Use of composition for preparing drug for improving cognitive function

Abstract

To provide use of a composition for preparing a drug for improving cognitive function in a subject.SOLUTION: The present invention provides use of a composition for preparing a drug for improving cognitive function in a subject, characterized by using dextromethorphan, valproic acid, or a combination of dextromethorphan and valproic acid for therapeutic purposes.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides use of a composition for preparing a medicament for improving cognitive function in a subject, wherein dextromethorphan, or valproic acid, or a combination of dextromethorphan and valproic acid is used for treatment. [Background technology]

[0002] Bipolar disorder is a severe and disabling mental disorder that encompasses many categories of clinical symptoms, and its main symptoms include mood disorders, specific risk behaviors, impulsivity, interpersonal disorders, and depression. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), bipolar disorder can be classified into four types: bipolar I disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder not otherwise specified.

[0003] The symptoms of bipolar II disorder are a combination of depressive and hypomanic episodes. Bipolar II disorder is often misdiagnosed because patients frequently experience depressive episodes, while hypomanic episodes are short-lived and less obvious. Therefore, patients often do not mention these symptoms during medical consultations, and doctors often do not ask about their medical history, leading to the condition being overlooked. As a result, patients with bipolar II disorder often do not receive a correct diagnosis and effective treatment. Compared with patients with bipolar I disorder, patients with bipolar II disorder have a similar or higher risk of suicide, more frequent episodes of affective syndromes, and more depressive episodes.

[0004] Numerous studies have shown that patients with bipolar disorder have a wide range of neuropsychological impairments during symptom periods, including executive function, sustained attention, working memory, verbal memory, verbal fluency, cognitive resilience, abstract reasoning and visuomotor skills, visuospatial abilities, and general cognitive function.

[0005] Therefore, how to improve the neuropsychological impairment of patients with bipolar disorder is a major challenge in clinical treatment. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) DETAILED DESCRIPTION OF THE INVENTION

[0007] As used herein, the terms "one" or "an" are used to describe elements and components of the invention. This is done merely for convenience and to give a general sense of the invention. This description should be interpreted as including one or at least one, and the singular also includes the plural unless it is clear that a different meaning is intended.

[0008] As used herein, the term "or" may mean "and / or."

[0009] As used herein, "cognitive function" refers to the mental process of becoming aware, perceiving, or understanding knowledge. Cognitive function involves all aspects of perception, thinking, reasoning, memory, and attention. In one embodiment, cognitive function includes global cognition, sustained cognition, memory, language, executive function, and attention. In a preferred embodiment, attention includes sustained attention.

[0010] The present invention provides use of a composition for preparing a medicament for improving sustained attention in a subject, wherein an active ingredient of the composition comprises dextromethorphan.

[0011] Furthermore, the present invention also provides use of the composition for preparing a medicament for improving memory in a subject, wherein the active ingredient of the composition comprises valproic acid or a pharmaceutically acceptable salt thereof.

[0012] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of humans and lower animals, within the limits of sound medical judgment, and does not cause excessive toxicity, irritation, allergic response, etc., at a reasonable benefit / risk ratio. In one embodiment, a pharmaceutically acceptable salt of valproic acid includes sodium valproate.

[0013] In the present invention, dextromethorphan can also be used to improve the memory of a subject. Thus, valproic acid taken together with dextromethorphan also has the effect of improving the memory of a subject. In one embodiment, the active ingredient of the composition for improving the memory of a subject further comprises dextromethorphan.

[0014] In another embodiment, memory includes verbal memory, spatial memory, immediate memory, delayed memory, and working memory.

[0015] As used herein, the terms "improve" or "improving" are meant to include not only enhancing cognitive function (sustained attention and memory), but also slowing, halting, or reversing the progression of cognitive deficits.

[0016] In one embodiment, the subject is a normal subject or a normal human.

