Application of composition in preparation of medicine for improving cognitive ability

Abstract

The invention provides application of a composition in preparation of a medicine for improving cognitive competence of an individual. The effective component of the composition comprises dextromethorphan and / or valproic acid.

Description

Technical Field

[0001] The present invention provides use of a composition in preparing a drug for improving an individual's cognitive ability, characterized in that dextromethorphan or valproic acid, or a combination of dextromethorphan and valproic acid is used for treatment. Background Art

[0002] Bipolar disorder is a severe and disabling mental illness encompassing a broad range of clinical manifestations characterized by mood disturbances, specific risk-taking behaviors, impulsivity, interpersonal difficulties, and depressive symptoms. Bipolar disorder can be categorized into four types: bipolar I, bipolar II, cyclothymia, and other unspecified mood disorders.

[0003] Bipolar II is characterized by recurrent episodes of depression and hypomania. However, Bipolar II is often misdiagnosed because patients often experience depressive symptoms, while hypomanic episodes are often brief and less pronounced. Consequently, patients often fail to mention these symptoms during consultations, and doctors neglect to carefully inquire about their medical history, often overlooking the condition. Consequently, patients with Bipolar II often receive an inaccurate diagnosis and, even less effective treatment. Compared to patients with Bipolar I, patients with Bipolar II have the same or a higher risk of suicide, more frequent mood symptoms, and more comorbid depressive episodes.

[0004] Many studies have shown that bipolar patients have extensive neuropsychological impairments during the symptomatic phase, including executive function, attention maintenance, working memory, verbal memory, verbal fluency, cognitive flexibility, abstract reasoning and visual-motor skills, visual-spatial ability, and general cognitive function.

[0005] Therefore, how to improve the neuropsychological impairment of bipolar patients is a major issue in clinical treatment. Summary of the Invention

[0006] As used herein, the terms "a" or "an" are used to describe elements and components of the present invention. This is merely for convenience and to give a general sense of the present invention. This description should be understood to include one or at least one, and the singular also includes the plural unless it is obvious that it means otherwise.

[0007] As used herein, the term "or" is used to describe "and / or".

[0008] As used herein, "cognitive ability" refers to the intellectual process of becoming aware, perceiving, or understanding an idea. Cognitive function involves all states of perception, thinking, reasoning, memory, and attention. In some embodiments, the cognitive ability includes global cognitive function, sustained cognition, memory, language, executive function, and sustained attention.

[0009] The present invention provides a use of a composition in preparing a drug for improving an individual's sustained attention, wherein the active ingredient of the composition comprises dextromethorphan.

[0010] In addition, the present invention also provides a use of a composition for preparing a drug for improving memory in an individual, wherein the active ingredient of the composition comprises valproic acid or a pharmaceutically acceptable salt thereof.

[0011] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals and do not cause undue toxicity, irritation, or allergic reactions, within a reasonable benefit / risk ratio. In one embodiment, the pharmaceutically acceptable salt of valproic acid comprises sodium valproate.

[0012] In the present invention, dextromethorphan can also improve a subject's memory. Therefore, taking valproic acid together with dextromethorphan also has the therapeutic effect of improving the subject's memory. In some embodiments, the active ingredient of the composition for improving the subject's memory further comprises dextromethorphan.

[0013] In another embodiment, the memory comprises verbal memory, spatial memory, immediate memory, delayed memory and working memory.

[0014] As used herein, the term "improve" refers to not only increasing cognitive function (sustained attention and memory) but also slowing, halting or reversing the progression of cognitive deficits.

[0015] In one embodiment, the individual is a normal individual or a normal human.

