JP2002020291A - Therapeutic agent for cognitive dysfunction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine effective for recovering cognitive function in schizophrenia so as to improve QOL of schizophrenic and to promote rehabilitation. SOLUTION: This therapeutic agent for cognitive dysfunction uses tandospirone or its pharmacologically acceptable salt as an active ingredient. The therapeutic agent can also be used together with a dopamine D2 receptor blocking agent and/or a serotonin HT2 receptor blocking agent and/or a serotonin-dopamine blocking agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for cognitive impairment in schizophrenia, and more particularly, to a therapeutic agent for cognitive impairment in schizophrenia containing tandospirone or a pharmacologically acceptable salt thereof as an active ingredient. The invention relates to the use of a therapeutic agent, as well as tandospirone or a pharmaceutically acceptable salt thereof, for the treatment of cognitive dysfunction in schizophrenia.

[0002]

2. Description of the Related Art Schizophrenia (hereinafter sometimes abbreviated as schizophrenia) has a high morbidity of about 1% of the general population and is one of the major diseases in the field of psychiatry and neurology. For schizophrenia, administration of antipsychotics is currently established as the most useful treatment. Until now, treatment with antipsychotics has been mainly aimed at reducing positive symptoms of schizophrenia such as hallucinations and delusions, and the degree of improvement using several clinical symptom evaluation scales has been used as an index of therapeutic effect. However, in order to promote schizophrenia patients' rehabilitation and improve their quality of life, it is necessary to reduce the negative symptoms of schizophrenia, such as decreased motivation and flattening of emotions, as well as cognitive dysfunction, which is also called the core symptom of schizophrenia Is done. Improving cognitive functions and emotional disorders, especially short-term memory, attention, language, etc., are indispensable factors for memorization and operation of telephone numbers, regular outpatient reception, taking prescription drugs, and returning to a smooth workplace after hospitalization. It is being recognized as. However, the treatment of these disorders is extremely difficult, and no drug has been found to be fully effective.

[0003] Typical antipsychotics, such as haloperidol and chlorplumazine, which have been conventionally used as first-line drugs for the treatment of schizophrenia, have excessive midbrain-limbic dopamine neurons due to potent dopamine D ₂ receptor blocking action. Suppression of transmission is regarded as its pharmacological mechanism of action, and an effect of improving positive symptoms of schizophrenia has been recognized. However, these drugs have only limited effects on negative symptoms and cognitive function, or may even exacerbate them. On the other hand, atypical antipsychotics such as clozapine and risperidone, which have been used relatively recently, have few adverse reactions such as extrapyramidal symptoms that occur frequently when typical antipsychotics are administered, and negative symptoms In recent years, it has been clarified that some cognitive functions have been improved. Such a feature of atypical antipsychotics is a potent serotonin 5-H
T ₂ receptor blocking action and moderate dopamine D ₂ receptor blocking action, ie, a serotonin-dopamine blocker (S
The dominant hypothesis of pharmacological properties as DA) is currently the most influential [Sumiyoshi T, Suzuki K, Sak
amoto H, Yamaguchi N, Mori H, Shiba K, YokogawaK),
Neuropsychopharmacology 1995, 12, pp 57-64].

[0004] In the treatment of schizophrenia, the necessity of a positive symptom ameliorating effect by a limbic dopamine D ₂ receptor blocking effect or a negative symptom or a cognitive function improving effect by a serotonin 5-HT ₂ blocking effect is considered for each schizophrenia. differ in their relative proportions as the condition of the patient, the ideal limit of obtaining the 5-HT ₂ / D ₂ receptor blocking effect of the balance has also been pointed out [Kapur and Remington in any patient with a single drug (KapurS, Remington G); Am. J. Psychi
atry, 1996; 153, pp. 466-76]. In addition, clozapine may cause agranulocytosis as a serious side effect, and risperidone, which has a strong D ₂ receptor receptor blocking effect, may cause extrapyramidal symptoms such as extrapyramidal symptoms as well as typical antipsychotics at high doses. Expression can occur.