[0017] In another specific embodiment, the subject suffers from a psychiatric disorder or a disease associated with neuronal apoptosis or neurodegeneration. In a preferred embodiment, the psychiatric disorder includes bipolar disorder, schizophrenia, attention-deficit hyperactivity disorder (ADHD), or depression. In a preferred embodiment, the disease associated with neuronal apoptosis or neurodegeneration includes stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis / Parkinson-dementia complex, Wilson's disease, multiple sclerosis, progressive supranuclear palsy, corticobasal degeneration, dementia, amyotrophic lateral sclerosis, epilepsy, transient ischemic attack, myocardial ischemia, head injury, spinal cord injury, or hypoxia. In another embodiment, the subject suffers from a bipolar disorder. In a preferred embodiment, the bipolar disorder is bipolar II disorder. In some embodiments, childhood-onset fluency disorder, psychiatric disorder, and diseases related to neuronal apoptosis or neurodegeneration cause the cognitive impairment of the subject.Therefore, the subject's sustained attention deficit and memory impairment (for example, memory deterioration or decline) are caused by childhood-onset fluency disorder, psychiatric disorder, mood disorder, neurological condition, neuronal apoptosis or neurodegeneration.

[0018] As used herein, the term "subject" refers to an animal. In preferred embodiments, the subject is a mammal. In more preferred embodiments, the subject is a human.

[0019] In the present invention, an effective amount of dextromethorphan, valproic acid, or sodium valproate is administered to a subject for treatment. As used herein, the term "effective amount" refers to an amount of a pharmaceutical ingredient that substantially induces, promotes, or produces a desired therapeutic effect. In the present invention, the effective amount of dextromethorphan is less than 30 mg / day. In one embodiment, the effective amount of dextromethorphan is in the range of 0.1 to 30 mg / day. In a preferred embodiment, the effective amount of dextromethorphan is in the range of 0.5 to 25 mg / day. In a more preferred embodiment, the effective amount of dextromethorphan is in the range of 1 to 20 mg / day. Therefore, an effective amount of dextromethorphan administered to a subject can result in a dextromethorphan level in the subject's plasma of 10 to 50 ng / ml (0.05 to 0.2 μM).

[0020] In another embodiment, the effective amount of valproic acid or sodium valproate is in the range of 0.1 to 2500 mg / day. In a preferred embodiment, the effective amount of valproic acid or sodium valproate is in the range of 100 to 2000 mg / day. In a more preferred embodiment, the effective amount of valproic acid or sodium valproate is in the range of 500 to 1000 mg / day. In another embodiment, the effective amount of valproic acid or sodium valproate is in the range of 500 to 2500 mg / day. Thus, an effective amount of valproic acid or sodium valproate administered to a subject can result in a dextromethorphan level in the subject's plasma of 50 to 100 μg / dL.

[0021] The drug of the present invention further comprises a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent or vehicle used to enhance the delivery and / or pharmacokinetic properties of the pharmaceutical ingredient(s) combined therewith, but which itself has no therapeutic effect and does not induce or cause any undesirable or harmful effects or adverse reactions in the subject. Therefore, the active ingredients of the present invention (dextromethorphan, valproic acid, or sodium valproate) can be easily formulated into dosages suitable for oral administration by using pharmaceutically acceptable carriers well known in the art, which is also preferred in the practice of the present invention. Such carriers allow the compounds of the present invention to be formulated into dosage forms such as tablets, lozenges, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. These carriers may be selected from sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers, emulsifiers, isotonic saline, and pyrogen-free water.

[0022] In some embodiments, when the composition is formulated in tablet or lozenge form, the unit dose of dextromethorphan in each tablet or lozenge is 0.1, 0.5, 1, 5, 10, 15, or 30 mg. The unit dose of dextromethorphan is designed to approach or meet the daily dextromethorphan requirement of less than 30 mg when administered one or two tablets / lozenges daily. Furthermore, the unit dose of sodium valproate in each tablet or lozenge is 0.1, 10, 50, 100, 250, 500, or 1000 mg. The unit dose of sodium valproate is designed to approach or meet the daily sodium valproate requirement of 0.1 to 2500 mg when administered one or two tablets / lozenges daily.