[0016] In other embodiments, the individual suffers from a mental illness, or a disease related to neuronal apoptosis or neurodegeneration. In some preferred embodiments, the mental illness comprises bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD), or depression. In some preferred embodiments, the disease related to neuronal apoptosis or neurodegeneration comprises stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob's disease, Parkinson's-ALS-dementia complex, Wilson's disease, multiple sclerosis, progressive supranuclear palsy, corticobasal degeneration, dementia, amyotrophic lateral sclerosis, epilepsy, transient ischemic attack, myocardial ischemia, muscular ischemia, head injury, spinal cord injury, or hypoxia. In other embodiments, the individual suffers from bipolar disorder. In some preferred embodiments, the bipolar disorder is bipolar II. In some aspects, the subject's deterioration or decline in sustained attention or memory is caused by affective disorders and neurological conditions, or degeneration or apoptosis of nerve cells.

[0017] As used herein, the term "subject" refers to an animal. In some preferred embodiments, the subject is a mammal. In some more preferred embodiments, the subject is a human.

[0018] As used herein, the term "effective dose" refers to the dose of a pharmaceutical ingredient that substantially induces, promotes, or results in the desired therapeutic effect. In the present invention, the effective dose of dextromethorphan is less than 30 mg per day. In some specific embodiments, the effective dose of dextromethorphan is 0.1-30 mg / day. In some preferred specific embodiments, the effective dose of dextromethorphan is 0.5-25 mg / day. In some more preferred specific embodiments, the effective dose of dextromethorphan is 1-20 mg / day. Therefore, the effective dose of dextromethorphan administered can achieve a dextromethorphan concentration in the individual's plasma of 10-50 ng / ml (0.05-0.2 μM).

[0019] In other embodiments, the effective dose of sodium valproate is 0.1-2500 mg / day. In some preferred embodiments, the effective dose of sodium valproate is 100-2000 mg / day. In some more preferred embodiments, the effective dose of sodium valproate is 500-1000 mg / day. Thus, the effective dose of sodium valproate administered can achieve a sodium valproate concentration in the subject's plasma of 50-100 μg / dL.

[0020] The drug of the present invention also includes 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 drug ingredient, but does not itself have a therapeutic effect and does not induce or cause unpleasant or unexpected effects or adverse reactions in the individual. Therefore, the active ingredient of the present invention (dextromethorphan or valproic acid) can be easily formulated into a dosage suitable for oral administration using pharmaceutically acceptable carriers well known in the art, which is also preferred for the implementation of the present invention. Such carriers can be formulated into dosage forms such as tablets, lozenges, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral intake by the patient to be treated. These carriers can be selected from sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered saline, emulsifiers, isotonic saline and pyrogen-free water.

[0021] In some aspects, when the composition is prepared in the form of a tablet or lozenge, the unit dose of dextromethorphan contained in each tablet or lozenge is 0.1, 0.5, 1, 5, 10, or 15 mg. The design of the above-mentioned unit dose of dextromethorphan allows the individual to approach or achieve the effective daily dose of dextromethorphan of less than 30 mg by taking one or two tablets / lozenges per day. In addition, the unit dose of sodium valproate contained in each tablet or lozenge is 0.1, 10, 50, 100, 250, 500, or 1000 mg. The design of the above-mentioned unit dose of sodium valproate allows the individual to approach or achieve the effective daily dose of 0.1-2500 mg of sodium valproate by taking one or two tablets / lozenges per day.

[0022] In various embodiments, the drug is in a form suitable for administration by a route selected from parenteral, transdermal, oral and topical. In some preferred embodiments, the drug is administered orally.

[0023] In some embodiments, the drug is administered daily for at least one week. In some preferred embodiments, the drug is administered daily for at least two weeks. In some more preferred embodiments, the drug is administered daily for at least four weeks. In other embodiments, the drug is administered daily for at least six weeks. In some preferred embodiments, the drug is administered daily for at least eight weeks. In other embodiments, the drug is administered continuously for at least 12 weeks. DETAILED DESCRIPTION

[0024] The embodiments of the present invention may have different implementation contents and are not limited to the examples given below. The following embodiments only represent various aspects and features of the present invention.

