WO2010098475A1 - Agent for prevention and treatment of eating disorders - Google Patents

Abstract

Disclosed is an agent for prevention and treatment of eating disorders, which exhibits excellent preventive and curative effects on eating disorders without having side effects. Specifically disclosed is an agent for prevention and treatment of eating disorders, which contains, as an active ingredient, at least one substance selected from a group consisting of D-serine, pharmaceutically acceptable prodrugs and derivatives thereof, and pharmacologically acceptable salts of D-serine, the prodrugs and the derivatives.

Description

Eating disorder prevention and treatment

The present invention relates to an agent for preventing and treating eating disorders.

Eating disorders (eating disorder: ED) are unknown causes, and eating behavior is known to occur frequently in adolescent and adolescent women (95% of all patients are adolescent and adolescent women in Japan) It is a chronic intractable disease based on abnormality.

In recent years, there has been an increasing trend in Japan, and according to a 1998 survey, the number of recipients is said to be 18.5 per 100,000. In addition, it may be accompanied by depression or physical illness in the middle of the course, which has a great impact on society and is designated as an intractable disease (specific disease).

In the case of 4 years after the start of treatment, all the pleasant people are 53%, but the mortality rate is also 7%. Among them, ANbp (mucha-eating discharge type) is said to have the worst prognosis. The main cause of death is concomitant infection and arrhythmia due to extreme malnutrition.

In the treatment of eating disorders, various types of psychotherapy such as medical advice and psychotherapy, as well as nutritional guidance and drug therapy are used. Nutrition therapy includes improvement of starvation syndrome, prevention of complications and sequelae associated with undernutrition, securing of necessary energy intake, use of high-calorie liquid food, tube feeding, and parenteral nutrition. In the psychosis method, coping skills are promoted (the ability to handle stress appropriately) and the like. Drug therapy is only used as an adjunct. Drugs used for anorexia, overeating, and vomiting, and comorbid psychiatric symptoms include amitriptyline for patients with anorexia (i.e., anorexia nervosa), and the antihistamine cyproheptadine. In addition, desipramine, imipramine, and monoamine oxidase inhibitor phenelzine for patients with bulimia (ie, bulimia nervosa) can be mentioned. However, psychotherapy and nutritional guidance are difficult to implement because patients themselves often refuse treatment, and any drug used in drug therapy has side effects.

Also, the cause of eating disorders is still unknown and there is no effective treatment. Therefore, it is a poor area to select a medical treatment method based on a scientific basis in medicine. Currently, various psychotherapy is mainly performed worldwide, and prophylactic and therapeutic agents with excellent side effects and low side effects are highly desired.

Treatment Vol.91, No.1 Page.131-135 <2009.1>

An object of the present invention is to provide an agent for preventing and treating eating disorders that exhibits excellent effects on preventing and treating eating disorders without causing side effects.

The present inventors have sought a substance that has a sufficient effect of preventing and treating eating disorders and has few side effects. As a result, D-serine has been found to be excellent in preventing and treating eating disorders and having few side effects.

Therefore, the present invention provides, for example, an eating disorder preventive and therapeutic agent, an eating disorder treatment method and the like described in the following section:
Item 1. An agent for preventing and treating eating disorders containing, as an active ingredient, at least one selected from the group consisting of D-serine, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof.
Item 2. Item 2. The agent for preventing and treating eating disorders according to Item 1, wherein the pharmaceutically acceptable derivative of D-serine is a prodrug of D-serine.
Item 3. Item 3. The agent for preventing and treating eating disorders according to Item 1 or 2, wherein the pharmaceutically acceptable derivative of D-serine is O-benzyl-D-serine or N-glycyl-D-serine.
Item 4. Item 4. The agent for preventing and treating eating disorders according to any one of Items 1 to 3, wherein the eating disorder is anorexia nervosa.
Item 5. Item 5. The agent for preventing and treating eating disorders according to any one of Items 1 to 4, which is applied as a preparation for intravenous administration.
Item 6. Item 6. The agent for preventing and treating eating disorders according to any one of Items 1 to 5, which is formulated such that 0.01 to 2 g / kg (body weight) is administered per day in terms of D-serine content.
Item 7. An effective amount selected from the group consisting of D-serine, a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable salt thereof is administered to an eating disordered person. Eating disorder treatment method.
Item 8. Item 8. The eating disorder treatment method according to Item 7, wherein the eating disorder person is anorexia nervosa.
Item 9. Item 9. The eating disorder treatment method according to Item 7 or 8, wherein the administration route is intravenous.
Item 10. Use of at least one selected from the group consisting of D-serine, a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable salt thereof for the manufacture of an agent for preventing and treating eating disorders.
Item 11. Item 11. The use according to Item 10, wherein the eating disorder is anorexia nervosa.
Item 12. Item 12. The use according to Item 10 or 11, wherein the agent for preventing and treating eating disorders is in the form of a preparation for intravenous administration.
Item 13. At least one compound selected from the group consisting of D-serine, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof for use in a method for preventing and treating eating disorders.
Item 14. Item 14. The compound according to Item 13, wherein the eating disorder is anorexia nervosa.
Item 15. Item 15. The compound according to Item 13 or 14, wherein the compound is administered intravenously.