[0023] In various embodiments, the drug is administered in a form suitable for use by parenteral, transdermal, oral, and topical routes. In a preferred embodiment, the drug is administered by the oral route.

[0024] In one embodiment, the drug is administered daily for at least one week. In a preferred embodiment, the drug is administered daily for at least two weeks. In a more preferred embodiment, the drug is administered daily for at least four weeks. In another embodiment, the drug is administered daily for at least six weeks. In a preferred embodiment, the drug is administered daily for at least eight weeks. In one embodiment, the drug is administered for at least 12 consecutive weeks.

[0025] Example This invention may be embodied in many different forms and should not be construed as limited to the examples set forth herein, as the scope of the invention as defined in the claims is not limited to the examples set forth herein.

[0026] The present study recruited patients diagnosed with bipolar II disorder (BD-II). Patients were diagnosed by psychiatrists using an improved Chinese version of the Schedule of Affective Disorder and Schizophrenia-Life Time (SADS-L), which has high inter-rater reliability, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), thereby confirming that the patients met the DSM-IV-TR criteria for bipolar II disorder.

[0027] The purpose of the present study is to investigate whether dextromethorphan (DM) and sodium valproate (trade name: Depakine (antihistamine)) may improve cognitive function in patients. Therefore, in this study, patients with bipolar II disorder were divided into two groups. One group was patients who took dextromethorphan and sodium valproate together (BD). DM ), and the other group was patients who received sodium valproate and placebo (BD PlIn the present invention, before the two groups of patients started taking the drug, the following evaluation tests were used to perform baseline evaluations on the two groups of patients.

[0028] (A) Efficacy evaluation test: (1) Hamilton Depression Rating Scale (HDRS) For patients with bipolar disorder in the depressed phase, the severity of depression was assessed by HDRS at baseline and at each follow-up visit during the study. In this study, a 17-item version of HDRS was adopted, including depressed mood, guilt, suicidal ideation or behavior, difficulty falling asleep, waking up in the middle of the night, waking up early in the morning, work and interest (evaluation of pleasure and function), psychomotor retardation, psychomotor agitation, mental anxiety, somatic anxiety, appetite, fatigue, sexual interest, hypochondriasis, weight loss, and insight into illness.

[0029] (2) Young Mania Rating Scale (YMRS) For patients with bipolar disorder in the hypomanic or manic phase, the severity of mania will be assessed by the YMRS at baseline and at each follow-up visit during the study. The YMRS is applicable to assess mania and has 11 items: elevated mood, increased motor activity / energy, sexual interest, sleep, irritability, speech, language / thought disorder, content, disruptive / aggressive behavior, blindness, and insight.

[0030] (B) Neuropsychological testing: (1) Wechsler Memory Scale-III (WMS-III) (Chinese version) This study used the WMS-III (Chinese version) to measure key index scores, including verbal memory, spatial memory, immediate memory, delayed memory, and working memory, across various levels of memory. The key index scores were used to indicate the patient's memory status. The split-half reliability coefficients for the key indexes of the WMS-III (Chinese version) ranged from 0.74 to 0.96, with a median of 0.90. The mean test-retest interval was 36.57 days, and the test-retest reliability coefficients for the key indexes ranged from 0.47 to 0.83, with a median of 0.71.

[0031] (2) Continuous Processing Task (CPT) In this study, we used a computerized version of Conner's CPT II20, which was used to detect patients' sustained attention. The split-half reliability of Conner's CPT II ranged from 0.66 to 0.95, and the test-retest reliability after 3 months ranged from 0.55 to 0.84. For Han Chinese living in Taiwan, the CPT has excellent reliability and validity.