[0025] The present invention recruited patients diagnosed with bipolar II disorder (BD-II). All patients were diagnosed by psychiatrists and confirmed to meet the integrated criteria for bipolar II in the DSM-IV-TR using the Chinese version of the modified Schedule of Affective Disorder and Schizophrenia-Lifetime (SADS-L) with good inter-rater reliability and the diagnostic categories in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).

[0026] The purpose of the present invention is to test whether dextromethorphan (DM) and sodium valproate (trade name: Depakine) can improve the cognitive ability of patients. Therefore, the present invention first divides patients with type II bipolar disorder into two groups: one group is the group that takes dextromethorphan and sodium valproate together (BD DM ), and the other group took sodium valproate and placebo (BD Pl Before each group of patients took the medication, the present invention first used the following assessment test to conduct a basic assessment on the two groups of patients.

[0027] (A) Efficacy evaluation test:

[0028] (1) Hamilton Depression Rating Scale (HDRS)

[0029] For bipolar patients in the depressive phase, the severity of depressive symptoms was assessed using the Hand Depression Scale (HDS) at baseline and at each follow-up visit during the trial. This 17-item version of the HDS was used, including depressive mood, guilt, suicidal thoughts, early-onset insomnia, mid-onset insomnia, late-onset insomnia, work and activity status, sluggishness, irritability, mental anxiety, physical anxiety, gastrointestinal symptoms, general physical symptoms, reproductive symptoms (e.g., decreased libido, menstrual irregularities), anxiety, weight loss, and a sense of illness.

[0030] (2) Young Mania Rating Scale (YMRS)

[0031] For bipolar patients experiencing hypomania or mania, the severity of their manic symptoms was assessed using the Young Mania Scale (YMRS) at baseline and at each follow-up visit during the trial. The YMRS, which can be used to assess any manic episode, consists of 11 items: elevated mood, increased activity and energy, sexual interest, sleep, irritability, speech (rate and volume), speech-thought disturbances, thought content, disruptive-aggressive behavior, appearance, and perception of illness.

[0032] (B) Neuropsychological test:

[0033] (1) Wechsler Memory Scale-III (WMS-III)

[0034] The present invention uses the Welsh Memory Scale-III (Chinese version), which measures multiple aspects of memory, including verbal memory, spatial memory, immediate memory, delayed memory, and working memory. These scores are presented as index scores that reflect the patient's multi-dimensional memory. The split-half reliability coefficients for the main indexes of the WMS-III (Chinese version) range from 0.74 to 0.96, with a median of 0.90. The average retest interval is 36.57 days, and the retest reliability coefficients for the main index scores range from 0.47 to 0.83, with a median of 0.71.

[0035] (2) Continuous Performance Test (CPT)

[0036] The present invention uses the computerized version of Conner's CPT II 20, which is used to assess patients' sustained attention. Conner's CPT II reliability measures show split-half reliability of 0.66-0.95, and retest reliability after three months of use of 0.55-0.84. The CPT has good reliability and validity for Han Chinese living in Taiwan.

[0037] The basic information of the patients on the baseline date obtained through the above assessment test is shown in Table 1.

[0038] Table 1. Comparison of demographic information of each group on the base date

[0039]

[0040] The two groups started taking medication. The group taking dextromethorphan and sodium valproate (BDDM The treatment course of the BD group was to take 1-30 mg of dextromethorphan and 500-2500 mg of sodium valproate daily for 12 weeks. Pl The treatment course (2 groups) consisted of daily doses of 500-2500 mg of sodium valproate and placebo for 12 weeks. At the end of the treatment period, plasma dextromethorphan concentrations were approximately 10-50 ng / ml (0.05-0.2 μM), and sodium valproate concentrations were approximately 50-100 μg / dL.