According to the present invention, it is possible to provide an agent for preventing and treating eating disorders that has few side effects and is excellent in preventing and treating eating disorders. Moreover, even if the agent for preventing and treating eating disorders of the present invention is intravenously injected, the active ingredient reaches the brain, and the desired effect of preventing and treating eating disorders can be obtained.

The appearance of each rat when MK-801 is administered to male and female rats is shown. In male rats, there is no significant difference in appearance between MK-801 intraperitoneally administered rats and physiological saline intraperitoneally administered rats, but in female rats, MK-801 intraperitoneally administered rats It can be seen that black discharge is flowing out or adhering (so-called red tears). “Raw diet administration” indicates that physiological saline was administered, and “MK-801-i.p.” Indicates that MK-801 was administered intraperitoneally. The amount of activity (average) of 3 monkeys administered MK-801 is shown. The left side shows the amount of activity on the first day of administration, and the right side shows the amount of activity on the second day of administration. Normal indicates the amount of activity on the day before administration. The activity amount of the monkey which administered MK-801 is shown. The left side shows the amount of activity on the first day of administration, and the right side shows the amount of activity on the second day of administration. Normal indicates the amount of activity on the day before administration.

Hereinafter, the present invention will be described in more detail. Eating disorders targeted by the preventive and therapeutic agents of the present invention include anorexia nervosa, bulimia nervosa, and other atypical eating disorders.

The agent for preventing and treating eating disorders of the present invention contains at least one selected from the group consisting of D-serine, a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable salt thereof as an active ingredient. In particular, it is preferable to contain D-serine and pharmaceutically acceptable salts thereof.

The eating disorder preventive and therapeutic agent of the present invention may contain a pharmaceutically acceptable derivative of D-serine as an active ingredient. As the pharmaceutically acceptable derivatives, pharmaceutically acceptable derivatives that can be used in place of D-serine in pharmaceutical applications can be widely used. Examples of such D-serine derivatives include D-serine in which a hydroxyl group, amino group, or carboxyl group constituting D-serine is substituted with an appropriate substituent. Examples of these include the following compounds:

For example, the hydrogen atom of the hydroxyl group constituting D-serine is a linear or branched alkyl group having 1 to 6 carbon atoms (for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec- Butyl group, isobutyl group, t-butyl group), acetyl group, benzyl group, phosphono group, sulfo group or the like.

In addition, for example, one hydrogen atom in the amino group constituting D-serine is a linear or branched acyl group having 2 to 6 carbon atoms (for example, acetyl group, propionyl group, butyryl group, isobutyryl group), Examples thereof include compounds substituted with a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms (eg, t-butoxycarbonyl group), benzyloxycarbonyl group, or carbobenzoxy group.

Further, for example, a linear or branched alkyl group in which the hydrogen atom of the carboxyl group constituting D-serine has 1 to 6 carbon atoms (for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group) , Sec-butyl group, isobutyl group, t-butyl group) or a benzyl group.

Furthermore, a compound in which an amino group and / or carboxyl group constituting D-serine is bonded to another amino acid by a peptide bond is also included in the D-serine derivative referred to in the present invention. The amino acid that binds to D-serine is not particularly limited. Glutamic acid, lysine, arginine, histidine and the like can be mentioned, among which glycine is preferable.

The above-described substitution and binding to an amino acid may be performed with any one of a hydroxyl group, an amino group, and a carboxyl group constituting D-serine, or may be performed with two or three groups. For example, the hydrogen atom of the hydroxyl group constituting D-serine may be substituted with a methyl group, and one hydrogen atom in the amino group may be substituted with a t-butoxycarbonyl group. Note that the compound corresponds to N- (t-butoxycarbonyl) -O-methyl-D-serine.

