements, and limb and orofacial dyskinesias.

[0062] In some embodiments, the akathisia is withdrawal or "rebound" akathisia. In some instances, withdrawal or "rebound" akathisia refers to akathisia associated with drug switching, which usually develops within 6 weeks of discontinuing or reducing the dose of a drug.

[0063] In some embodiments, disclosed herein are methods for treating akathisia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal or "rebound" akathisia. In some cases, disclosed herein are methods for treating acute akathisia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating chronic akathisia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating pseudoakathisia by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, disclosed herein are methods for treating withdrawal or "rebound" akathisia with the administration of a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. <Drug-induced Parkinsonism> In some embodiments, as disclosed herein, the extrapyramidal syndrome is drug-induced parkinsonism. In some cases, drug-induced parkinsonism is a movement disorder characterized by rigidity, bradykinesia, tremor, masked facies, shuffling gait, stooped posture, salivation, and seborrhea. In some embodiments, disclosed herein are methods for treating drug-induced parkinsonism with the administration of a therapeutically effective amount of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts.

[0064] Transcriptome signature of extrapyramidal syndrome In some embodiments, disclosed herein are panels of markers associated with extrapyramidal syndrome. In some embodiments, the panel includes markers associated with activator protein 1 (AP-1), cholesterol synthesis and unfolded protein response, ERK signaling, and cell cycle progression. In some cases, AP-1-related markers include FOSL2, JUN, JUND, and ATF3. In some cases, cholesterol synthesis and unfolded protein response-related markers include SREBF2, INSIG1, MVK, MVD, LDLR, and HMGCR. In some cases, ERK signaling-related markers include DUSP14, SQSTM1, and IER3. In some cases, cell cycle-related markers include CDKN1A, MYC, and BCL2. In some embodiments, the panel of markers associated with extrapyramidal syndrome comprises FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some embodiments, the panel of markers associated with extrapyramidal syndrome comprises JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some embodiments, the panel of markers associated with extrapyramidal syndrome comprises FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some instances, the nerves associated with extrapyramidal syndrome include FOSL2, JUN, SREBF1, CEBPB, UBC, and ERK. In some instances, the nerves associated with extrapyramidal syndrome include MYC and BCL2.

[0065] In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with a transcriptomic signature of a drug that causes the syndrome or drug-induced dysmotility disorder. In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with increased ERK signaling activity. In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with upregulation of transcription factors and proteins associated with activator protein 1. In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with upregulation of FOS. In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with upregulation of JUN. In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with upregulation of JUND. In some cases, the computational analysis correlates extrapyramidal syndrome or drug-induced dysmotility disorder with upregulation of ATF3. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of transcription factors and proteins associated with cholesterol synthesis and unfolded protein response. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of SREBF1. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of CEBPB. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of UBC. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of INSIG1. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of MVK. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of MVD. In some cases, computational analysis correlates extrapyramidal syndromes or drug-induced movement disorders with upregulation of the LDLR.In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of HMGCR. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with upregulation of ERK (e.g., ERK1, ERK2). In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with downregulation of transcription factors and proteins related to cell cycle progression. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with downregulation of MYC. In some cases, the computational analysis correlates with extrapyramidal syndrome or drug-induced movement disorder associated with downregulation of BCL2.

[0066] In some embodiments, the computational analysis correlates extrapyramidal syndrome or drug-induced movement disorder with a compound that reverses the transcriptomic signature. In some cases, the compound is trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, administration of a therapeutically effective amount of trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof modulates the expression of FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some cases, administration of a therapeutically effective amount of trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof downregulates FOSL2, JUN, SREBF1, CEBPB, UBC, ERK, or a combination thereof. In additional cases, administration of a therapeutically effective amount of trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof upregulates MYC, BCL2, or a combination thereof. Also disclosed herein in some embodiments is a method for monitoring a treatment regimen in a subject administered a therapeutically effective amount of trapidil, its derivative, metabolite, or pharmaceutically acceptable salt. In some instances, the method includes administering a therapeutically effective amount of trapidil, its derivative, metabolite, or pharmaceutically acceptable salt to the subject; determining the expression of a marker selected from the panel of markers FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2; and continuing or discontinuing treatment based on the expression level of the marker. In some cases, the method includes contacting at least one gene selected from the panel: FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2 with a set of primers to produce amplified nucleic acid, wherein the at least one gene is isolated from a sample obtained from the subject after initiation of treatment, and determining the level of the amplified nucleic acid in the sample relative to a control.In some cases, if the expression level of FOSL2, JUN, SREBF1, CEBPB, UBC, ERK, or a combination thereof is downregulated compared to the control, the dosage of treatment is optionally reduced or stopped.In some cases, if the expression level of MYC, BCL2, or a combination thereof is upregulated compared to the control, the dosage of treatment is optionally reduced or stopped.In some cases, protein expression level is determined instead of nucleic acid level.In some cases, the control is the expression level of a panel of markers from normal samples or from samples obtained from subjects who do not suffer from extrapyramidal syndrome.

[0068] Also disclosed herein in some embodiments are methods for selecting a subject for treatment based on the expression level of a marker from a panel of the following markers: FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, and BCL2. In some cases, a subject with an elevated expression level of FOSL2, JUN, SREBF1, CEBPB, UBC, ERK, or a combination thereof relative to the expression level from a control; and / or a decreased expression level of MYC, BCL2, or a combination thereof relative to the expression level from a control, is treated with a therapeutically effective amount of trapidil, a derivative, metabolite, or a pharmaceutically acceptable salt thereof. In some cases, the expression level is a nucleic acid level. In other cases, the expression level is a protein expression level. In some cases, the control is the expression level of a panel of markers from a normal sample or from a sample obtained from a subject not suffering from an extrapyramidal syndrome.

[0069] Activator protein 1 (AP-1) AP-1 (activator protein 1) is a dimeric transcription factor containing Jun, Fos, or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1 binding site, and is involved in cell proliferation, differentiation, and apoptosis.

[0070] FOS The Fos gene family includes four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that dimerize with JUN family proteins, thereby forming the transcription factor complex AP-1. In some cases, FOS proteins are regulators of cell proliferation, differentiation, and transformation. In some cases, expression of FOS genes is associated with apoptotic cell death.

[0071] JUN JUN is a protein that, together with Fos, forms the AP-1 transcription factor, which is activated by dual phosphorylation via the JNK pathway.

[0072] JUND JUND, or JunD proto-oncogene, is an intronless gene that encodes a protein that is a member of the JUN family and a functional component of the AP1 transcription factor complex.

[0073] ATF3 ATF3, or activating transcription factor 3, encodes a member of the mammalian activating transcription factor / cAMP response element-binding (CREB) protein family of transcription factors. ATF3 represses transcription from promoters that contain ATF sites.

[0074] <Cholesterol synthesis and unfolded protein reactions> Cholesterol is an important biomolecule with a role in membrane structure as well as being a precursor for the synthesis of steroid hormones, bile acids, and vitamin D.

[0075] SREBF1 SREBF1, or sterol regulatory element-binding transcription factor 1, encodes a transcription factor that binds to the sterol regulatory element 1 (SRE1), a decameric protein adjacent to the low-density lipoprotein receptor gene and several genes involved in sterol biosynthesis. The protein is a member of the basic-helix-loop-helix leucine zipper (bHLH-Zip) transcription factor family.

[0076] SREBF2 SREBF2, or sterol regulatory element-binding transcription factor 2, encodes a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating the transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif.

[0077] CEBPB CEBPB is an intronless gene encoding a transcription factor containing a basic leucine zipper (bZIP) domain. The encoded protein functions as a homodimer but, in some cases, forms heterodimers with CCAAT / enhancer-binding proteins alpha, delta, and gamma. The activity of this protein is important for regulating genes involved in immune and inflammatory responses, among other processes.

[0078] UBC UBC, or ubiquitin C, encodes the polyubiquitin precursor protein. Ubiquitination is associated with protein degradation, DNA repair, cell cycle regulation, kinase modification, endocytosis, and the regulation of other cell signaling pathways.

[0079] INSIG1 INSIG1, that is, insulin-induced gene 1, encodes an endoplasmic reticulum membrane protein that regulates cholesterol metabolism, lipidogenesis, and glucose homeostasis. It mediates the feedback control of cholesterol synthesis by controlling SCAP and HMGCR and functions by blocking the processing of sterol regulatory element-binding protein (SREBP).

[0080] MVK MVK, that is, mevalonate kinase, encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is an important intermediate, and mevalonate kinase is an important initial enzyme in the synthesis of isoprenoids and sterols.

[0081] MVD MVD, that is, mevalonate diphosphate decarboxylase, catalyzes the conversion of mevalonate pyrophosphate to isopentenyl pyrophosphate in one of the initial steps in cholesterol biosynthesis.

[0082] LDLR LDLR, that is, low-density lipoprotein receptor, a gene family, consists of cell surface proteins associated with receptor-dependent endocytosis of specific ligands. LDLR binds LDL, a lipoprotein that transports the major cholesterol in plasma, and transports it into cells by endocytosis.

[0083] HMGCR HMGCR, that is, HMG-CoA reductase, is the rate-limiting enzyme for cholesterol synthesis and is regulated by a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by the reductase.

[0084] <ERK Signaling> The ERK signaling cascade, defined by extracellular signal-regulated kinase-1 (ERK1) and ERK2, plays a role in regulating various cellular processes, such as proliferation, differentiation, progression, learning, survival, and, in some cases, apoptosis.

[0085] DUSP14 DUSP14, dual specificity phosphatase 14, plays a role in the inactivation of MAP kinases, dephosphorylating ERK, JNK and p38 MAP kinases.

[0086] SQSTM1 SQSTM1, or sequestosome 1, encodes a multifunctional protein that binds ubiquitin and regulates the activation of the nuclear factor kappa-B (NF-kB) signaling pathway. SQSTM1 plays a role in cell differentiation, apoptosis, immune response, and K(+) channel regulation.

[0087] IER3 IER3, or immediate early response 3, functions in protecting cells from Fas- or tumor necrosis factor type alpha-induced apoptosis. In some cases, IER3 plays a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by the phosphatase PP2A-PPP2R5C holoenzyme. In some cases, IER3 acts as a downstream effector of ERK that mediates survival.

[0088] <Cell cycle> CDKN1A CDKN1A, or cyclin-dependent kinase inhibitor 1A, encodes a cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase 2 or cyclin-cyclin-cyclin-dependent kinase 4 complexes, thus functioning as a regulator of cell cycle progression in G1. In some cases, CDKN1A interacts with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S-phase DNA replication and DNA damage repair.

[0089] MYC MYC encodes a multifunctional nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis, and cell transformation. It functions as a transcription factor that regulates the transcription of specific target genes.

