JP2000095695A - Therapeutic agent for schizophrenia - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent for schizophrenia, effective against every schizophrenia in adolescence, and hardly causing side effects by including an adenosine phosphate ester (salt) as an active ingredient. SOLUTION: The objective therapeutic agent contains an adenosine phosphate ester (salt) as an active ingredient. Adenosine monophosphate, adenosine diphosphate and adenosine triphosphate are cited as the adenosine phosphate ester. The salt thereof is preferably an alkali metal salt, especially a sodium salt. A tablet, a granule, an enteric tablet or the like is cited as the form of the therapeutic agent. An oral medicine in an amount of a daily dose of 30-720 mg is preferably administered by dividing the dose into 1-3 times. Preferably an injection medicine in 5-100 mg per dose is intravenously injected once or twice a day, or the one in 20-160 mg per dose is injected y intravenous drip. In the case of intramuscular administration and subcutaneous administration, 5-100 mg per dose of the therapeutic agent is administered once or twice a day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a drug for treating schizophrenia.

[0002]

2. Description of the Related Art Various mental disorders and adjustment disorders are seen in adolescence, and the most serious and serious problem is said to be schizophrenia. The lower the age of onset, the more severe the decline in activity, lack of age-appropriate interest, autism, dull emotion, threatening / threatening attachment, regressive and so-called negative symptoms. Schizophrenia is a complex disease that remains unclear, and presents a variety of symptoms.

[0003] Conventionally, the prognosis has been poor for young onset patients, but Eggers et al. (Eggers, C .: J. Autism. Child Schi
z., 8: 21-36, 1978) before the introduction of antipsychotics and in Stu
(Stutte, H., Med. Klin., 58: 526-529, 1963) conducted a prognostic study of adolescent schizophrenia using drugs.
He reported remission and remission was better than expected, around 50%.

[0004] However, antipsychotics include central nervous system, extrapyramidal symptoms and autonomic nervous system, as well as endocrine systems such as obesity and lactation, allergic symptoms such as liver disorders and skin symptoms.
In addition, there are various side effects such as cardiac and vascular disorders or teratogenic effects such as sudden death. Especially in adolescent schizophrenia, there is concern that irreversible brain damage may be caused by continuous administration of antipsychotics. Is done. Gross et al. (Gross, H., Kaltenback,
E .: Zentralbl. Ges, Neurol. Psychiat., 188, 400, 1
996) in patients given continuous dosing over several years.
He reports that glial proliferation and fatty degeneration were observed in the diffuse cortex, especially in the basal ganglia and midbrain. Although the possibility of antipsychotics causing brain alterations in this way cannot be ruled out, at present we cannot afford to slow down schizophrenia drug therapy. With the exception of some, schizophrenics and their families must fight not only the disease but also the painful and unexpected side effects of antipsychotics. Given that the drug sometimes causes long-term or irreversible or rarely fatal changes even if the mental symptoms disappear, it is necessary to provide as delicate and rational drug therapy as possible (Kazuhiko Nakayama, Naotaka Yoshimuta, Neuropsychiatry, 15 (6), 325-331 (199
3)).

[0005] With respect to anti-schizophrenia drugs for adolescents, which are generally fragile both mentally and physically and are considered to be in the process of development, the emergence of more effective drugs with few side effects has been observed from the viewpoint of not only the main effects but also side effects. Is desired.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug which is effective for the desired schizophrenia and has few side effects.

[0007]

[Means for Solving the Problems] The brain nervous system is the most highly differentiated tissue in a living body, and neurons that form a network and glial cells that support the function cooperate to integrate biological functions. . Sugar chains have an enormous amount of information, and it is presumed that they play an important role in the communication of these mental systems along with the immune system. Thus, the present inventors have conducted intensive studies to elucidate the role of sugar chains in the nervous system, and found that α-1,3 fucose transferase activity in schizophrenic patients is lower than that in healthy individuals. did. Then, when adenosine triphosphate (ATP) was added to the measurement system of α-1,3 fucose transferase activity and the measurement was performed, it was found that the increase was 1.3-fold in a healthy person. ,
The increase in schizophrenic patients was found to reach up to five-fold.