Specific examples of D-serine derivatives include, for example, O-benzyl-D-serine, N-glycyl-D-serine, N- (t-butoxycarbonyl) -D-serine, N-carbobenzoxy-D- Serine, D-serine methyl ester, N- (t-butoxycarbonyl) -O-benzyl-D-serine, O-phospho-D-serine, N- (t-butoxycarbonyl) -O-methyl-D-serine, etc. Although not limited thereto, it is not limited thereto.

Here, in the present invention, the derivative of D-serine includes its pharmaceutically acceptable prodrug. A pharmaceutically acceptable prodrug refers to a prodrug that is converted into D-serine by physiological conditions in vivo, for example, hydrolysis, oxidation, or reduction reaction with an enzyme or the like. For example, alkylated D-serine, esterified D-serine, amidated D-serine, D-serine linked to other amino acids via peptide bonds, and the like can be mentioned.

The prodrug of D-serine is metabolized in vivo and converted to D-serine, and the converted D-serine has an effect of preventing and treating eating disorders. Although no limited interpretation is desired, it is believed that the prodrug of D-serine is metabolized and converted to D-serine in the liver.

Examples of the alkylated D-serine include D-serine substituted with a linear or branched alkyl group having 1 to 6 carbon atoms. As alkylated D-serine, specifically, a linear or branched alkyl group in which the hydrogen atom of the hydroxyl group constituting D-serine has 1 to 6 carbon atoms (for example, methyl group, ethyl group, propyl group) Group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, t-butyl group). These include, for example, O-methyl-D-serine, O-ethyl-D-serine, O-propyl-D-serine, O-isopropyl-D-serine, O-t-butyl-D-serine and the like.

Examples of the esterified D-serine include pharmaceutically acceptable esterified D-serine substituted with an aromatic alcohol, a lower alkyl alcohol, or the like. The lower alkyl alcohol here is usually a linear or branched alkyl alcohol having 1 to 6 carbon atoms. As esterified D-serine, specifically, a linear or branched alkyl group in which the hydrogen atom of the carboxyl group constituting D-serine has 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, Examples include compounds substituted with a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a t-butyl group), or a benzyl group. More specifically, for example, D-serine methyl ester, D-serine ethyl ester, D-serine benzyl ester and the like can be mentioned.

Examples of the amidated D-serine include, for example, a linear or branched acyl group in which one hydrogen atom in the amino group constituting D-serine has 2 to 6 carbon atoms (for example, an acetyl group or a propionyl group). , Butyryl group, isobutyryl group), a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms (eg, t-butoxycarbonyl group), a benzyloxycarbonyl group, or a carbobenzoxy group. Can be mentioned. Specifically, for example, N-acetyl-D-serine, N-benzyloxycarbonyl-D-serine, N- (t-butoxycarbonyl) -D-serine, N-carbobenzoxy-D-serine, etc. Can be mentioned.

Examples of D-serine bonded to other amino acids through peptide bonds include compounds in which an amino group and / or carboxyl group constituting D-serine is bonded to other amino acids through peptide bonds. Specific examples include N-glycyl-D-serine.

Furthermore, a compound in which the hydrogen atom of the hydroxyl group constituting D-serine is substituted with a phosphono group (O-phospho-D-serine) can also be used as a prodrug for D-serine.

A compound in which the above-described substitution and binding to an amino acid are performed in two or three groups among the hydroxyl group, amino group, and carboxyl group constituting D-serine can also be used as a prodrug for D-serine.

In addition, as a prodrug of D-serine, O-benzyl-D-serine or N-glycyl-D-serine is particularly preferable.

D-serine used in the present invention and pharmaceutically acceptable derivatives thereof are known compounds or compounds that can be easily produced according to known methods.

Moreover, D-serine and pharmaceutically acceptable derivatives thereof may be used in the form of a suitable salt. Suitable salts thereof are pharmacologically acceptable salts obtained by adding an appropriate acid to D-serine and the like, such as chloride, hydrochloride, sulfate, gluconate, sulphate. Acid salts, fumarate, maleate, tartrate, citrate and the like are included.

In addition, the D-serine and pharmaceutically acceptable derivatives thereof used in the present invention may be used in the form of solvates thereof (for example, hydrates, ethanolates, etc.).