[0041] During treatment, patients in both groups returned for biweekly visits and took the Hansen Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). The Sustained Attention Test (CPT) and the Wedgman Memory Scale (WMS) were only administered at baseline and at week 12 of treatment. Therefore, efficacy assessments were conducted over a 12-week period.

[0042] During the 12-week efficacy tracking process, some patients were excluded from the present invention due to certain conditions and circumstances. Therefore, the efficacy evaluation results of the two groups after the 12-week treatment are shown in Table 2.

[0043] Table 2. Comparison of demographic information among groups at baseline and 12 weeks after treatment

[0044]

[0045]

[0046] It can be seen from Table 2 that the changes in HDRS and YMRS scores are not correlated with the changes in CPT and WMS scores, which means that dextromethorphan and sodium valproate can also be used to improve the cognitive ability of normal people.

[0047] From the scores of the Sustained Attention Test (CPT) in Table 2, we can see that BD Pl The sustained attention of the two groups (taking sodium valproate and placebo) did not improve after the end of the treatment. DM The group (taking dextromethorphan and sodium valproate) showed significant improvement in sustained attention after the treatment. Since the difference between the two groups was the dextromethorphan treatment, this result indicates that the improvement in sustained attention was due to the efficacy of dextromethorphan.

[0048] From the scores of the Wedgman Memory Scale (WMS) in Table 2, we can see that BD Pl The memory of the two groups (those taking sodium valproate and placebo) was significantly improved after the end of the treatment. DMThe group taking dextromethorphan and sodium valproate also showed significant improvements in memory after the treatment. This result indicates that taking sodium valproate or dextromethorphan alone, or using dextromethorphan and valproate together, can effectively improve memory.

[0049] Those skilled in the art will understand the above summary as a description of methods for conveying the information deposited herein. Those skilled in the art will recognize that these are merely illustrative and that many equivalents are possible.

Claims

1. Use of a composition for preparing a drug for improving sustained attention in an individual, wherein the active ingredient of the composition comprises dextromethorphan.

2. The use according to claim 1, wherein the individual suffers from a psychiatric disorder, or a disease associated with neuronal apoptosis or neurodegeneration.

3. The method of claim 2, wherein the psychiatric disorder comprises bipolar disorder, schizophrenia, attention deficit hyperactivity disorder, or depression.

4. The method of claim 2, wherein the disease associated with neuronal apoptosis or neurodegeneration comprises stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, Parkinson's-ALS-dementia complex, Wilson's disease, multiple sclerosis, progressive supranuclear palsy, corticobasal degeneration, dementia, amyotrophic lateral sclerosis, epilepsy, transient ischemic attack, myocardial ischemia, muscular ischemia, head injury, spinal cord injury, or hypoxia.

5. The method of claim 1, wherein the effective dose of dextromethorphan is 0.1-30 mg / day.

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

7. The method of claim 6, wherein the pharmaceutically acceptable salt of valproic acid comprises sodium valproate.

8. The use according to claim 6, wherein the composition further comprises dextromethorphan.

9. The method of claim 6, wherein the memory comprises verbal memory, spatial memory, immediate memory, delayed memory and working memory.

10. The use according to claim 6, wherein the individual suffers from a psychiatric disorder, or a disease associated with neuronal apoptosis or neurodegeneration.

11. The method of claim 10, wherein the psychiatric disorder comprises bipolar disorder, schizophrenia, attention deficit hyperactivity disorder, or depression.

12. The method of claim 9, wherein the disease associated with neuronal apoptosis or neurodegeneration comprises stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, Parkinson's-ALS-dementia complex, Wilson's disease, multiple sclerosis, progressive supranuclear palsy, corticobasal degeneration, dementia, amyotrophic lateral sclerosis, epilepsy, transient ischemic attack, myocardial ischemia, muscular ischemia, head injury, spinal cord injury, or hypoxia.

13. The use according to claim 6, wherein the effective dose of valproic acid is 0.1-2500 mg / day.

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