Tandospirone has the chemical name (1R, 2S,
3R, 4S) -N- [4- [4- (2-pyrimidinyl) -1-
Piperazinyl] butyl] -2,3-bicyclo [2.2.1] heptanedicarboximide, a recently developed 5-
It is an HT _1A receptor agonist, and its production method and anxiolytic effect are described in JP-A-58-126865. In addition, the citrate is already commercially available as a serotonergic anxiolytic. In addition, 4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl-substituted dicarboximide compound similar to tandospirone is used.
-[4- (2-pyrimidinyl) -1-piperazinyl) -1-
Piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione (generic name buspirone) or a pharmaceutically acceptable salt thereof has been clinically used as a short-term memory improving agent, In addition, various patients for other drugs,
For example, it has been reported that the present invention has been applied to elderly patients, Alzheimer's disease patients, and cognitive dysfunction patients to improve cognitive function (US Pat. No. 4,687,772).

[0006]

SUMMARY OF THE INVENTION QO of schizophrenic patients
Development of new drugs useful for restoring cognitive function in schizophrenia in order to improve L and promote social rehabilitation has been desired. In particular, dopamine D ₂ receptor blockers and serotonin 5-HT ₂ receptors have been desired. There is a need for the development of new drugs that can improve cognitive function in schizophrenic patients in combination with blockers.

[0007]

The present inventors have discovered that tandospirone, which is marketed as an anxiolytic, has a beneficial effect on the memory of chronic schizophrenic patients, and that tandospirone or its pharmacologically Acceptable salts are useful in the treatment of cognitive dysfunction in schizophrenia, especially while maintaining maintenance therapy with typical antipsychotics such as haloperidol, a common antipsychotic, while taking tandospirone or its pharmacological The present inventors have found that administration of an acceptable salt can improve cognitive dysfunction and completed the present invention.

That is, an object of the present invention is to provide a therapeutic agent for cognitive dysfunction in schizophrenia, comprising tandospirone or a pharmacologically acceptable salt thereof as an active ingredient. Another object of the invention is the use of tandospirone or a pharmacologically acceptable salt thereof for the treatment of cognitive dysfunction in schizophrenia, in particular dopamine D ₂
Receptor blockers and / or serotonin 5-HT ₂ receptor in maintenance therapy by blockers tandospirone or a pharmaceutically acceptable for the treatment of cognitive dysfunction in schizophrenia of jointly using a salt thereof Provide use.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The therapeutic agent for cognitive dysfunction according to the present invention contains tandospirone or a pharmacologically acceptable salt thereof as an active ingredient. Pharmaceutically acceptable salts of tandospirone include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, butyrate, tartrate, citrate, maleic acid Salts and salts with organic acids such as fumarate are included, and among them, citrate is preferred.

The therapeutic agent of the present invention can be administered orally or parenterally. That is, it can be orally administered in a commonly used dosage form, for example, a tablet, capsule, sublingual tablet, syrup, suspension or the like. Or,
The liquid form can be administered parenterally as an injection. It can also be administered rectally in the form of a suppository. The above dosage forms can be produced by mixing tandospirone or a pharmacologically acceptable salt thereof with acceptable ordinary carriers, excipients, binders, stabilizers and the like. When used as an injection preparation, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dose of the therapeutic agent of the present invention, the number of times of administration varies depending on the patient's symptoms, age, body weight, dosage form, etc., but in the case of oral administration, usually for adults, approximately 10 to 60 mg per day as tandospirone, Preferably, 20 to 40 mg can be administered.

Tandospirone or its pharmacology according to the present invention
Of cognitive dysfunction using biologically acceptable salts as active ingredients
Therapeutic agents are dopamine, commonly used to treat mental illness.
D _TwoHaloperidol, a receptor blocker, chlorpula
Typical antipsychotics such as mazine, or serotonin 5-H
T_TwoReceptor blockers such as clozapine and risperidone
Atypical antipsychotics, and even antiparkin such as piperidene
To be used in combination with maintenance therapy such as a treatment for Song's disease
When used with such other drugs,
Is about the same as or higher than the dose for single administration above
Also, a slightly smaller amount is used.

[0012]

EXAMPLES Experimental examples and preparation examples of the therapeutic agent for cognitive dysfunction of the present invention are shown below.