[0090] BCL2 BCL2 encodes an integral outer mitochondrial membrane protein that blocks apoptotic death of some cells, including lymphocytes and neurons.

[0091] <Trapidil> Trapidil, a triazolopyrimidine, belongs to the class of antiplatelet drugs. In some cases, trapidil has been shown to reduce ERK activity. In some cases, trapidil has been shown to exert anti-inflammatory properties, for example, by reducing the production of IL-6, IL-12, and TNF-α and reducing NF-κB activity. Furthermore, trapidil has been observed to reduce lipid peroxidation and increase the availability of nitric oxide precursors, which are associated with, for example, tardive dyskinesia. In some embodiments, disclosed herein are methods and pharmaceutical combinations for treating extrapyramidal syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of trapidil to the subject. In other embodiments, disclosed herein are methods and pharmaceutical combinations for preventing extrapyramidal syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of trapidil to the subject. In additional embodiments, disclosed herein are methods and pharmaceutical combinations for treating or preventing extrapyramidal syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt of trapidil.

[0092] 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:

[0093] [ka]

[0094] In some instances, trapidil is also called AR 12008, Avantrin, Trapymin, Trapymine, Trapidilum, Angichromen, Estelinol, Karnachol, Perucarate, Rocornal, Trapidil Towa Yakuhin, and Travisco. In additional instances, trapidil is referred to herein as SB-0107.

[0095] Exemplary trapidil derivatives include, but are not limited to, AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565.

[0096] Exemplary trapidil metabolites 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.

[0097] In some embodiments, exemplary pharmaceutically 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.

[0098] In some embodiments, the trapidil is the trapidil disclosed in US Pat. No. 6,015,578; European Patent No. 0301423; or PCT International No. WO1993 / 009781.

[0099] 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), 389-92; 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.

[0100] In some embodiments, 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.

[0101] In some embodiments, the trapidil is a trapidil salt disclosed in US Pat. No. 6,369,065.

[0102] In some embodiments, the present specification also discloses a method for treating a patient with upregulated ERK pathway-related proteins by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some cases, the ERK pathway-related proteins include JUN, FOS, UBC, SREBF1, CEBPB, or MYC proteins. In some embodiments, the present specification also discloses a method for treating a patient with upregulated JUN, FOS, UBC, SREBF1, CEBPB, or MYC proteins by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0103] In some instances, disclosed herein are methods for treating patients with upregulated inflammatory markers by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof. In some instances, the inflammatory markers include TNF-α, IL-1a, IL-1b, IL-6, IL-12, or NF-κB. In some instances, disclosed herein are methods for treating patients with upregulated inflammatory markers, such as TNF-α, IL-1a, IL-1b, IL-6, IL-12, or NF-κB, by administering a therapeutically effective amount of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0104] In some embodiments, trapidil is AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, AR 12560, or AR 12565; 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; pharmaceutically acceptable salts of trapidil, such as salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid.

[0105] In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in a dosage range of about 10 mg per day to about 3000 mg per day. In some instances, the dosage range is about 10 mg per day to about 2900 mg per day, about 10 mg per day to about 2800 mg per day, about 10 mg per day to about 2700 mg per day, about 10 mg per day to about 2600 mg per day, about 10 mg per day to about 2500 mg per day, about 10 mg per day to about 2400 mg per day, about 10 mg per day to about 2300 mg per day, about 10 mg per day to about 2200 mg per day, or about 10 mg per day to about 2600 mg per day. 00mg, from about 10mg per day to about 2100mg per day, from about 10mg per day to about 2000mg per day, from about 10mg per day to about 1900mg per day, from about 10mg per day to about 1800mg per day, from about 10mg per day to about 1700mg per day, from about 10mg per day to about 1600mg per day, from about 10mg per day to about 1500mg per day, from about 10mg per day to about 1400mg 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 800 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 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 200 mg per day to about 3000 mg per day, 300mg to about 3000mg per day, about 400mg per day to about 3000mg per day, about 500mg per day to about 3000mg per day, about 600mg per day to about 3000mg per day, about 700mg per day to about 3000mg per day, about 800mg per day to about 3000mg per day, about 900mg per day to about 3000mg per day, about 1000mg per day to about 3000mg per day, about 1100mg per day to about 3000mg per day , about 1200 mg per day to about 3000 mg per day, about 1300 mg per day to about 3000 mg per day, about 1400 mg per day to about 3000 mg per day, about 1500 mg per day to about 3000 mg per day, about 1600 mg per day to about 3000 mg per day, about 1700 mg per day to about 3000 mg per day, about 1800 mg per day to about 3000 mg per day, about 1900 mg per day to about 3000 mg per day, about 2000 mg per day to up 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,About 2900 mg per day to about 3000 mg per day, about 50 mg per day to about 2800 mg per day, about 100 mg per day to about 2800 mg per day, about 150 mg per day to about 2800 mg per day, about 200 mg per day to about 2800 mg per day, about 300 mg per day to about 2800 mg per day, about 400 mg per day to about 2800 mg per day, about 500 mg per day to about 2800 mg per day, 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 1500 mg per day to about 2800 mg per day from about 1600 mg per day to about 2800 mg per day, from about 1700 mg per day to about 2800 mg per day, from about 1800 mg per day to about 2800 mg per day, from about 1900 mg per day to about 2800 mg per day, from about 2000 mg per day to about 2800 mg per day, from about 2100 mg per day to about 2800 mg per day, from about 2200 mg per day to about 2800 mg per day, from about 2300 mg per day to about 2800 mg per day, 2400mg 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, about 300mg per day to about 2500mg per day,About 400mg per day to about 2500mg per day, about 500mg per day to about 2500mg per day, about 600mg per day to about 2500mg per day, about 700mg per day to about 2500mg per day, about 800mg per day to about 2500mg per day, about 900mg per day to about 2500mg per day, about 1000mg per day to about 2500mg per day, about 1100mg per day to about 2500mg per day, about 1200mg per day to about 2500mg per day 0 mg, about 1300 mg per day to about 2500 mg per day, about 1400 mg per day to about 2500 mg per day, about 1500 mg per day to about 2500 mg per day, about 1600 mg per day to about 2500 mg per day, about 1700 mg per day to about 2500 mg per day, about 1800 mg per day to about 2500 mg per day, about 1900 mg per day to about 2500 mg per day, about 2000 mg per day to about 2500 mg per day, about 2100 mg per day from about 2500 mg per day, from about 2200 mg per day to about 2500 mg per day, from about 2300 mg per day to about 2500 mg per day, from about 2400 mg per day to about 2500 mg per day, from about 50 mg per day to about 2200 mg per day, from about 100 mg per day to about 2200 mg per day, from about 150 mg per day to about 2200 mg per day, from about 200 mg per day to about 2200 mg per day, from about 300 mg per day to about 2200 mg per day, 400mg to about 2200mg per day, about 500mg per day to about 2200mg per day, about 600mg per day to about 2200mg per day, about 700mg per day to about 2200mg per day, about 800mg per day to about 2200mg per day, about 900mg per day to about 2200mg per day, about 1000mg per day to about 2200mg per day, about 1100mg per day to about 2200mg per day, about 1200mg per day to about 2200mg 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 2000 mg per day, from about 700 mg per day to about 1000 mg per day up to about 2000mg per day, from about 800mg per day to about 2000mg per day, from about 900mg per day to about 2000mg per day, from about 1000mg per day to about 2000mg per day, from about 1100mg per day to about 2000mg per day, from about 1200mg per day to about 2000mg per day, from about 1300mg per day to about 2000mg per day, from about 1400mg per day to about 2000mg per day, from about 1500mg per day to about 2000mg per day, about 1600 mg to about 2000 mg per day, about 1700 mg per day to about 2000 mg per day, about 1800 mg per day to about 2000 mg per day, about 1900 mg per day to about 2000 mg per day, about 50 mg per day to about 1800 mg per day, about 100 mg per day to about 1800 mg per day, about 150 mg per day to about 1800 mg per day, about 200 mg per day to about 1800 mg per day, about 300 mg per day to about 1800 mg per day,about 400 mg per day to about 1800 mg per day, about 500 mg per day to about 1800 mg per day, about 600 mg per day to about 1800 mg per day, about 700 mg per day to about 1800 mg per day, about 800 mg per day to about 1800 mg per day, about 900 mg per day, from about 1000 mg per day to about 1800 mg per day, from about 1100 mg per day to about 1800 mg per day, from about 1200 mg per day to about 1800 mg per day, from about 1300 mg per day to about 1800 mg per day, from about 1400 mg per day to about 1800 mg per day, from about 1500 mg per day to about 1800 mg per day, from about 1600 mg per day to about 1800 mg per day, from about 1700 mg per day to about 1800 mg per day g, 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 up to about 1500 mg, from about 800 mg per day to about 1500 mg per day, from about 900 mg per day to about 1500 mg per day, from about 1000 mg per day to about 1500 mg per day, from about 1100 mg per day to about 1500 mg per day, from about 1200 mg per day to about 1500 mg per day, from about 1300 mg per day to about 1500 mg per day, from about 1400 mg per day to about 1500 mg per day, from about 50 mg per day to about 1200 mg per day, from about 1 00mg to about 1200mg per day, about 150mg per day to about 1200mg per day, about 200mg per day to about 1200mg per day, about 300mg per day to about 1200mg per day, about 400mg per day to about 1200mg per day, about 500mg per day to about 1200mg per day, about 600mg per day to about 1200mg per day, about 700mg per day to about 1200mg per day, about 800mg per day to about 1200mg per day,About 900 mg per day to about 1200 mg per day, about 1000 mg per day to about 1200 mg per day, about 1100 mg per day to about 1200 mg per day, about 50 mg per day to about 1000 mg per day, about 100 mg per day to about 1000 mg per day, about 150 mg per day to about 1000 mg per day, about 200 mg per day to about 1000 mg per day, about 300 mg per day to about 1000 mg per day, 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 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, about 300 mg per day to about 600 mg per day, about 400 mg per day to about 600 mg per day, about 500 mg per day to about 600 mg per day, about 50 mg per day to about 500 mg per day, about 100 mg per day to about 500 mg per day, about 150 mg per day to about 500 mg per day, about 200 mg per day to about 500 mg per day, about 300 mg per day to about 500 mg per day, 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.

[0106] In some cases, the dosage 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 1500 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 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 2100 mg per day, about 2200 mg per day, about 2300 mg per day, about 2400 mg per day, about 250 mg per day 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.

[0107] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally, parenterally (e.g., intravenously, subcutaneously, intramuscularly), intranasally, bucally, topically, rectally, or transdermally. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered parenterally (e.g., intravenously, subcutaneously, intramuscularly). In other cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered transdermally.