The agent for preventing and treating eating disorders of the present invention (hereinafter sometimes simply referred to as the pharmaceutical composition of the present invention) is practically used as a form of a general pharmaceutical preparation. Examples of the pharmaceutically acceptable carrier used in the composition include diluents, excipients and the like that are usually used. Furthermore, the carrier can be appropriately selected and used depending on the use form of the preparation. This includes, for example, fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants and the like.

As the dosage unit form of the pharmaceutical composition of the present invention, various forms can be selected depending on the purpose of treatment. Typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.

In the case of molding into a tablet form, examples of the pharmaceutically acceptable carrier include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and potassium phosphate. Excipients; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and other binders; sodium carboxymethylcellulose, carboxymethylcellulose calcium, low degree of substitution Disintegrants such as hydroxypropylcellulose, dry starch, sodium alginate, agar powder, naminaran powder, sodium bicarbonate, calcium carbonate; polyoxyethylene sorbitan fatty acid ester , Surfactants such as sodium lauryl sulfate and monoglyceride stearate; decay inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil; absorption promoters such as quaternary ammonium base and sodium lauryl sulfate; glycerin, starch and the like Moisturizers; adsorbents such as starch, lactose, kaolin, bennite, colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol, etc. can be used. Furthermore, the tablet can be made into a tablet coated with a normal coating as necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, or a film-coated tablet. Moreover, a tablet can be made into a double tablet and a multilayer tablet.

In shaping into a pill form, as a pharmaceutically acceptable carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc; gum arabic powder, tragacanth powder, Binders such as gelatin and ethanol; disintegrants such as laminaran and agar can be used.

When forming into a suppository form, for example, polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like can be used as a pharmaceutically acceptable carrier.

Capsules are usually prepared by mixing the compounds of the present invention with various pharmaceutically acceptable carriers exemplified above and filling them into hard gelatin capsules, soft gelatin capsules and the like according to a conventional method.

When prepared into solutions, emulsions, suspensions, etc., and used as intravenous preparations such as injections and infusions, they are preferably sterilized and isotonic with blood. In this case, for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester or the like can be used as a diluent. In the present invention, an aqueous preparation is preferred. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. are added. May be.

Furthermore, a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other medicines may be added to the pharmaceutical composition of the present invention as necessary to prepare a pharmaceutical preparation.

The amount of the compound of the present invention (active ingredient compound) to be contained in the pharmaceutical composition of the present invention is not particularly limited, and is appropriately selected from a wide range so as to satisfy the dose described below. The pharmaceutical composition of the present invention may be used as it is, containing about 0.1 to 25% by weight of the active ingredient compound, and is usually about 0.007 to 1.4% by weight, preferably about 0.035 to 0.7% by weight. It may be applied by dissolving or diluting to the extent that it is used.

The administration method of the above pharmaceutical preparation is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, and the degree of disease. A preferred method of administration is intravenous administration. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally, and injections are administered alone or mixed with normal fluids such as glucose and amino acids intravenously or muscles. It is administered intraperitoneally, intradermally, subcutaneously or intraperitoneally, and suppositories are administered intrarectally.

When the eating disorder preventive and therapeutic agent of this embodiment is applied, the dosage is appropriately selected depending on the usage, the type of dosage form, the age of the patient, gender and other conditions, the degree of disease, the administration method, etc. However, in terms of the amount of D-serine, it is usually about 0.01 to 2 g / kg (body weight) / day, preferably about 0.01 to 1 g / kg (body weight) / day, more preferably about 0.1. It is preferable that the amount be about 05 to 0.7 g / kg (body weight) / day. Moreover, the administration method can employ | adopt any method of taking once or several times a day. The timing of administration can be before meals, between meals, after meals, or during meals.

The present invention is characterized in that at least one compound selected from the group consisting of D-serine, a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable salt thereof is administered to an eating disorder person. A method for treating eating disorders is also provided. In this method, the conditions such as the administration subject, dosage, and dosage form are as described above.

Next, as a production example, a reference example, and an example, the eating disorder preventive and therapeutic agent of the present invention will be described with specific examples, but the present invention is not limited to these examples.

Production Example 1
420 mg of D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in physiological saline to make 100 mL, and an eating disorder preventive and therapeutic agent was prepared.

Production Example 2
840 mg of D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) and 1.8 g of sodium chloride were dissolved in 200 mL of water for injection and sterilized to prepare an eating disorder preventive and therapeutic agent.