Experimental Example The effect of tandospirone administration was examined on 5 outpatients (men / women = 3: 2, ages 16-40) who were on treatment with schizophrenia and met DMS-IV criteria. All patients were treated with antipsychotics (haloperidol, dose: 4.15 ± 2.
75 mg / day) and piperidene (dose (equivalent to benzotropine): 2.80 ± 0.8) as an anti-Parkinson's disease therapeutic agent
4 mg / day) for at least 3 months. The average (SD) age of the patients was 27.8 (8.7) years and had completed 12.4 ± 2.2 years of education. The onset period was 5.9 ± 5.1 years and the age of onset was 22.0 ± 4.4 years. Diagnosis was based on interviews and medical history with an experienced psychiatrist. Patients with a history of abuse of alcohol and other psychostimulant drugs, or with epilepsy, brain damage, or neuropathy, were excluded from the study. After basic assessment of psychopathology and memory function, patients were started on oral administration of tandospirone (30 mg / day, administered three times daily). The dose of tandospirone was kept constant for 4 weeks. All other psychotropic drugs were continued unchanged during the study.

[0014] Wechsle memory scale revised edition (Wechsle
r Memory Scale-Revised (WMS-R) was used to calculate the memory function before administration of tandospirone (basal value) and 4 weeks after the start of administration. Eight subtests from the WMS-R were performed each time by a trained clinical psychologist unaware of the subject's medication status; Logical Memory I
And language versus associative learning I (linguistic memory), graphic memory, visual versus associative learning I and visual reproduction I (visual memory), mental control, numeration and visual memory range (attention / concentration). To exclude the effects of the practice effects, six healthy males (mean ± SD age = 23.0 ± 3.3, range 20-29 years, education, 15.3
(± 4.1 years), the WMS-R subtest was performed twice at four-week intervals. Brief Psychiatric Rating Scale (Brief Psy
18-item version of the chiatric rating scale (BPRS; 0-6 scale) and extrapyramidal symptoms for the evaluation of side effects
(Simpson Angus Scale; SAS) for (Extrapyramidal Symptoms) was performed by an experienced psychiatrist who was not informed of the medication status and the results of the memory function test at the time of conducting the WMS-R test. The interrater reliability of these measurements is 0.80.
That was all. Between subjects facto
r), repeated measures variance [variate] analysis (ANOV) for diagnosis (tandospirone-treated versus control subjects)
A) and the within-subjects factor
The effect of tandospirone on each measurement of the WMS-R test was evaluated using the time of the test (when calculating the basal value versus 4 weeks later). WMS-R test at baseline and 4 weeks later, BPRS score (total, positive and negative scores,
Comparisons between measurements of the "depression", "anxiety" subscales) and SAS scores were made using the Wilcoxon signed rank test. Table 1 shows the results.

[0015]

[Table 1]

As is clear from Table 1 above, there was no significant difference in the average values of the age and the duration of education between tandospirone-administered patients and normal control subjects (data not shown). Diagnosis × time effect is language vs. associative learning (F =
8.32, df = 1.9, p = 0.02) and visual memory range (F = 5.79, df = 1.9, p = 0.05) were significant in each subtest. Furthermore, there was a significant trend in the diagnosis × time effect in each of the subtests of visual versus associative learning, logical memory, numeration and visual reproduction. That is, administration of tandospirone for 4 weeks increased the score of language versus associative learning by 32.5% in schizophrenic patients, and
9.2%), visual versus associative learning (31.6%) and visual regeneration
(4.3%) showed an improvement trend in the subtest. On the other hand, no such change was observed in control subjects. In contrast, control subjects had several singers (10
%) And visual memory range (20.8%) showed good scores 4 weeks after basal measurement, but these scores were unchanged in schizophrenic patients. In schizophrenic patients receiving tandospirone, BP
There were no significant changes in RS scores (total, positive, negative scores, and subtests for depression and anxiety) and SAS scores.

As shown in the above results, the scores of the vocal and visual memory subtests, which reflect the attention / concentration function of the WMS-R test, were week 4 when compared to basal values only in control subjects. Slightly increased. On the other hand, in the schizophrenic group, the scores of the vocal and mental control subtests when retested at 4-week intervals did not change, indicating that chronic psychiatric patients receiving continuous administration of typical antipsychotics were not affected. Schizophrenic patients underwent WMS testing twice at the same 4-week interval, consistent with previous studies at other centers.

Tandospirone administration improved WMS-R subtest scores related to memory function in schizophrenic patients. This effect was most pronounced in verbal memory scores.