[0008] The increase in α-1,3 fucose transferase activity by adenosine triphosphate was also observed with adenosine monophosphate and adenosine diphosphate.

In order to solve the above problems, the present inventor has proposed an adenosine phosphate, which is clinically used as a cerebral metabolic activator or for increasing blood flow in various organ tissues due to vasodilatory action. When an ester or a salt thereof was applied to a schizophrenic patient, it was confirmed to be useful, and the present invention was completed.

That is, the present invention provides a remedy for schizophrenia containing adenosine phosphate or a salt thereof as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Adenosine phosphate or a salt thereof is used clinically for the purpose of increasing the blood flow of various organs by cerebral metabolic activators and vasodilators, but is effective for schizophrenia. There is no report.

As the adenosine phosphate, adenosine monophosphate, adenosine diphosphate and adenosine triphosphate are mentioned as described above. As the salts thereof, alkali metal salts, particularly, sodium salts are preferable. Further, these active ingredients may be used alone or in combination of two or more.

Examples of the form of the therapeutic agent of the present invention include oral preparations such as tablets, granules and enteric coatings and injections, and these forms are already commercially available and can be used as appropriate.

In general, it is preferable to take a daily dose of 30 to 720 mg daily in 1 to 3 divided doses. For injection, 5 to 100 mg once or twice a day or 20 to 1 once a day
A method in which 60 mg is injected intravenously is preferred. For intramuscular administration or subcutaneous administration, it is preferable to administer 5 to 100 mg once or twice a day.

[0015]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 20 healthy subjects and 35 schizophrenic patients (3 non-medicated patients)
Using plasma obtained according to a conventional method, α-1,
3 Fucose transferase activity was measured. (Reaction solution: total volume 50 μl) ・ Plasma 10 μl ・ HEPES-NaOH Buffer (pH 7.0) 4 μmol / 10 μl ・ MnCl ₂ 1 μmol / 10 μl ・ Sugar receptor (2 ′ FucLacNAcβBn: Anal. Biochem., 152: 22-28, 1986) (Fucα1 → 2Galβ1 → 4GlcNAcβ1Bn) 10 nmol / 10 μl Sugar donor (GDP- [ ³ H] fucose; manufactured by Dupont) 78,000 dpm / 10 μl After keeping the reaction solution at 37 ° C. for 16 hours, 100 μl ethanol is added to carry out the reaction. After stopping, a centrifugal supernatant (reaction liquid) was obtained. Products in the reaction solution:

[0017]

Embedded image

[0018] Sep-Pak Plas C18 (Waters)
Separated and extracted using Radioactivity was measured using a liquid scintillation counter, and the activity was determined as α-1,3 fucose transferase activity. The results are shown in FIG.

The α-1,3 fucose transferase activity of a healthy subject was 7,972.94 ± 3,092.8 (mean ± SD).
In schizophrenic patients, 1,71
It was 4.0 ± 1,039.7 (mean ± SD) dpm, and it was revealed that α-1,3 fucose transferase activity in the plasma of the patient was extremely low.

Next, when measuring the activity of α-1,3 fucose transferase in the plasma of 14 healthy subjects and 26 schizophrenic patients, 0.2 μmol of adenosine triphosphate was added to the above reaction system. Measured similarly. The results are shown in FIG.

As a result, when adenosine triphosphate is added in the measurement of the α-1,3 fucose transferase activity, the α-1,3 fucose transferase activity of a healthy subject can be reduced to 1
In the case of schizophrenia patients, it was 8,512 ± 5,366 compared to 0,523 ± 3,323 (mean ± SD) dpm.
(Mean ± SD) dpm, α in plasma of schizophrenic patients
It was found that when adenosine triphosphate was added during the measurement of -1,3 fucose transferase activity, α-1,3 fucose transferase activity was increased about 5-fold, and the difference from healthy subjects was reduced.