Production Example 3
420 mg of D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in a high-calorie infusion (Neopalen No. 1: Otsuka Pharmaceutical Co., Ltd.) to make 100 mL, and an eating disorder preventive and therapeutic agent was prepared.

Production Example 4
10 g of D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.9 g of sodium chloride are dissolved in 100 mL of water for injection, and after aseptic filtration, each 20 mL is filled into a plastic ampule and sealed to form a dosage form for injection. An agent for preventing and treating eating disorders was prepared.

Production Example 5
10 g D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.9 g sodium chloride are dissolved in 100 mL of water for injection, and after aseptic filtration, 20 mL each is filled into a disposable syringe and sealed to form a prefilled syringe formulation An agent for preventing and treating eating disorders was produced.

Production Example 6
An agent for preventing and treating eating disorders was prepared in the same manner as in Production Example 1, except that 150 mg of O-benzyl-D-serine was used instead of 420 mg of D-serine.

Production Example 7
An agent for preventing and treating eating disorders was prepared in the same manner as in Production Example 1 except that 648 mg of N-glycyl-D-serine was used instead of 420 mg of D-serine.

Reference Example 1: Eating disorder model animal production An attempt was made to produce an eating disorder model animal by administering MK-801. MK-801 is a compound represented by the following structural formula.

<Preparation of sample>
Purified water was used after purifying ion-exchanged water with MILLI-Q SP Reagent Water System (Nippon Millipore Corporation).

Physiological saline solution manufactured by Otsuka Pharmaceutical Factory was used.

(+)-MK-801-hydrogen-maleate (sigma-aldrich) was used for administration of MK-801. For intraperitoneal administration, an MK-801 solution in which (+)-MK-801 hydrogen maleate was dissolved in physiological saline was used.

<Production of eating disorder model animals 1: model rats>
36 groups of 7 to 8 weeks old Crl: CD (SD) male and 36 female rats were purchased from Japan Charles River Co., Ltd., and after 4 weeks of pre-breeding period, body weight was measured and 4 groups They were divided into groups. Specifically, a control group (9 males, 9 females), a test group administered with MK-801 1.0 mg / kg (9 males, 9 females), a test group administered with MK-801 0.5 mg / kg (9 males) Mice and 9 females) and MK-801 0.2 mg / kg administration test group (9 males and 9 females). The grouping was performed so that the average weight of each group was almost the same.

These rats were raised under free drinking (feed: solid feed CRF-1 for mice, rats and hamsters (Oriental Yeast Co., Ltd.)). The detailed breeding conditions are as follows. In addition,
Rats were raised under these conditions unless otherwise noted:
Temperature: 23 ± 3 ℃
Humidity: 55 ± 15%
Ventilation frequency: 13-16 times / hour Lighting time: 7: 00-19: 00
Maximum capacity per cage: 1 animal Water supply method: Use a breeding rack with an automatic water supply device and freely take tap water

In each test group, MK-801 solution was intraperitoneally administered once a day at PM 4:00. 1.0 mg / kg, 0.5 mg / kg, 0.2 mg / kg, 0.2 mg / kg, 0.2 mg / kg, and 0.2 mg / kg, respectively. kg was administered.

Instead of the control group, physiological saline was administered at a dose of 2 mL / kg.

In addition, the body weight of each rat was measured immediately before administration once a day.

In addition, a certain amount of feed was measured every day and fed, and the amount of food intake was measured from the remaining amount of feed. The measurement was performed every day.

Table 1 summarizes the breakdown of rats.

In this way, MK-801 was administered for 2 days (the first day of administration was given as the first day and administered twice in total), and the body weight value 24 hours after the last administration was 100% of the weight at the first grouping. It was calculated what percentage it was.

Table 2 shows the results of the MK-801-1.0 mg / kg administration group and the control group. The amount of food intake is also shown. The amount of food intake (%) is a value calculated by calculating the percentage of the amount of food intake the day after the last administration when the amount of food intake on the day of the first MK-801 administration is 100%. (In addition, each value shows the average value of each group).

As shown in Table 2, there was almost no increase or decrease in food intake and body weight in male rats after MK-801 administration, whereas there was a significant decrease in food intake and body weight in female rats. .

Moreover, the photograph which shows the external appearance of a test group and a control group is shown in FIG.

In male rats, there is no noticeable difference in appearance between the test group (MK-801 administration group) rat and the control group rat, but in the female rat the eyelid of the test group (MK-801 administration group) rat It was observed that red or black effluent was discharged or adhered (in a so-called red tear state). And as the dose of MK-801 increased, the symptoms became prominent.