[0108] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally. In some embodiments, the oral dose ranges from about 10 mg per day to about 3000 mg per day. In some cases, the oral dose ranges are 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 23 ... Up to about 2200 mg per day, from about 10 mg per day to about 2100 mg per day, from about 10 mg per day to about 2000 mg per day, from about 10 mg per day to about 1900 mg per day, from about 10 mg per day to about 1800 mg per day, from about 10 mg per day to about 1700 mg per day, from about 10 mg per day to about 1600 mg per day, from about 10 mg per day to about 1500 mg per day, from about 10 mg per day to about 1 up 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 up to about 800 mg, 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 200 mg per day to about 250 mg per day, from about 1 ... 00mg to about 3000mg per day, about 300mg per day to about 3000mg per day, about 400mg per day to about 3000mg per day, about 500mg per day to about 3000mg per day, about 600mg per day to about 3000mg per day, about 700mg per day to about 3000mg per day, about 800mg per day to about 3000mg per day, about 900mg per day to about 3000mg per day, about 1000mg per day to about 3000mg 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, about 2000 mg per day to about 3000 mg per day, about 2100 mg per day to about 3000 mg per day, about 2200 mg per day to about 3000 mg per day, about 2300 mg per day to about 3000 mg per day, about 2400 mg per day to about 3000 mg per day, about 2500 mg per day to about 3000 mg per day, about 2600 mg per day to about 3000 mg per day, 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, about 600 mg per day to about 2800 mg per day, about 700 mg per day to about 2800 mg per day, about 800 mg per day to about 2800 mg per day, about 900 mg per day to about 2800 mg per day, about 1000 mg per day to about 2800 mg per day, about 1100 mg per day to about 2800 mg per day, about 1200 mg per day to about 2800 mg per day, about 1300 mg per day to about 2800 mg per day, about 1400 mg per day to about 2800 mg per day from about 1500 mg per day to about 2800 mg per day, from about 1600 mg per day to about 2800 mg per day, from about 1700 mg per day to about 2800 mg per day, from about 1800 mg per day to about 2800 mg per day, from about 1900 mg per day to about 2800 mg per day, from about 2000 mg per day to about 2800 mg per day, from about 2100 mg per day to about 2800 mg per day, from about 2200 mg per day to about 2800 mg per day, from about 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,About 300mg per day to about 2500mg per day, about 400mg per day to about 2500mg per day, about 500mg per day to about 2500mg per day, about 600mg per day to about 2500mg per day, about 700mg per day to about 2500mg per day, about 800mg per day to about 2500mg per day, about 900mg per day to about 2500mg per day, about 1000mg per day to about 2500mg per day, about 1100mg per day to about 2500mg per day mg, about 1200 mg per day to about 2500 mg per day, about 1300 mg per day to about 2500 mg per day, about 1400 mg per day to about 2500 mg per day, about 1500 mg per day to about 2500 mg per day, about 1600 mg per day to about 2500 mg per day, about 1700 mg per day to about 2500 mg per day, about 1800 mg per day to about 2500 mg per day, about 1900 mg per day to about 2500 mg per day, about 2000 mg per day from about 2500 mg per day, from about 2100 mg per day to about 2500 mg per day, from about 2200 mg per day to about 2500 mg per day, from about 2300 mg per day to about 2500 mg per day, from about 2400 mg per day to about 2500 mg per day, from about 50 mg per day to about 2200 mg per day, from about 100 mg per day to about 2200 mg per day, from about 150 mg per day to about 2200 mg per day, from about 200 mg per day to about 2200 mg per day, about 300 mg to about 2200 mg per day, about 400 mg per day to about 2200 mg per day, about 500 mg per day to about 2200 mg per day, about 600 mg per day to about 2200 mg per day, about 700 mg per day to about 2200 mg per day, about 800 mg per day to about 2200 mg per day, about 900 mg per day to about 2200 mg per day, about 1000 mg per day to about 2200 mg per day, 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 about 2200 mg per day, about 2100 mg per day to about 2200 mg per day, about 50 mg per day to about 2000 mg per day, about 100 mg per day to about 2000 mg per day, about 150 mg per day to about 2000 mg per day, about 200 mg per day to about 2000 mg per day, about 300 mg per day to about 2000 mg per day, about 400 mg per day to about 2000 mg per day, about 500 mg per day to about 2000 mg per day, about 600 mg per day to about 1000 mg per day 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, from about 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,about 300mg per day to about 1800mg per day, about 400mg per day to about 1800mg per day, about 500mg per day to about 1800mg per day, about 600mg per day to about 1800mg per day, about 700mg per day to about 1800mg per day, about 800mg per day to about 180, 0 mg, about 900 mg per day to about 1800 mg per day, about 1000 mg per day to about 1800 mg per day, about 1100 mg per day to about 1800 mg per day, about 1200 mg per day to about 1800 mg per day, about 1300 mg per day to about 1800 mg per day, about 1400 mg per day to about 1800 mg per day, about 1500 mg per day to about 1800 mg per day, about 1600 mg per day to about 1800 mg per day, about 1700 mg per day from about 1800 mg per day, from about 50 mg per day to about 1500 mg per day, from about 100 mg per day to about 1500 mg per day, from about 150 mg per day to about 1500 mg per day, from about 200 mg per day to about 1500 mg per day, from about 300 mg per day to about 1500 mg per day, from about 400 mg per day to about 1500 mg per day, from about 500 mg per day to about 1500 mg per day, from about 600 mg per day to about 1500 mg per day, from about 700 mg per day to about 1500 mg per day mg 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 1100 mg per day to about 1500 mg per day, about 1200 mg per day to about 1500 mg per day, about 1300 mg per day to about 1500 mg per day, about 1400 mg per day to about 1500 mg per day, about 50 mg per day to about 1200 mg per day, about 100mg per day to about 1200mg per day, about 150mg per day to about 1200mg per day, about 200mg per day to about 1200mg per day, about 300mg per day to about 1200mg per day, about 400mg per day to about 1200mg per day, about 500mg per day to about 1200mg per day, about 600mg per day to about 1200mg per day, about 700mg per day to about 1200mg per day, about 800mg per day to about 1200mg per day,About 900 mg per day to about 1200 mg per day, about 1000 mg per day to about 1200 mg per day, about 1100 mg per day to about 1200 mg per day, about 50 mg per day to about 1000 mg per day, about 100 mg per day to about 1000 mg per day, about 150 mg per day to about 1000 mg per day, about 200 mg per day to about 1000 mg per day, about 300 mg per day to about 1000 mg per day, 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 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, about 300 mg per day to about 600 mg per day, about 400 mg per day to about 600 mg per day, about 500 mg per day to about 600 mg per day, about 50 mg per day to about 500 mg per day, about 100 mg per day to about 500 mg per day, about 150 mg per day to about 500 mg per day, about 200 mg per day to about 500 mg per day, about 300 mg per day to about 500 mg per day, 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.

[0109] 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 1500 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 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 2100 mg per day, about 2200 mg per day, about 2300 mg per day, about 2400 mg per day, about 250 mg per 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.

[0110] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in a single dose. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in several doses (e.g., 2, 3, 4, 5, 6, or more doses per day). In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered intravenously or subcutaneously. In such cases, the intravenous or subcutaneous dosage 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.

[0111] <Combination therapy> Disclosed herein, in some embodiments, are methods for treating extrapyramidal syndrome, wherein trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

[0112] In some cases, the additional therapeutic agent comprises an antipsychotic, levodopa, an antidepressant, an anticholinergic, an antiemetic, an anxiolytic, an antiepileptic, an antiparkinsonian, an antimalarial, or an antihistamine. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in combination with an antipsychotic, levodopa, an antidepressant, an anticholinergic, an antiemetic, an anxiolytic, an antiepileptic, an antiparkinsonian, an antimalarial, or an antihistamine. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in combination with an antipsychotic. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in combination with levodopa. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an antidepressant. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an anticholinergic. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an antiemetic. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an anxiolytic. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an antiepileptic drug. In some cases, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an antiparkinsonian drug. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in combination with an antimalarial drug. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered in combination with an antihistamine.

[0113] In some embodiments, the additional therapeutic agent comprises clonazepam, ginkgo biloba, clozapine, risperidone, quetiapine, vitamin E, levodopa, benzodiazepine, botulinum toxin, reserpine, tetrabenazine, propranolol, a dopamine-depleting agent, ondansetron, zotepine, aripiprazole, zopiclone, zonisamide, trihexyphenidyl (Broflex), biperiden, procyclidine, diazepam, baclofen, tizanidine, carbamazepine, gabapentin, lorazepam, mianserin, cyproheptadine, mirtazapine, benztropine, trihexyphenidyl, carbidopa, ropinirole, pramipexole, bromocriptine, selegiline, rasagiline, ziprasidone, olanzapine, amantadine, valbenazine, deutetrabenazine, or diphenhydramine. In some embodiments, the additional therapeutic agent is administered orally, hi some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously.

[0114] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are selected from the group consisting of clonazepam, ginkgo biloba, clozapine, risperidone, quetiapine, vitamin E, levodopa, benzodiazepines, botulinum toxin, reserpine, tetrabenazine, propranolol, dopamine depleting agents, ondansetron, zotepine, aripiprazole, zopiclone, zonisamide, trihexyphenidyl (Broflex), biperiden, procyclidine, diazepam, baclofen, tizanidine, carbamazepine, gabapentin, lorazepam, mianserin, cyproheptadine, mirtazapine, benztropine, In some embodiments, the additional therapeutic agent is administered in combination with trihexyphenidyl, carbidopa, ropinirole, pramipexole, bromocriptine, selegiline, rasagiline, ziprasidone, olanzapine, amantadine, valbenazine, deutetrabenazine, or diphenhydramine. In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously.

[0115] In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered before the additional therapeutic agent. In some cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof, is administered after the additional therapeutic agent. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically 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 pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered in separate dosage forms.

[0116] Pharmaceutical Combinations and Formulations In certain embodiments, the present specification discloses pharmaceutical compositions or combinations comprising trapidil and additional therapeutic agents.In some cases, pharmaceutical compositions or combinations are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents, which facilitate the processing of active compounds into pharmaceutically usable preparations.Appropriate formulations depend on the route of administration selected.All well-known techniques, carriers, and excipients are used as appropriate and understood in the art. Summaries of the 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, H.A. 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), which are incorporated herein by reference in their entireties.

[0117] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein, such as trapidil and an additional therapeutic agent, with a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The pharmaceutical composition or combination facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or condition 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 compound can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0118] In certain embodiments, the composition or combination also contains one or more pH adjusters or buffers, 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 tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in the amounts required to maintain the pH of the composition within an acceptable range.