There are at least two possible mechanisms for explaining the effect of tandospirone on memory function in schizophrenia. One is, as described above, 5-HT
Promotion of DA transmission function in the cerebral cortex through regulation of serotonergic nervous system activity by acting on _1A autoreceptors. The other is the direct effect of tandospirone on the postsynaptic 5-HT _1A receptor in the cerebral cortex or hippocampus. Postmortem brain studies of increased cerebral cortex 5-HT _1A receptors suggest that postsynaptic serotonin neurotransmission abnormalities are present in schizophrenic patients. Thus, tandospirone, which acts as an agonist at the postsynaptic 5-HT _1A receptor, may regulate some areas of cognitive function in schizophrenic patients by normalizing serotonin neurotransmission in the cerebral cortex and / or hippocampus. It is also thought to improve. Furthermore, there is a report that a 5-HT _1A agonist enhances acetylcholine neurotransmission in the cerebral cortex, which may be related to the effect of tandospirone on improving the memory function.

As shown by the BPRS and SAS scores, there was no significant change in psychiatric and extrapyramidal symptoms with tandospirone in this study, but a study of a larger number of subjects showed that schizophrenia The efficacy of tandospirone for psychiatric and / or extrapyramidal symptoms in sick patients may be apparent. In conclusion, a preliminary study conducted in a small number of subjects showed that the use of a 5-HT _1A agonist in combination with antipsychotic treatment was effective in ameliorating some of the memory deficits in schizophrenic patients. It was suggested that there is.

Formulation Examples 1-3 Preparation of Film-coated Tablets According to the formulation shown in Table 2, pulverized tandospirone citrate, lactose, corn starch and carmellose calcium were charged into a fluid bed granulator, and polyvinyl alcohol (partial). An aqueous solution of saponified product is sprayed to granulate and sized to produce granules. Magnesium stearate is added to the granules, mixed, and tabletted to form tablets. To this tablet were added hydroxypropyl methylcellulose 2910, concentrated glycerin, yellow iron sesquioxide (5 mg
Film-coated tablets are produced by spraying a coating solution prepared from titanium oxide, carnauba wax and purified water.

[0022]

[Table 2] (Prescription)

Formulation Examples 4 to 6 Production of Film-coated Tablets According to the formulation shown in Table 3, pulverized tandospirone citrate, lactose, corn starch and low-substituted hydroxypropylcellulose were charged into a fluid bed granulator, and povidone was added. An aqueous solution (K value: 30) is sprayed to granulate and sized to produce granules. Magnesium stearate is added to the granules, mixed, and tabletted to form tablets. To this tablet were added hydroxypropyl methylcellulose 2910, concentrated glycerin, yellow iron sesquioxide (5 mg
(In the case of tablets only), a coating solution prepared from titanium oxide and purified water is sprayed to produce film-coated tablets.

[0024]

[Table 3] (Prescription)

Formulation Example 7 Production of Fine Granules A pulverized product of tandospirone citrate, lactose, and corn starch are mixed, a corn starch aqueous solution is heated and gelatinized, kneaded, extruded, dried, and sized. Produce fine granules.

Formulation Example 8 Preparation of Sustainable Granules According to the formulation shown in Table 4, a pulverized product of tandospirone citrate, lactose and corn starch are mixed, kneaded by adding an aqueous solution of polyvinyl alcohol (partially saponified), and extruded. It is molded, sized with a marmellaizer, and dried to produce granules. The obtained granules are charged into a fluidized bed coating machine, and sprayed with a coating solution comprising ethyl cellulose, hydroxypropyl methyl cellulose 2910, methylene chloride and ethanol to obtain persistent granules.

[0027]

[Table 4] (Prescription)

[0028]

Industrial Applicability Tandospirone or a pharmacologically acceptable salt thereof is used in schizophrenic patients, in particular, dopamine D ₂
When administered to a patient being treated with a receptor blocker, a serotonin 5-HT ₂ receptor blocker, SDA, or the like, it has an effect of improving memory function and the like, and is useful for treating cognitive dysfunction in schizophrenia. is there.

Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 43/00 114 A61P 43/00 114 // C07D 403/12 C07D 403/12

Claims (4)

[Claims] 1. A therapeutic agent for cognitive dysfunction in schizophrenia, comprising tandospirone or a pharmacologically acceptable salt thereof as an active ingredient. 2. The therapeutic agent according to claim 1, wherein the active ingredient is tandospirone citrate. 3. Use of tandospirone or a pharmaceutically acceptable salt thereof for the treatment of cognitive dysfunction in schizophrenia. 4. Use according to claim 3, in combination with a dopamine D ₂ receptor blocker and / or a serotonin 5-HT ₂ receptor blocker and / or a serotonin-dopamine blocker (SDA).