Such so-called red tears are caused by the porphyrin contained in the secretion of the Harder's gland reacting with light and appearing red, and are known to be caused by autonomic abnormalities and stress.

Based on the above, the administration of MK-801 showed a decrease in food intake and body weight specifically in female rats, and such female rats had strong autonomic abnormalities / stresses in proportion to the dose of MK-801. Found to show symptoms.

Human eating disorder (anorexia nervosa) is a disease that mainly occurs in women and is often accompanied by significant dietary rejection and mental disorders such as depression. It can be said that the symptoms are very similar to human eating disorders. Therefore, the female rat was considered useful as an eating disorder model animal. It was also found that the eating disorder model animal can be produced by administering MK-801 to female rats.

Reference Example 2: Confirmation of D-serine translocation into the brain The following experiment was conducted to confirm that D-serine, which is considered a candidate drug for preventing and / or treating eating disorders, migrates into the brain by intravenous administration. Went.

<Preparation of sample>
D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) was used as a test substance. 210 mg of the D-serine was dissolved in 100 mL of physiological saline (prepared before use) and used as a D-serine solution for intravenous administration to rats.

For the anesthesia, diethyl ether or Nembutal injection (Dainippon Sumitomo Pharma Co., Ltd.) was used.

Note that the same purified water and physiological saline as in Reference Example 1 were used.

<D-Serine transfer confirmation experiment>
Twenty-five 7-8 week old Crl: CD (SD) female rats were purchased from Japan Charles River Co., Ltd. and weighed and divided into control group (12 animals) and test group (13 animals) did. Rats were fed a chow CRF-1 and were fed for several days under free drinking.

Thereafter, the administration route of each rat was secured as follows. Under diethyl ether anesthesia, the catheter was inserted into the rat's external jugular vein and the end was placed in the anterior vena cava. The opposite end of the catheter was led out of the body from the middle part of the scapula via the hypodermis, and connected to a sieve through a protective metal harness. Rats were housed in individual metabolic cages to allow continuous administration without restriction. The sieve was connected in advance to a syringe set in a syringe pump (JMS syringe pump, SP-110) via a nutrition catheter.

After securing the administration route, the feed was changed to powdered feed CRF-1 and reared under free drinking.

After securing the administration route, D-serine solution is continuously administered intravenously at 142.9 mL / kg / day (ie, D-serine 300 mg / kg / day) to the test group rats, and the cumulative dose is given approximately every day. Recorded. The dose was calculated based on the body weight at the time of grouping. In addition, physiological saline was similarly administered to the control group rats instead of the D-serine solution.

After continuous administration of D-serine solution for 4 days, the abdomen was opened under Nembutal anesthesia, and whole blood was collected from the abdominal aorta using a syringe. The collected blood was transferred to a Spitz tube (no coagulation, with a separating agent) to which 20 uU heparin had been added in advance for blood biochemical examination. This was ice-cooled and promptly centrifuged at 3000 rpm for 15 minutes at 4 ° C. Plasma was collected and stored at -80 ° C or lower until the serine concentration was measured. Further, after blood collection, the brain was collected, water was removed with a paper towel, the weight was measured, frozen with liquid nitrogen, and stored at −80 ° C. until the serine concentration was measured.

Serine concentrations in the plasma and brain obtained as described above were measured by liquid chromatography. In addition, about the serine concentration in a brain, it added to the 2.5% amount of 2.5% sulfosalicylic acid aqueous solution of the weight of a brain, and it used for the measurement after homogenizing.

The results are shown in Table 3.

As shown in Table 3, the plasma serine concentration in the test group was significantly higher than that in the control group, and the brain serine concentration in the test group was also significantly higher than that in the control group. From this, it was confirmed that the continuous administration of D-serine intravenously significantly increased the serine concentration not only in the blood but also in the brain.

From the above, it was confirmed that when D-serine was administered intravenously, D-serine migrated into the brain.

Example 1 Examination of Eating Disorder Symptom Improvement Effect of D-Serine The following experiment was conducted to confirm whether D-serine has an effect of improving eating disorder symptom. In the following experiment, MK-801 administration and D-serine administration for preparing an eating disorder model are performed in parallel in the test group. As is well known to those skilled in the art, a drug for preparing a model animal and a candidate compound are administered in parallel, particularly when screening for a compound that acts on the central nervous system and may have a medicinal effect. This is a common practice, and this study is based on that.