Example 2 Accordingly, the inhibitory effect of adenosine phosphate on the degradation activity of GDP-fucose was examined. (Reaction solution: total volume 50 μl) ・ Plasma 10 μl ・ HEPES-NaOH Buffer (pH 7.0) 4 μmol / 10 μl ・ MnCl ₂ 1 μmol / 10 μl ・ GDP- [ ³ H] fucose Dilute stock solution 10-fold with DDW ・ GDP-fucose 10 μmol Adenosine phosphate ester 0.2 μmol / 10 μl (AMP, ADP or ATP) The reaction solution was kept at 37 ° C. for 2 hours, ethanol was added to stop the reaction, and a centrifuged supernatant (reaction solution) was obtained. Decomposition products in the reaction solution: [ ³ H] fucose was separated by developing the reaction solution by paper chromatography. Radioactivity was measured using a liquid scintillation counter, and the activity was defined as Hydrolase activity.
The result is shown in FIG.

It has been clarified that the GDP-fucose degradation activity in plasma of schizophrenic patients is blocked by any of adenosine monophosphate, adenosine diphosphate and adenosine triphosphate. Further, when 0.2, 0.5 and 1.0 μmol of adenosine triphosphate were added to the above reaction system and the concentration dependence was examined, the adenosine triphosphate GDP-fucose degrading enzyme was found as shown in FIG. Concentration dependence was observed in the inhibitory effect.

Example 3 To five patients diagnosed with schizophrenia according to the diagnostic criteria according to ICD-10, 60 mg of adenosine triphosphate was orally administered daily for 2 to 6 weeks, and the clinical symptoms of the patients were evaluated by BPRS (Brief Psyc
hiatric Rating Scale). As shown in Table 1, symptom improvement was observed in 3 out of 5 cases in the comprehensive evaluation of BPRS. As shown in FIG. 3, α-1,3 fucose transferase activity in plasma was measured.
An increase in 1,3 fucose transferase activity was observed. Of the three cases whose symptoms were improved, two cases showed an increase in α-1,3 fucose transferase activity.

[0025]

[Table 1]

As is clear from Table 1 and FIG. 3, when 5 patients with schizophrenia were continuously administered with adenosine triphosphate for 2 to 6 weeks, an increase in α-1,3 fucose transferase activity was observed in 3 of 5 cases. The patient's symptoms improved.

Example 4 In a patient diagnosed with schizophrenia according to the diagnostic criteria according to ICD-10, 5 cases of adenosine triphosphate administration group of 180 mg / day and 5 cases of 360 mg / day administration group were orally administered for 4 consecutive weeks. After administration, the patient's clinical symptoms were evaluated before and after the administration based on the total score of BPRS. As a result, in a dose-dependent manner, 40% in the 180 mg / day administration group (2 out of 5 cases) and 80% in the 360 mg / day administration group
(4 out of 5 cases) improved the symptoms.

[0028]

According to the present invention, various symptoms of schizophrenia can be improved and side effects are extremely small.

[Brief description of the drawings]

FIG. 1. AT in healthy subjects (a) and schizophrenic patients
It is a figure which shows the change of the blood alpha-1,3 fucose transferase activity by P administration.

FIG. 2 shows the GDP-fucose degradation activity of adenosine phosphate (a) and the GDP-fucose degradation activity in plasma of schizophrenic patients (b).

FIG. 3 is a graph showing the effect of adenosine phosphate on α-1,3 fucose transferase activity in plasma of schizophrenic patients.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Shoichi Adachi 3493-9 Ishiharacho, Takasaki City, Gunma Prefecture

Claims (2)

[Claims] 1. A therapeutic agent for schizophrenia comprising an adenosine phosphate or a salt thereof as an active ingredient. 2. The remedy for schizophrenia according to claim 1, wherein the adenosine phosphate or a salt thereof is at least one selected from adenosine monophosphate, adenosine diphosphate, adenosine triphosphate and salts thereof. .