[0032] Based on the above evaluations and tests, Table 1 shows the patient demographics at baseline.

[0033] [Table 1]

[0034] Both groups were treated with medication. The treatment course for the group taking dextromethorphan and sodium valproate (BDDM group) was to take dextromethorphan 1-30 mg / day and sodium valproate 500-2500 mg / day for 12 weeks. The treatment course for the group taking sodium valproate and placebo (BDDM group) was to take dextromethorphan 1-30 mg / day and sodium valproate 500-2500 mg / day for 12 weeks. Pl The treatment course for the 12-week group consisted of 500 to 2500 mg / day of sodium valproate or placebo. After treatment, patients' plasma dextromethorphan concentrations were approximately 10 to 50 ng / ml (0.05 to 0.2 μM), and plasma sodium valproate concentrations were approximately 50 to 100 μg / dl.

[0035] During treatment, patients in both groups visited the clinic every two weeks and underwent HDRS and YMRS assessments. CPT and WMS assessments were conducted only at baseline and at the end of the 12-week treatment period. Therefore, the efficacy study lasted for 12 weeks.

[0036] During the 12-week follow-up period of the efficacy study, the data of some patients were excluded due to various factors and conditions. Therefore, the efficacy evaluation results of the two groups after 12 weeks of treatment are shown in Table 2.

[0037] [Table 2]

[0038] As shown in Table 2, there was no correlation between the changes in HDRS and YMRS scores and the changes in CPT and WMS scores. These results suggest that dextromethorphan and sodium valproate can also be used to improve cognitive function in normal humans.

[0039] According to the CPT scores in Table 2, after the treatment course, BD Pl There was no improvement in sustained attention in the BD group (taking sodium valproate and placebo). DM The group (taking dextromethorphan and sodium valproate) showed a significant improvement in sustained attention after the end of the treatment course. Because the difference in effect between the two groups was due to dextromethorphan treatment, these results indicate that the improvement in sustained attention was due to the effectiveness of dextromethorphan.

[0040] According to the WMS scores in Table 2, BD Pl Both groups (taking sodium valproate and placebo) showed significant improvements in memory after the treatment course. DM The group (taking dextromethorphan and sodium valproate) also showed significant improvements in memory after the treatment course. These results suggest that sodium valproate, dextromethorphan, or their combination may be effective in improving memory.

[0041] Those skilled in the art will recognize the foregoing summary as a description of methods for communicating hosted application information, and will recognize that these are merely examples and that many equivalents are possible.

Claims

1. 10. Use of a composition for preparing a medicament for improving memory in a subject, wherein the active ingredient of the composition comprises valproic acid or a pharmaceutically acceptable salt thereof.

2. 2. The use according to claim 1, wherein the pharmaceutically acceptable salt of valproic acid comprises sodium valproate.

3. 10. The use of claim 1, wherein the composition further comprises dextromethorphan.

4. The use according to claim 1 , wherein the memory comprises verbal memory, spatial memory, immediate memory, delayed memory, and working memory.

5. The use according to claim 1, wherein the subject is suffering from a psychiatric disorder or a disease associated with neuronal apoptosis or neurodegeneration.

6. 6. The use of claim 5, wherein the psychiatric disorder comprises bipolar disorder, schizophrenia, attention deficit hyperactivity disorder, or depression.

7. 6. The use of claim 5, wherein the disease associated with neuronal apoptosis or neurodegeneration includes stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis / Parkinsonism-dementia complex, Wilson's disease, multiple sclerosis, progressive supranuclear palsy, corticobasal degeneration, dementia, amyotrophic lateral sclerosis, epilepsy, transient ischemic attack, myocardial ischemia, head injury, spinal cord injury, or hypoxia.

8. 2. The use according to claim 1, wherein the effective amount of valproic acid is in the range of 500 to 2500 mg / day.

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