<Preparation of sample>
D-serine (manufactured by Wako Pure Chemical Industries, Ltd.) was used as a test substance. 210 mg of the D-serine was dissolved in 50 mL of physiological saline (prepared at the time of use) and used as a D-serine solution for intravenous administration to rats.

(+)-MK-801-hydrogen-maleate (sigma-aldrich) was used for administration of MK-801. For intraperitoneal administration, an MK-801 solution (0.25 mg / mL) in which (+)-MK-801 hydrogen maleate was dissolved in physiological saline was used.

For anesthesia, diethyl ether injection or Nembutal injection (Dainippon Sumitomo Pharma Co., Ltd.) was used.

Note that the same purified water and physiological saline as in Reference Example 1 were used.

<Confirmation experiment of D-serine for improving eating disorder symptoms>
Thirty six-week-old Crl: CD (SD) female rats were purchased from Japan Charles River Co., Ltd., fed with solid feed CRF-1 and bred for several days under free drinking. In this experiment, rats were weighed and recorded every day from the beginning at 4:00 PM (only on the last day before dissection).

After rearing for several days, the administration route of each rat was secured in the same manner as in Reference Example 2. The administration route was maintained with physiological saline for 3 days (that is, physiological saline was intravenously administered continuously for 3 days).

After securing the administration route, the feed was changed to powdered feed CRF-1 and reared under free drinking. In addition, a constant amount of feed was measured every day, and the amount of food intake was measured from the remaining amount of feed. The measurement was performed every day. Then, according to the amount of food intake for 3 days at the time of physiological saline administration, the cells were grouped by stratified randomization (standard group: 10 animals, control group: 10 animals, test group: 10 animals).

After administration of physiological saline for 3 days, D-serine solution was continuously administered intravenously at 142.9 mL / kg / day (ie, D-serine 600 mg / kg / day) to the test group rats. The cumulative dose was recorded. The dose was calculated based on the body weight when securing the administration route (during cannulation). Further, physiological saline was similarly administered to the control group rats and the standard group rats instead of the D-serine solution.

MK-801 solution once a day at PM 4:00 (after body weight measurement) for the test group rats and the control group rats from the third day of continuous intravenous administration of D-serine (the first day of administration is the first day) Was intraperitoneally administered (0.5 mg / kg). The dose was calculated based on the body weight on the day before the administration. In the standard group rats, physiological saline was similarly administered intraperitoneally (administered with the same volume of physiological saline as the amount of MK-801 solution when the MK-801 solution was assumed to be administered). The animals were kept under free drinking and continued intravenous administration of D-serine.

The intraperitoneal administration of MK-801 (or physiological saline) was continued for 2 days (ie twice). The body weight of each rat was measured 24 hours after the second administration.

Table 4 shows the cumulative amount of food consumed during the 4-day period of intravenous administration of D-serine.

As shown in Table 4, a significant recovery of food intake was observed in the test group. Since it was known from Example 2 that MK-801 was administered to female rats to exhibit eating disorder symptoms, it was recognized that the recovery of the food intake improved the eating disorder symptoms. From this, it was confirmed that D-serine has an excellent effect of improving the symptoms of eating disorders, and that D-serine can be used as an agent for preventing and / or treating eating disorders. During the experiment, no special side effects were observed in the test group. Of course, D-serine prodrugs (eg, O-benzyl-D-serine, N-glycyl-D-serine, etc.) are also metabolized in vivo and converted to D-serine. It is thought that it has the effect of.

Reference Example 3: Eating disorder model animal production 2
<Production of eating disorder model animals 2: model monkey>
Three 3-5 year old female cynomolgus monkeys (body weight 2-5 kg) were purchased and quarantined and acclimatized for 14 days. During the quarantine and acclimatization period, general condition observation and body weight measurement were carried out, and it was confirmed that there was no abnormality in the health condition. During the period, cynomolgus monkeys were given a solid feed for raising monkeys (PS feed; Oriental Yeast Co., Ltd.) for free drinking. Three cynomolgus monkeys were numbered No. 1 to No. 3, respectively.

The transmitter for measuring body temperature and activity (D70-PCT, Data Sciences International) was attached to these cynomolgus monkeys as follows. And what kind of change was seen in body temperature and activity amount by MK-801 administration was examined. In addition, we also examined how food intake behavior and food intake changed with MK-801 administration.