[0119] In other embodiments, the composition or combination also contains 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; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0120] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining 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., a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound described herein and a co-agent, are administered to a patient simultaneously, in parallel, or sequentially as separate entities with no specific time limit between them, such that such administration provides effective levels of the two compounds to the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0121] 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-dissolve formulations, tablets, capsules, pills, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multiparticulate formulations, and combinations of immediate-release and controlled-release formulations.

[0122] In some cases, pharmaceutical compositions containing the compounds described herein are manufactured by conventional methods such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0123] In some cases, "defoamers" reduce foaming during processing that can result in flocculation of the aqueous dispersion, air bubbles in the finished film, or generally impair processing. Typical defoamers include silicone emulsions or sorbitan sesquoleate.

[0124] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium bisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability when needed.

[0125] 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 thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridium chloride.

[0126] In additional 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.

[0127] "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®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; acids); bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; sugars such as tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as gum arabic, tragacanth, gum ghatti, mucilage of isapol husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0128] "Carriers" or "carrier materials" also include excipients commonly used in pharmaceutics 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. Typical 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, gum arabic, 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. For example, 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, HAand 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).

[0129] "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 coatings or erosion matrices. Typical 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 K100). 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 such as tragacanth, gum arabic, guar gum, xanthan, including xanthan gum, sugars, cellulosics such as 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 can also be used as dispersing agents. Particularly useful dispersing agents in liposomal and self-emulsifying dispersions are dimyristoylphosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol, and isopropyl myristate.

[0130] Combinations of one or more corrosion promoters with one or more diffusion promoters may also be used in the compositions of the present invention.

[0131] The term "diluent" refers to a chemical compound used to dilute a compound of interest prior to delivery. Diluents can be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffers (which can also provide pH control or maintenance) 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 volume for a homogeneous blend for capsule embedding. 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 grain solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0132] The term "disintegrate" includes both dissolution and dispersion of the dosage form when contacted with gastrointestinal fluids. A "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, methylcrystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming crosslinked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone; 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;

[0133] "Drug absorption" or "absorption" typically refers to the process of movement of a drug from the site of administration across a barrier to the blood vessel or site of action, for example, a drug moves from the gastrointestinal tract into the portal vein or lymphatic system.

[0134] 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 comprise polymeric materials that prevent release in the low pH environment of the stomach, but ionize at higher pHs, typically between 6 and 7, and therefore dissolve sufficiently in the small intestine or colon to release the active agent therein.

[0135] "Corrosion promoters" include substances that control the erosion of certain materials in gastrointestinal fluids. Corrosion promoters are generally known to those skilled in the art. Typical corrosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0136] "Fillers" 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.

[0137] Useful "flavoring agents" and / or "sweeteners" in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, 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, citrus Lamate, Cyclamate, Dextrose, Eucalyptus, Eugenol, Fructose, Fruit Punch, Ginger, Glycyrrhetinate, Glycyrrhiza (Licorice) Syrup, Grapes, Grapefruit, Honey, Isomalt, Lemon, Lime, Lemon Cream, Monoammonium Glycyrrhizate (MagnaSweet®), Maltol, Mannitol, Maple, Marshmallow, Menthol, Mint Cream, Mixed Berry, Neohesperidin DC, Neohesperidin Flavoring ingredients include tame, 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, 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.

[0138] "Lubricants" and "gliding agents" are compounds that prevent, reduce, or inhibit adhesion or friction of materials. Typical lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil, or hydrogenated vegetable oils 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.

[0139] "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, that is absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng / ml or μg / ml.

[0140] "Pharmacodynamics" refers to the factors that determine the biological response observed relative to the concentration of drug at the site of action.

[0141] "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of an adequate concentration of a drug at a site of action.

[0142] "Plasticizers" are compounds used to soften microencapsulation materials or film coatings, making 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 can also function as dispersing or wetting agents.

[0143] "Solubilizers" 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.

[0144] "Stabilizers" include compounds such as antioxidants, buffers, acids, preservatives, and the like.

[0145] "Steady state," as used herein, is the state when the amount of drug administered equals the amount of drug removed within a single dosing interval, resulting in a plateau or constant plasma drug exposure.

[0146] "Suspending agents" include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), 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, hydroxypropylmethylcellulose, hydroxymethylcellulose stearate, acetate, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth, gum arabic, 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.

[0147] "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, e.g., Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., Octoxynol 10, Octoxynol 40. In some embodiments, surfactants are included to enhance physical stability or for other purposes.

[0148] "Viscosity enhancing agents" include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose stearate acetate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, and combinations thereof.

[0149] "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.

[0150] <Dosage form> In some embodiments, the compositions or combinations described herein are formulated for administration to a subject by 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.

[0151] Furthermore, the pharmaceutical compositions described herein comprising trapidil and an additional therapeutic agent are formulated into suitable dosage forms 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-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations, and combinations of immediate and controlled release formulations.

[0152] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then processing the mixture of granules, if desired, to obtain tablets or dragees, after adding suitable excipients.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 can also be added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salt, such as sodium alginate.

[0153] The dragee core is provided with a suitable coating. For this purpose, a concentrated sugar solution is used, which optionally contains gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments are added to the tablets or dragee coating for identification or to characterize various combinations of active compound dosages.

[0154] Orally administered pharmaceutical preparations include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in combination with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All preparations for oral administration should be in a dosage suitable for such administration.

[0155] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including a suspension tablet, fast-dissolving tablet, bite-disintegration tablet, rapid-disintegration tablet, effervescent tablet, or caplet), a pill, a powder (including a sterile-packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-based gelatin or vegetable-based HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a bioerodible dosage form, a controlled-release formulation, a pulsed-release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol.

[0156] In other embodiments, the pharmaceutical preparation is in the form of a powder. In yet other embodiments, the pharmaceutical preparation is in the form of a tablet, including but not limited to, a fast-dissolving tablet. In addition, the pharmaceutical preparations described herein can be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical preparation is administered in two, three, or four capsules or tablets.

[0157] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of trapidil and / or additional therapeutic agents with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blends as homogeneous, it is intended that the particles of trapidil and / or additional therapeutic agents are uniformly dispersed 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 dosage forms may also include a film coating, which disintegrates upon oral ingestion or contact with a diluent. These formulations can be manufactured by conventional pharmaceutical techniques.

[0158] 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, e.g., 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, etc.

[0159] In some instances, the pharmaceutical solid dosage forms described herein comprise a compound described herein and one or more pharmaceutically acceptable excipients, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. In yet other aspects, a film coating is provided around the trapidil and / or additional therapeutic agent formulation using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In another embodiment, some or all of the trapidil and / or additional therapeutic agent particles are not microencapsulated or coated.

[0160] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, gum arabic, 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 stearate acetate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0161] 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 stearate acetate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0162] Disintegrants are often used in formulations to release the trapidil compound 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 help rupture the dosage form matrix 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, 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, methylcrystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming cross-linked starches such as sodium starch glycolate; cross-linked polymers such as crospovidone; cross-linked 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;

[0163] Binders provide cohesive properties to solid oral dosage form formulations: for powder-filled capsule formulations, they aid in plug formation and can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blend uniformity before 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 HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (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, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®),

[0033] Ingredients include: sugars such as lactose, natural or synthetic gums such as gum arabic, tragacanth, and gum ghatti, isapol bark mucilage, 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.

[0164] Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. The level of binder use in tablet formulations varies depending on whether it is direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that can act as moderate binders themselves. A skilled formulator in the art can determine the binder level for a formulation, but binder use levels of up to 70% in tablet formulations are common.

[0165] 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 metal 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™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[0166] 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 maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0167] The term "water-insoluble diluent" includes calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, and finely divided cellulose (e.g., about 0.45 g / cm 3These represent compounds typically used in pharmaceutical formulations, such as cellulose stearate, powdered cellulose (e.g., Avicel, powdered cellulose having a density of 1000 .mu.m), as well as talc.

[0168] Suitable humectants 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 monooleate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, and the like.

[0169] 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.

[0170] Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, 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), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, methyl ... Gums, sugars, cellulosics such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, xanthan, including tragacanth, gum arabic, guar gum, xanthan, including xanthan gum, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0171] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene, sodium ascorbate, and tocopherol (BHT), sodium ascorbate, and tocopherol.

[0172] It should be recognized that there is considerable overlap between the additives used in the solid dosage forms described herein. Thus, the additives listed above should be considered merely representative and not limiting of the types of additives that may be included in the solid dosage forms described herein. The amount of such additives can be easily determined by those skilled in the art depending on the specific properties desired.

[0173] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Exemplarily, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers can be added to the coating composition in an amount of about 0.01% to about 50% by weight (w / w). 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.

[0174] Compressed tablets are solid dosage forms prepared by compressing bulk blends of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavoring agents. In other embodiments, compressed tablets contain 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, the compressed tablet contains one or more excipients.

[0175] Capsules are prepared, for example, by placing a bulk blend of the above-described trapidil and / or additional therapeutic agent formulations inside the capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed inside a soft gelatin capsule. In other embodiments, the formulations are placed inside a non-gelatin capsule, such as a standard gelatin capsule or a capsule containing HPMC. In other embodiments, the formulations are placed inside a sprinkle capsule, where the capsule is swallowed whole or the capsule is opened and the 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 total amount of the formulation is delivered in capsule form.

[0176] In various embodiments, particles of trapidil and / or additional therapeutic agent and one or more excipients are dry blended and, after oral administration, mixed and compressed into a mass, such as a tablet, having sufficient hardness to provide a pharmaceutical composition that substantially disintegrates within 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, thereby releasing the formulation into gastrointestinal fluids.

[0177] In another aspect, the dosage form may contain a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Typical materials include, but are not limited to, pH adjusters, corrosion 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.

[0178] Materials useful for microencapsulation as described herein include materials compatible with trapidil and / or additional therapeutic agents that sufficiently separate the trapidil or additional therapeutic agent compound from other incompatible excipients. Materials compatible with trapidil or additional therapeutic agent compounds are materials that retard release of the trapidil or additional therapeutic agent compound in vivo.

[0179] 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® NE 30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms, such as mixtures of HPMC and stearic acid, cyclodextrin, and mixtures of these materials.

[0180] In yet other embodiments, plasticizers such as polyethylene glycols, 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 release of pharmaceutical compositions are materials from the USP or National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methocel.

[0181] Microencapsulated compounds, either trapidil or an additional therapeutic agent, can be formulated by methods known to those skilled in the art. Such known methods include, for example, spray-drying, spinning-disk solvent, thermal dissolution, spray-chilling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at a liquid-gas or solid-gas interface, pressure extrusion, or spray-solvent extraction. In addition, several chemical techniques, such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in a liquid medium, in situ polymerization, submerged drying, and desolvation in a liquid medium, can also be used. Furthermore, other methods, such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating, can also be used.

[0182] In other embodiments, a solid dosage formulation of either trapidil and / or an additional therapeutic agent is plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high-boiling solid or liquid. Suitable plasticizers may be added in an amount of 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.

[0183] In other embodiments, powders containing formulations having any of the compounds described herein, trapidil and / or additional therapeutic agents, may be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and / or a wetting agent. This bulk blend is then uniformly subdivided into unit-dose or multi-dose packaging units.

[0184] In yet another embodiment, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medications in water for oral administration. Effervescent salts are granules or coarse powders containing medications in a dry mixture, typically 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 can be used in place of sodium bicarbonate and citric and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0185] In some embodiments, the solid dosage forms described herein can 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 tract. Enterically coated dosage forms can be compressed, molded, or extruded tablets / molded tablets (coated or uncoated) that themselves contain granules, powders, pellets, beads, or particles of the active ingredient and / or other compositional ingredients, which may be coated or uncoated. Enterically coated oral dosage forms can also be capsules (coated or uncoated) that themselves contain pellets, beads, or granules of the solid carrier or composition, which may be coated or uncoated.

[0186] The term "delayed release" as used herein refers to delivery that can achieve release at some generally predictable location in the intestinal tract that is more distal than the location that would have been achieved without the delayed release modification. In some embodiments, the method for delayed release is a coating. The coating must be applied to a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH above about 5. It is expected that anionic polymers that exhibit a pH-dependent solubility profile can be used as enteric coatings in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and their compatible mixtures, and some of their properties, include, but are not limited to: Shellac, also called purified lac, is a refined product obtained from the resin secretion of insects. This coating dissolves in media with a pH > 7; Acrylic polymers. The performance of acrylic polymers (mainly their solubility in biological fluids) can be influenced by 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 as soluble in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are osmotic 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; Cellulose derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; a reaction mixture of phthalic anhydride and a partial acetate ester of cellulose. Its performance may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH >6. Aquateric (FMC) is a water-based, spray-dried CAP pseudolatex with particles <1 μm. Other components in Aquateric may include Pluronic, Tween, 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 depending on the degree and type of substitution. For example, HPMCP such as grades HP-50, HP-55, HP-55S, and HP-55F are suitable. The performance may vary depending 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 pHs above that. These polymers are available as granules or fine powders for aqueous dispersion; Polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH >5 and is not very permeable to water vapor and gastric juices.

[0187] In some embodiments, the coating can, and typically 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), acetyltriethyl 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 carboxylic acrylic polymers typically contain 10-25% by weight of the plasticizers dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray or pan coating, are utilized to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery within the intestinal tract is reached.

[0188] Colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnauba wax or PEG), in addition to plasticizers, may be added to the coating to make the coating material soluble or dispersible and to improve coating performance and the coated product.

[0189] In other embodiments, the formulations described herein containing 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 predetermined times after a controlled delay time or at specific sites. 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 polycaprolactone; non-polymer-based systems, including porous matrices, sterols such as cholesterol, cholesterol esters, and fatty acids, or lipids such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, etc. For example, 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. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,52 See No. 7, No. 5,622,721, No. 5,686,105, No. 5,700,410, No. 5,977,175, No. 6,465,014, and No. 6,932,983.

[0190] In some embodiments, a pharmaceutical formulation is provided comprising particles of trapidil and / or an additional therapeutic agent 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 upon mixing with water results in a substantially uniform suspension.

[0191] The liquid dosage form for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757(2002).In addition, the liquid dosage form may contain 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 contain a crystallization inhibitor.

[0192] The aqueous suspensions and dispersions described herein can remain homogeneous, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. Homogeneity should be determined by consistent sampling methods for determining the homogeneity of the entire composition. 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, agitation is not required to maintain a homogeneous aqueous dispersion.

[0193] Examples of disintegrants used in aqueous suspensions and dispersions include, but are not limited to, starches, for example, 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®; methylcrystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming cross-linked starches such as sodium starch glycolate; cross-linked polymers such as crospovidone; cross-linked 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.

[0194] 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 K100). K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose stearate acetate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer (Plasdone®, e.g., S-630), 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). Corporation, Parsippany, NJ).In other embodiments, the dispersing agent is selected from the group consisting of none of the following agents: 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®).

[0195] Suitable wetting agents for 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.

[0196] 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 parahydroxybenzoic 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 dosage forms at concentrations sufficient to inhibit microbial growth.

[0197] 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, alginate, gum arabic, chitosan, and combinations thereof. The concentration of the viscosity enhancing agent will depend on the agent selected and the viscosity desired.

[0198] 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, 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, 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 can include a sweetener or flavoring agent at a concentration ranging from about 0.001% to about 1.0% of the aqueous dispersion, hi another embodiment, the aqueous liquid dispersion can include a sweetener or flavoring agent at a concentration ranging from about 0.005% to about 0.5% of the aqueous dispersion.In yet another embodiment, the aqueous liquid dispersion may include sweeteners or flavoring agents in concentrations ranging from about 0.01% to about 1.0% of the aqueous dispersion.

[0199] In addition to the additives listed above, the liquid formulation may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers.Typical 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.

[0200] 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, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously form emulsions when excess water is added, without external mechanical dispersion or agitation. The advantage of SEDDS is that only light mixing is required to distribute the droplets throughout the solution. Additionally, water or an aqueous phase can be added immediately before administration, ensuring the stability of unstable or hydrophobic active ingredients. Therefore, SEDDS provide an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS may result in improved 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.

[0201] It should be recognized that there is overlap between the above-listed additives used in the aqueous dispersion or suspension described herein, because a given additive is often classified differently by different practitioners in this field or generally used for any of several different functions.Therefore, the above-listed additives should be interpreted as merely representative and should not be interpreted as limiting 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.

[0202] <Injection preparation> Formulations containing trapidil or an additional therapeutic agent compound suitable for intramuscular, subcutaneous, peritumoral, or intravenous injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders 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 (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. 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.

[0203] For intravenous injection, the compounds described herein can be formulated in aqueous solution, preferably in physiologically compatible buffers 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 can include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients.Such excipients are generally known in the art.

[0204] 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 added preservatives. 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 contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound may be prepared as appropriate 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 compound, allowing 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.

[0205] <Additional preparations> In certain embodiments, delivery systems for pharmaceutical compounds such as, for example, liposomes and emulsions may be utilized. In certain embodiments, the compositions provided herein may also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran, among others.

[0206] In some embodiments, the compounds described herein may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0207] In some cases, 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.

[0208] <Treatment regimen> In some embodiments, the trapidil pharmaceutical compositions described herein are administered for therapeutic applications. In some embodiments, the pharmaceutical compositions are administered once daily, twice daily, three times daily, or more. The pharmaceutical compositions are administered daily, every other day, five days a week, once a week, every other week, two weeks per month, three weeks per month, once a month, twice a month, three times a month, or more. The pharmaceutical compositions are 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.

[0209] In some embodiments, trapidil and the additional therapeutic agent are administered simultaneously, sequentially, or at an interval of time. In some embodiments, trapidil and the additional therapeutic agent are administered simultaneously. In some cases, trapidil and the additional therapeutic agent are administered sequentially. In additional cases, 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)).

[0210] Alternatively, the dose of the composition being administered may be temporarily reduced or temporarily suspended for a specified period of time (i.e., a "drug holiday"). In some cases, the length of the drug holiday may vary 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 between 10%-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%.

[0211] Once the patient's condition has improved, a maintenance dose is administered if necessary. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained.

[0212] In some embodiments, the amount of a given agent that corresponds to such an amount will depend on factors such as the particular compound, the severity of the disease, the nature (e.g., weight) of the subject or host requiring treatment, and the like, but will nevertheless be routinely determined by methods known in the art according to the particular circumstances surrounding the case, including, for example, the specific agent being administered, the route of administration, and the subject or host being treated. In some cases, the desired dosage is suitably provided in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, e.g., two, three, four or more subdoses per day.

[0213] The foregoing ranges are only suggestive, as the number of variables regarding any particular treatment regimen is great and substantial 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.

[0214] In some embodiments, the 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, determining 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. Data obtained from cell culture assays and animal studies are used to formulate a dosage range for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that includes the ED50 with minimal toxicity. Dosage will vary within this range depending on the dosage form and route of administration utilized.

[0215] <Detection method> In some embodiments, methods for detecting the expression level of one or more markers from a panel described herein include, but are not limited to, Western blot, Northern blot, Southern blot, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunofluorescence, radioimmunoassay, immunocytochemistry, nucleic acid hybridization techniques, nucleic acid reverse transcription methods, nucleic acid amplification methods, or combinations thereof. In some cases, the panel includes FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, BCL2, or a combination thereof.

[0216] In some embodiments, the expression level of one or more markers described herein is determined at the nucleic acid level. Nucleic acid-based techniques for evaluating expression are well known in the art, including, for example, determining the level of marker mRNA in biological samples. Many expression detection methods use isolated RNA. RNA isolation techniques that do not select for mRNA isolation are utilized for RNA purification (see, for example, Ausubel et al., ed. (1987-1999) Current Protocols in Molecular Biology (John Wiley & Sons, New York)). In addition, a large number of tissue samples can be easily processed using techniques well known to those skilled in the art, such as the one-step RNA isolation process disclosed in U.S. Patent No. 4,843,155.

[0217] As used herein, the term "nucleic acid probe" refers to a molecule that can selectively bind to a specifically intended target nucleic acid molecule, e.g., a nucleotide transcript. Suitable methods for synthesizing nucleic acid probes are also described in Caruthers, Science, 230:281-285, (1985). In some cases, probes suitable for use herein include those formed from nucleic acids such as RNA and / or DNA, nucleic acid analogs, locked nucleic acids, modified nucleic acids, and mixed classes of chimeric probes that include nucleic acids with other organic components, such as peptide nucleic acids. In some cases, the probe is single-stranded. In other cases, the probe is double-stranded. Exemplary nucleotide analogs include phosphate esters of deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, adenosine, cytidine, guanosine, and uridine. Other examples of non-natural nucleotides include xanthine or hypoxanthine; 5-bromouracil, 2-aminopurine, deoxyinosine, or methylated cytosine, such as 5-methylcytosine and N4-methoxydeoxycytosine. Also included are bases of polynucleotide mimetics, such as methylated nucleic acids, e.g., 2'-O-methRNA, peptide nucleic acids, modified peptide nucleic acids, and other structural moieties that can act substantially like a nucleotide or base, for example, by exhibiting base complementarity with one or more bases occurring in DNA or RNA. In some cases, the probe used for detection optionally contains a detectable label, such as a radiolabel, a fluorescent label, or an enzyme label. See, for example, Lancaster et al., U.S. Pat. No. 5,869,717. In some embodiments, the probe is fluorescently labeled. Fluorescently labeled nucleotides can be produced by various techniques, such as those described in Kambara et al., Bio / Technol., 6:816-21, (1988); Smith et al., Nucl. Acid Res., 13:2399-2412, (1985); and Smith et al., Nature, 321:674-679, (1986). The fluorescent dye can be linked to deoxyribose by a linker arm that is easily cleaved by chemical or enzymatic means. Oligonucleotides and Analogues: A Practical Approach, IRL Press, Oxford, (1991); Zuckerman et al., Polynucleotides Res., 15: 5305-5321, (1987); Sharma et al., Polynucleotides Res., 19: 3019, (1991); Giusti et al., PCR Methods and Applications, 2: 223-227, (1993); Fung et al. (U.S. Patent No. 4,757,141); Stabinsky (U.S. Patent No. 4,739,044); Agrawal et al., Tetrahedron Letters, 31: 1543-1546, (1990); Sproat et al., Polynucleotides Res., 15: 4837, (1987); and Nelson et al., Polynucleotides Res., 17:7187-7194, (1989), there are many linkers and methods for attaching labels to nucleotides. Extensive guidance exists in the literature for derivatizing fluorophores and quencher molecules for covalent attachment via common reactive groups that can be added to nucleotides.Numerous linking moieties and methods also exist for attaching fluorophore moieties to nucleotides, as described in Oligonucleotides and Analogues, supra; Guisti et al., supra; Agrawal et al., supra; and Sproat et al., supra.

[0218] In some cases, the detectable label attached to the probe can be directly or indirectly detectable. In some embodiments, the exact label can be selected based at least in part on the specific type of detection method used. Typical detection methods include radioactive detection, absorbance detection (e.g., UV-visible absorbance detection), luminescence detection (e.g., fluorescence; phosphorescence or chemiluminescence; Raman scattering). Preferred labels include optically detectable labels, such as fluorescent labels. Examples of fluorescent labels include, but are not limited to, 4-acetamido-4'-isothiocyanatostilbene-2,2'disulfonic acid; acridine and derivatives: acridine, acridine isothiocyanate; 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS); 4-amino-N-[3-vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate; N-(4-anilino-1-naphthyl)maleimide; anthranilamide; BODIPY; alexa; fluorescein; conjugated polychromatic dyes; brilliant yellow; coumarin and derivatives; coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), 7-amino-4-trifluoromethylcoumarin (Coumaran 151); Cyanine dyes; Cyanosine; 4',6-Diaminidino-2-phenylindole (DAPI); 5',5''-Dibromopyrogallol-sulfonaphthalein (Bromopyrogallol Red); 7-Diethylamino-3-(4'-isothiocyanatophenyl)-4-methylcoumarin; Diethylenetriaminepentaacetate; 4,4'-Diisothiocyanatodihydro-stilbene-2,2'-disulfonic acid; 4,4' -Diisothiocyanatostilbene-2,2'-disulfonic acid;5-[dimethylamino]naphthalene-1-sulfonyl chloride (DNS, dansyl chloride);4-dimethylaminophenylazophenyl-4'-isothiocyanate;Eosin and derivatives;Eosin, eosin isothiocyanate, erythrosin and derivatives;Erythrosin B, erythrosin isothiocyanate;Ethidium;Fluorescein and derivatives;5-carboxyfluorescein (FAM), 5-(4,6-dichlorotriazin-2-yl)aminofluorescein (DTAF), 2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein, fluorescein, fluorescein isothiocyanate, QFITC ​​(XRITC); fluorescamine; IR144; IR1446; malachite green isothiocyanate; 4-methylumbelliferone ortho cresolphthalein; nitrotyrosine; pararosaniline; phenol red; B-phycoerythrin; o-phthaldialdehyde; pyrene and derivatives: pyrene, pyrene butyrate, succinimidyl 1-pyrene; butyrate quantum dots; reactive red 4 (Cibacron™ Brilliant Red) 3B-A) Rhodamine and derivatives: 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), Lissamine rhodamine B sulfonyl chloride rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, sulforhodamine B, sulforhodamine, sulfonyl chloride derivative of sulforhodamine 101 (Texas Red); N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA); tetramethylrhodamine; tetramethylrhodamine isothiocyanate (TRITC); riboflavin; rosolic acid; terbium chelate derivatives; Atto dyes, Cy3; Cy5; Cy5.5; Cy7; IRD 700; IRD 800; La Jolta Blue; phthalocyanines; and naphthalocyanines. Labels other than fluorescent labels, including other optically detectable labels, are contemplated by the present invention. ;

[0219] The detection of bound probes can be measured using any of a variety of techniques depending on the label used, such as techniques known to those skilled in the art. Typical detection methods include radioactive detection, absorbance detection (e.g., UV-visible absorbance detection), and luminescence detection (e.g., fluorescence or chemiluminescence). Devices that can sense fluorescence from single molecules include scanning tunneling microscopes (SIMS) and atomic force microscopes (AFMs). Hybridization patterns can also be scanned using a CCD camera (e.g., Model TE / CCD512SF, Princeton Instruments, Trenton, NJ) equipped with appropriate optics (Ploem, in Fluorescent and Luminescent Probes for Biological Activity, Mason, TGEd., Academic Press, Landon, pp. 1-11 (1993)), as described in Yershov et al., Proc. Natl. Acad. Sci. 93:4913 (1996), or imaged by TV monitoring. For emission signals, phosphorimager devices can be used (Johnston et al., Electrophoresis, 13:566, 1990; Drmanac et al., Electrophoresis, 13:566, 1992; 1993). Other commercial suppliers of imaging equipment include General Scanning Inc. (Watertown, Massachusetts; on the World Wide Web at genscan.com), Genix Technologies (Waterloo, Ontario, Canada; on the World Wide Web at confocal.com), and Applied Precision Inc.

[0220] In certain embodiments, the target nucleic acid or nucleic acid ligand, or both, are quantified using methods known in the art. For example, isolated mRNA is used in hybridization or amplification assays, including but not limited to Southern or Northern analysis, polymerase chain reaction analysis, and probe arrays. One method for detecting mRNA levels involves contacting isolated mRNA with a nucleic acid molecule (probe) that hybridizes to the mRNA encoded by the gene being detected. The nucleic acid probe is composed of a portion thereof, such as a full-length cDNA or an oligonucleotide that is at least 7, 15, 30, 50, 100, 250, or 500 nucleotides in length and sufficient to specifically hybridize to the mRNA or genomic DNA encoding the marker described hereinabove under stringent conditions. Hybridization of mRNA with the probe indicates that the marker or other target protein of interest is expressed.

[0221] In one embodiment, mRNA is fixed on a solid surface, and for example, by running isolated mRNA on agarose gel, and transferring mRNA from gel to a membrane such as nitrocellulose, and then contacting with probe.In an alternative embodiment, probe is fixed on a solid surface, and mRNA is contacted with probe, for example, in gene chip array.Those skilled in the art can easily adapt known mRNA detection methods for use in detecting the level of mRNA that encodes target marker or other protein.

[0222] Alternative methods for determining the level of a target mRNA in a sample include, for example, nucleic acid amplification by RT-PCR (see, e.g., U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88:189-193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87:1874-1878), transcription amplification systems (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-beta replicase (Lizardi et al. (1988) Bio / Technology 6:1197), rolling circle replication (U.S. Pat. No. 5,854,033), or other nucleic acid amplification methods, followed by detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are particularly useful for detecting nucleic acid molecules when such molecules are present in very low numbers. In certain embodiments of the invention, marker expression is assessed by quantitative fluorogenic RT-PCR (i.e., the TaqMan System).

[0223] The modification or expression level of target RNA can be monitored using membrane blot (such as those used in hybridization analysis, such as Northern, dot, etc.), or microwell, sample tube, gel, bead or fiber (or solid support that contains bound nucleic acid).See U.S. Patent Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference.Expression detection can also include using nucleic acid probes in solution.

[0224] In some embodiments, microarrays are used to determine the expression or presence of one or more markers. Microarrays are particularly well suited for this purpose due to their reproducibility between different experiments. DNA microarrays provide one method for simultaneously measuring the expression levels of a large number of genes. Each array consists of a reproducible pattern of capture probes attached to a solid support. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. The hybridization intensity for each probe on the array is determined and converted to a quantitative value representing the relative gene expression level. See U.S. Patent Nos. 6,040,138, 5,800,992, 6,020,135, 6,033,860, 6,344,316, and U.S. Patent Publication No. 20120208706. High-density oligonucleotide arrays are particularly useful for determining the gene expression profile for a large number of RNAs in a sample. Exemplary microarray chips include FoundationOne and FoundationOne Heme from Foundation Medicine, Inc.; GeneChip® Human Genome U133 Plus 2.0 from Affymetrix; and Human DiscoveryMAP® 250+ v.2.0 from Myraid RBM.

[0225] Techniques for the synthesis of these arrays using mechanical synthesis methods are described, for example, in U.S. Patent No. 5,384,261. In some embodiments, arrays are fabricated on surfaces of virtually any shape or variety. In some embodiments, the array is a planar array surface. In some embodiments, the array comprises peptides or nucleic acids on beads, gels, polymer surfaces, fibers such as fiber optics, glass, or other suitable substrates. See U.S. Patent Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193, and 5,800,992, each of which is incorporated herein in its entirety for all purposes. In some embodiments, the array is packaged in a manner that allows for comprehensive device diagnostics or other operations.

[0226] In some cases, the method for quantification is quantitative polymerase chain reaction (QPCR). As used herein, "QPCR" refers to a PCR reaction performed in such a manner and under controlled conditions such that the results of the assay are quantitative, i.e., the assay can quantify the amount or concentration of nucleic acid ligand present in a test sample. QPCR is a polymerase chain reaction-based technology used to simultaneously amplify and quantify targeted nucleic acid molecules. QPCR allows both the detection and quantification (as absolute number of copies or relative amount when normalized to DNA input or an additional normalizing gene) of specific sequences in a DNA sample. The procedure follows the general principles of PCR, with the additional feature that amplified DNA is quantified as it accumulates in the reaction in real time after each amplification cycle. QPCR is described, for example, in Kurnit et al. (U.S. Patent No. 6,033,854), Wang et al. (U.S. Patent Nos. 5,567,583 and 5,348,853), Ma et al. (The Journal of American Science, 2(3), (2006)), Heid et al. (Genome Research 986-994, (1996)), Sambrook and Russell (Quantitative PCR, Cold Spring Harbor Protocols, (2006)), and Higuchi (U.S. Patent Nos. 6,171,785 and 5,994,056).

[0227] In some embodiments, the expression level is protein expression, and the protein expression level of the gene described herein is detected.In some cases, the detection method includes contacting a biological sample with an antibody that specifically recognizes or specifically binds to a protein (e.g., a protein encoded by the gene FOSL2, JUN, JUND, ATF3, SREBF2, INSIG1, MVK, MVD, LDLR, HMGCR, ERK, DUSP14, SQSTM1, IER3, CDKN1A, MYC, or BCL2).In some cases, the level of protein expression is determined by immunoassay, including but not limited to, radioimmunoassay, Western blot assay, ELISA, immunofluorescence assay, enzyme immunoassay, immunoprecipitation, chemiluminescence assay, immunohistochemistry assay, dot blot assay, and slot blot assay.

[0228] <Kit / Product> In certain embodiments, the present specification discloses kits and products for use with one or more methods described herein.Such kits include a carrier, packaging, or container that is divided to contain one or more containers, such as vials, tubes, etc., and each container contains one of the individual components used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.In one embodiment, the container is made of various materials, such as glass or plastic.

[0229] The products provided herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and other packaging materials appropriate for the selected formulation and intended mode of administration and treatment.

[0230] For example, the container contains trapidil, optionally in a composition or in combination with an additional therapeutic agent as disclosed herein. Such kits optionally include an identifying description or label or instructions for use in the methods described herein.

[0231] The kit also includes a label listing the contents and / or instructions for use, and a package insert accompanied by the instructions for use. A set of instructions is also typically included. In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other characters forming it are applied, molded, or etched into the container itself, and is associated with the container when present in a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0232] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack comprises, for example, metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser also carries a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the agency of the drug form for human or veterinary administration. Such notice, for example, is labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated disease. [Example]

[0233] The following examples are provided for the purpose of illustrating various embodiments of the disclosure and are not intended to limit the disclosure in any way. The examples, along with the methods described herein, are representative and exemplary of preferred embodiments and are not intended to limit the scope of the disclosure. Variations thereof and other uses encompassed within the spirit of the disclosure, as defined by the scope of the claims, will occur to those skilled in the art.

[0234] Example 1 - In vitro and computational analyses to discover transcriptomic signatures of extrapyramidal syndromes. Gene expression data for drug-perturbed cell lines (MCF7, HL60, and PC3) representing over 1,000 compounds, including but not limited to FDA- and internationally approved drugs, were obtained from the public resource Connectivity Map (Lamb, J., The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 2006. 313(5795): pp. 1929-35). Data were quality-controlled, standardized, and normalized. Concurrently, adverse drug reactions for compounds were tabulated using drug labels, primary literature, and statistical analysis of the FDA Adverse Event Reporting System (https: / / open.fda.gov / data / faers).

[0235] Gene expression data for ~400 drugs with known adverse drug reactions were input for computational analysis. Drugs were divided into groups that either caused or did not cause extrapyramidal syndromes (such as tardive dyskinesia and akathisia). A machine learning algorithm coupled with feature selection was implemented to discover a transcriptomic signature for compounds known to cause extrapyramidal syndromes. This signature had the accuracy to predict whether a compound was likely to cause extrapyramidal syndromes (5-fold cross-validation, AUROC = 0.858). Randomized labeling was used to validate the signature (5-fold cross-validation, AUROC = 0.552) after nulling the results, confirming that the accuracy was related to the biological data and not an artifact of the algorithm.

[0236] The transcriptome signature encompassed 433 genes and, in some cases, was associated with increased ERK signaling activity induced by compounds causing extrapyramidal syndrome. Upregulated transcription factors and proteins included those related to activator protein 1 (FOS and JUN), cholesterol synthesis and unfolded protein response (SREBF1 / 2, CEBPB, and UBC), and ERK2. Downregulated transcription factors and proteins related to cell cycle progression: MYC and BCL2.

[0237] The identified in vitro signature is consistent with in vitro and in vivo animal data on the compounds and associated dyskinesias (Deslauriers, J., et al., Implication of the ERK / MAPK pathway in antipsychotics-induced dopamine D2 receptor upregulation and in the preventive effects of (+ / -)-alpha-lipoic acid in SH-SY5Y neuroblastoma cells. Journal of molecular neuroscience, 2014. 52(3): pp. 378-83; Cao, X., et al., Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements. The Journal of neuroscience: the official journal of the Society for Neuroscience, 2010. 30(21): pp. 7335-43; Nguyen, TV, et al., Differential expression of c-fos and zif268 in rat striatum after Haloperidol, clozapine, and amphetamine. Proc Natl Acad Sci USA, 1992. 89(10): p. 4270-74).

[0238] Example 2 - In vitro and computational analysis elucidating trapidil as a treatment for extrapyramidal syndrome. After elucidating the transcriptomic signatures of drugs that cause extrapyramidal syndromes, we computationally identified compounds that reverse the transcriptomic signatures when administered alone under the same in vitro conditions. The computational algorithm scans the same transcriptomic data set but identifies compounds that maximally and preferentially reverse the 433 identified genes for extrapyramidal syndromes. Of the ~1100 compounds screened, trapidil was shown to reverse the transcriptomic signatures for various extrapyramidal syndromes, such as tardive dyskinesia, dyskinesia, akathisia, and drug-induced parkinsonism.

[0239] Example 3 - In vitro and computational analyses assessing the ability of trapidil to improve or reverse antipsychotic and dopamine transcriptomic signatures. To evaluate the qualitative ability of trapidil to reverse the identified transcriptomic signatures induced by causative compounds (or compounds that cause extrapyramidal symptoms such as tardive dyskinesia, dyskinesia, akathisia, or drug-induced parkinsonism), trapidil was coadministered with compounds known to cause tardive dyskinesia and levodopa-induced dyskinesia. Table 1 shows the two-perturbation design of the experiment. Haloperidol and risperidone were tested. Dopamine was chosen to replace levodopa in cell lines (e.g., MCF7) that do not possess the enzymes necessary to convert levodopa to dopamine.

[0240] [Table 1]

[0241] MCF7 cells were used. Cells were seeded 24 hours before compound administration and exposed to the compounds for 6 hours. All conditions were performed in triplicate. The dosage for trapidil was varied in both directions from the original concentration of 20 μM. The concentrations of haloperidol, risperidone, and dopamine were higher than the known physiological concentrations used for treatment in the brain and cerebrospinal fluid (100x physiological concentration for haloperidol, 30x physiological concentration for risperidone, and 100x physiological concentration for dopamine). The trapidil concentration was close to the physiological brain concentration approved for treatment (~13 μM). In some cases, high concentrations were used in in vitro studies to obtain rapid and robust responses by the cells. In such cases, in vitro results were performed at multiple concentrations (trapidil was repeated in triplicate) and qualitative trends were assessed.

[0242] After incubating compounds with MCF7 cells for 6 hours, total RNA was extracted. mRNA was enriched and sequencing library preparation was completed. Samples were then sequenced on an Illumina HiSeq X machine to generate RNA-seq data for assessing transcriptional changes. Each sample had a minimum of 20 million reads, with at least 80% of base pairs having a Q30 score. RNA-seq reads were aligned to the genome using STAR and counted in the mRNA region using HTSeq. Differential expression was determined using DESeq2.

[0243] Single perturbation RNA-seq results (H_V, RV, D_V, and V_T2) were compared to the Connectivity Map dataset for quality control using distance metrics. The RNA-seq data for haloperidol, dopamine, and trapidil were similar to their respective microarray data obtained from the Connectivity Map. The RNA-seq data for risperidone was found to be similar to the RNA-seq data for haloperidol and risperidone. Although both the risperidone RNA-seq and microarray data had similarly distinct genes, the RNA-seq data had larger scale changes, so haloperidol was chosen as the closer sample for the distance metric.

[0244] As a second quality control, we differentially expressed 433 transcriptome signatures for tardive dyskinesia, as determined by RNA-seq data for haloperidol (p = 1.57e-54) and risperidone (p = 9.20e-32). To assess whether the dopamine RNA-seq data altered genes involved in levodopa-induced dyskinesia, we compared the dopamine data with RNA-seq expression patterns in a rat model of levodopa-induced dyskinesia (Smith, LM, et al., "Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat." Neuroscience, 2016. 324: pp. 238-51). Concordance was found between two transcriptome signatures (p=0.0166) from different experimental conditions (in vitro vs. in vivo) and different organisms (human vs. rat).

[0245] After quality checks, we evaluated whether trapidil qualitatively improved or reversed the transcriptomic signatures induced by haloperidol and risperidone discussed in Example 1. In some cases, transcripts related to SREBF1, FOS, CEBPB, UBC, ERK2, and JUN were evaluated. Figure 1 shows the differential expression of haloperidol with various concentrations of trapidil. Figure 2 shows the differential expression of risperidone with various concentrations of trapidil. Near-physiological concentrations of trapidil reduced or reversed the transcriptomic signatures induced by high levels of haloperidol. Risperidone reduced or reversed trapidil induced transcriptomic changes. Changes to risperidone were more pronounced in accordance with haloperidol, a more potent first-generation antipsychotic. Changes with an FDR < 0.05 are shown in Figures 1 and 2. * The remaining genes show a qualitative trend towards reduced expression changes caused by antipsychotic drugs.

[0246] Additionally, we applied computational analysis to assess how the entire 433-gene transcriptome signature changed. The RNA-seq data was analyzed by a machine learning algorithm to determine whether a compound caused extrapyramidal syndromes (ESSs). This generated a "propensity score." The "propensity score" is the aggregate of transcriptome changes across the entire signature. Compounds with a score of 0 or less are predicted not to cause an ESD, while more positive drugs have a higher probability of causing an ESDs. As seen in Figure 3, haloperidol is predicted to have a much higher propensity to cause an ESDs than risperidone. The addition of trapidil reduces the propensity score for ESDs for both haloperidol and risperidone. For risperidone with 50 μM trapidil, the score drops below 0.

[0247] To evaluate the effects of trapidil on levodopa-induced dyskinesia, we compared the dopamine transcriptome signature with striatal transcriptome changes in a rat model of levodopa-induced dyskinesia at peak levodopa levels (Smith, LM, et al., Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat. Neuroscience, 2016. 324:238-51). Using connectivity scores as a metric of how similar various gene expression patterns were, we found that trapidil dose-dependently reduced the similarity of dopamine gene expression patterns from changes noted in the brains of levodopa-treated rats (Figure 4). Connectivity scores were used to assess how similar differential gene expression patterns were, with higher positive scores reflecting similarity and negative scores reflecting opposite expression patterns.

[0248] Using gene expression patterns from in vitro assays, it has been observed that trapidil dose-dependently reduces gene expression patterns elicited by haloperidol, risperidone, and dopamine that are associated with extrapyramidal syndromes, including tardive dyskinesia and levodopa-induced dyskinesia.

[0249] Example 4 - Initial dosage levels of trapidil and antipsychotics for animal model studies. Determine plasma and brain pharmacokinetics to characterize dose-exposure relationships: Trapidil is administered to Long-Evans rats via intraperitoneal (IP) injection to measure concentrations in blood and brain (Table 2).

[0250] The initial dose is selected based on FDA allometric scaling guidance and current human dosing. The calculated dose (30 mg / kg) is then varied by a factor of two in both directions (15 mg / kg and 60 mg / kg). Plasma samples are collected at eight time points to determine PK parameters (Groups 1-3). Based on the resulting plasma profiles, three time points are selected to determine brain concentrations of trapidil for a 30 mg / kg IP infusion (Groups 4-6).

[0251] [Table 2]

[0252] Determine potential drug-drug interactions with antipsychotics to design appropriate dosing strategies: Interactions between trapidil and antipsychotics are determined by measuring the plasma concentrations of the two compounds when administered together versus separately (Table 3). As an example, the first-generation antipsychotic haloperidol is shown. Other antipsychotics, such as the second-generation risperidone, are tested in a similar manner.

[0253] Haloperidol is administered via subcutaneously implanted pellets because continuous administration is more relevant to TD animal models. Plasma measurements of haloperidol and trapidil are performed after haloperidol reaches steady state (at 24, 48, and 72 hours after implantation) and at eight time points after IP infusion of trapidil (Table 3). To determine potential drug-drug interactions, trapidil concentrations are compared to dose groups in which the drugs are administered separately, while haloperidol concentrations are compared to an earlier time point before trapidil infusion. In some cases, trapidil has been shown to modulate CYP1A2, but CYP1A2 has not been shown to interact with haloperidol.

[0254] [Table 3]

[0255] Example 5 - Efficacy of trapidil in preventing or treating tardive dyskinesia using an established animal model of haloperidol-induced dyskinesia. Using the dosages from Example 4, trapidil will be administered to test its in vivo efficacy for the treatment and prevention of TD. A TD-like symptom known as vacuum chewing movements (VCM) is induced in rodents using antipsychotic drugs. There is a body of evidence supporting the applicability of VCM to TD, with haloperidol being most commonly used for induction. This is performed using the established rodent model of haloperidol-induced dyskinesia. An example is the use of haloperidol, although other antipsychotics, such as risperidone, can be used to induce VCM in rats. The goal is to reduce VCM by at least 30%, and the study is powered (n=10 per group).

[0256] Tardive dyskinesia-like symptoms are induced by chronic administration of haloperidol for 10 weeks. This is an established induction method in animals, including rats. Early symptoms (~3 weeks) reflect acute extrapyramidal symptoms, while delayed symptoms (~10 weeks) reflect TD. To achieve a human-like steady-state concentration of haloperidol, rats are implanted with subcutaneous sustained-release pellets (90 days). This method has been shown to induce reproducible symptoms of TD in rodents with the lowest coefficient of variation compared to oral and injection methods. Conventional testing quantifies the mean number and standard deviation of movements, and groups of n = 10 provide sufficient power to detect a 30% reduction in TD symptoms.

[0257] In this study, age-matched male Long-Evans rats (n = 10 per group, ~60 days old) are exposed to continuous administration of haloperidol. Haloperidol induction of orofacial dyskinesia is established in rats as a model of human TD. Long-Evans rats are chosen because they show a more robust response to haloperidol compared to other rat strains. Continuous administration of haloperidol was chosen for daily infusions because symptoms are more evident with continuously present HAL.

[0258] The ability of trapidil to treat and prevent TD will be tested (Figure 5). For prevention, trapidil will be co-administered with haloperidol to five groups for 10 weeks (Figure 5A). Symptoms of dyskinesia will be quantitatively assessed every other week by an observer blinded to treatment. To test the treatment of tardive symptoms, which are more indicative of TD, rats will be treated with haloperidol for 10 weeks, followed by trapidil administration. At this point, trapidil will be co-administered in two doses to the group treated with haloperidol for three weeks, and symptoms will be monitored weekly during this period. It will be important to test whether symptoms are reduced while still using haloperidol, as TD patients typically continue to use antipsychotic medications. Results from this group will be compared to 1) rats that continued to receive haloperidol alone, and 2) rats that continued to receive haloperidol and a positive control (e.g., tetrabenazine). Tetrabenazine is administered via IP infusion at 5 mg / kg / day, an effective dose in rats for depleting striatal dopamine. For each of these experiments, two different doses of trapidil are tested: 15 mg / kg / day (T) and 30 mg / kg / day (2T). Additional dosing regimens and concentrations are used to demonstrate dose-dependent responses. IP infusion vehicle is used to maintain consistency of infusion-induced stress across groups.

[0259] Rats are placed in separate cages and allowed to acclimate for 5 minutes. The number of VCMs (mouth opening not directed towards a physical object), protruding tongues, and facial twitches are then counted over a 5-minute period. Counts and times are stopped for grooming. Evaluators are blinded to treatment conditions.

[0260] Statistically significant changes in VCM indicate the potential utility of trapidil in influencing human TD.

[0261] Example 6 - Efficacy of trapidil in preventing or treating levodopa-induced dyskinesia using an established animal model. As in Example 5, trapidil dosing is tailored to Sprague-Dawley rats, commonly used for treating levodopa-induced dyskinesia. To assess plasma concentrations, trapidil is administered by IP injection at 15 mg / g / kg, 30 mg / g / kg, and 60 mg / g / kg. Brain and CSF concentrations are determined at selected time points after determining the initial pharmacokinetic profile.

[0262] As in Example 5, an established animal model exists for testing the efficacy of trapidil on levodopa-induced dyskinesia (LID). The 6-OHDA LID rat model is used. (Cenci, MA, and Lundblad, M., Ratings of L-DOPA-Induced Dyskinesia in the Unilateral 6-OHDA Lesion Model of Parkinson's Disease in Rats and Mice. Current Protocols in Neuroscience, 2007. doi:10.1002 / 0471142301.ns0925s41). Trapidil is tested to prevent and / or treat LID. Amantadine is used as a positive control in this example.

[0263] Example 7 – Trapidil for clinical studies in tardive dyskinesia The purpose of this study was to evaluate the efficacy of trapidil in tardive dyskinesia.

[0264] Study Type: Intervention

[0265] Allocation: Randomized

[0266] Endpoint Classification: Efficacy Trials

[0267] Intervention model: Parallel Assignment Masking: Double-blind (subjects, researchers, outcome assessors)

[0268] Primary purpose: treatment

[0269] Primary endpoint: The number of patients with a response to study drug will be measured [time frame: 8 weeks from first dose]. Participants will be followed up until disease progression. The primary efficacy endpoint is the change in AIMS total score by at least two trained reviewers blinded to treatment allocation.

[0270] standard Inclusion criteria: Men and women: 18-75 years; Diagnosis of schizophrenia / schizoaffective disorder according to DSM-IV criteria; Diagnosis is made based on the SCID interview and information from medical records, previous treatment psychiatrists, and family informants; history of antipsychotic-induced dyskinesia; a history of ≥3 months of treatment with antipsychotic medication and at least (at last) 4 weeks of current stable dose of antipsychotic medication; Implementation of the Schooler-KaneTD survey criteria for the first assessment was conducted 2-12 weeks prior to the start of the study, and implementation of the Schooler-KaneTD survey criteria for subsequent assessments was conducted prior to allocation to experimental treatments; Subjects must be capable of providing informed consent.

[0271] Exclusion criteria: Meeting criteria for other DSM-IV Axis I diagnoses; Presence of neurological disorders or history of significant head injury; Substance abuse or alcoholism during one's lifetime; clinically determined to be at risk for suicide or homicide; Pregnant or lactating female patients; female patients who are not pregnant or lactating must be using a medically accepted means of contraception if sexually active.

[0272] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It is understood that various alternatives to the embodiments of the present disclosure described herein may be utilized in practicing the present disclosure. It is intended that the following claims define the scope of the disclosure, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A trapidil compound or a pharmaceutically acceptable salt thereof for treating or prophylactic levodopa-induced dyskinesia in a subject.

2. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the subject is a human.

3. The trapidil compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein the pharmaceutically acceptable salt of the trapidil compound includes a salt having hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid.

4. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the trapidil compound or a pharmaceutically acceptable salt thereof is formulated for oral administration.

5. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the trapidil compound or a pharmaceutically acceptable salt thereof is formulated for parenteral administration.

6. The trapidil compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the trapidil compound is a derivative of trapidil selected from the group consisting of AR 12455, AR 12456, AR 12460, AR 12463, AR 12464, AR 12465, and AR 12565.

7. The trapidil compound according to claim 1, wherein the trapidil compound is deuterated trapidil, or a pharmaceutically acceptable salt thereof.

8. The trapidil compound according to claim 1, wherein the trapidil compound is a metabolite of trapidil comprising TP-1, TP-2, or desethyl-trapidil, or a pharmaceutically acceptable salt thereof.

9. The trapidil compound according to claim 1, wherein the trapidil compound is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-amine, or a pharmaceutically acceptable salt thereof.

10. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the subject is receiving levodopa for the treatment of Parkinson's disease or symptoms of Parkinson's disease.

11. The trapidil compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein the levodopa is formulated together with carbidopa.

12. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein the trapidil compound or a pharmaceutically acceptable salt thereof is administered before the administration of levodopa.

13. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein the trapidil compound or a pharmaceutically acceptable salt thereof is administered simultaneously with the administration of levodopa.

14. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein the trapidil compound or a pharmaceutically acceptable salt thereof is administered after the administration of levodopa.

15. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the trapidil compound or a pharmaceutically acceptable salt thereof is therapeutically effective in treating or preventing one or more symptoms of levodopa-induced dyskinesia.

16. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein one or more symptoms of the levodopa-induced dyskinesia are selected from the group consisting of hyperactivity, chorea, dystonia, involuntary muscle movement, and athetosis.

17. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the dose of the trapidil compound or a pharmaceutically acceptable salt thereof ranges from about 50 milligrams (mg) per day to about 1,000 mg per day.

18. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein the dose of the trapidil compound or a pharmaceutically acceptable salt thereof is administered between once and five times a day.

19. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein the dose of the trapidil compound or a pharmaceutically acceptable salt thereof is administered once daily.

20. The trapidil compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein the dose of the trapidil compound or a pharmaceutically acceptable salt thereof is administered about three times a day.

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