[Transmitter placement surgery]
For cynomolgus monkeys, an operation to install a transmitter was performed. Immediately before and 3 days after the surgery, antibiotics (bicillin for injection, Meiji Seika Co., Ltd., medium: water for injection) are administered intramuscularly twice daily at a dose of 250 mg (titer) / mL, 0.5 mL / body did.

Specifically, the cynomolgus monkey was anesthetized with ketamine (Daiichi Sankyo Propharma Co., Ltd.) and xylazine (Bayer Pharmaceutical Co., Ltd.), and then the abdomen was opened. The transmitter was placed in the abdominal cavity and the abdomen was closed. Immediately after the operation, buprenorphine hydrochloride (repetane injection 0.3 mg (Otsuka Pharmaceutical Co., Ltd.)) was intramuscularly administered once at a dose of 0.2 mg / body. In addition, an ointment containing antibiotics (terramycin ointment (Yoshindo Co., Ltd.) and isodine gel (Meiji Seika Co., Ltd.)) was applied to the surgical site. Regarding the cynomolgus monkeys that had undergone surgery, the progress of one week or more after the operation was observed, and it was confirmed that no abnormality was observed in the health condition.

[Administration of MK-801]
The MK-801 solution was administered subcutaneously (administered subcutaneously to the back) once a day for 2 consecutive days to each cynomolgus monkey attached with a transmitter as described above. The administration condition was 0.05 mg / 1 mL / kg. In addition, although the body weight value of each cynomolgus monkey is required for administration condition determination, the value measured just before administration was used for the said value.

[Measurement of activity]
The activity of cynomolgus monkeys was measured by a computer system for data acquisition and analysis (Dataquest ARTTM or DataquestTM OpenARTTM, Data Sciences International) through a receiver using a telemetry signal from a transmitter placed in the abdominal cavity. The measurement start time was immediately after completion of MK-801 solution administration, and the measurement start time was 0 minutes after administration. Activity was measured and recorded every hour from 0 minutes to 24 hours after administration. The amount of activity was measured data for 30 minutes before each measurement time point. The transmitter embedded in the abdominal cavity has a mechanism for transmitting a signal to the receiver by moving the embedded monkey. The amount of activity is represented by the number of times of the signal.

The average activity of three monkeys (No.1 to No.3) was calculated and summarized in a graph. Moreover, the average of the activity amount of the three monkeys the day before the first day of administration was also calculated and summarized as a “Normal” graph. The results are shown in FIG. Furthermore, the result of the activity amount measurement of No. 1 monkey is shown in FIG.

As shown in FIGS. 2 and 3, the amount of activity of monkeys administered with MK-801 was clearly increased. It is known that the amount of activity increases in anorexia nervosa, and it can be said that the monkey's symptoms are very similar to those of anorexia nervosa. Therefore, it was considered that a model of anorexia nervosa could be produced in monkeys by administering MK-801.

[Measurement of food intake]
For 3 days before the first day of MK-801 administration, a feeder containing 100 g of food was set every day, and after about 24 hours, the feeder was removed from the cage and the remaining amount was weighed. The remaining amount was 0 g for 3 days.

Also, on the first day of MK-801 administration, set a feeder containing 100 g of feed 1 hour after administration, and remove the feeder from the cage before administration of MK-801 on the second day of administration. The amount was weighed. On the second day of administration, set a feeder containing 100 g of food at 1 hour after administration, and remove the feeder from the cage at the same time as the measurement of food intake on the second day. Was weighed. The results are shown in Table 5.

Furthermore, on the first and second days of administration, the time from setting the feeder to starting eating and the time from starting to finishing eating were measured, respectively. The results are shown in Table 6.

As shown in Table 5, more than half of the No. 1 monkeys were left over on both the first and second day of administration. In addition, when normal cynomolgus monkeys finish eating around 30 minutes after feeding, as shown in Table 6, the No.1 and No.2 monkeys took a long time to start eating and the meal time was also large. Increased. In anorexia nervosa, it is known that due to anorexia, the amount of meal decreases and the feeding behavior changes, and it can be said that the monkey's symptoms are very similar to those of anorexia nervosa. Therefore, also in this respect, it was considered that the anorexia nervosa model could be produced in monkeys by administering MK-801.

As described above, it was confirmed that an anorexia nervosa model can be produced not only by rodent rats but also by primate cynomolgus monkeys by administration of MK-801. Therefore, the model rat produced in MK-801 in Reference Example 1 is useful as an eating disorder (anorexia nervosa) model, and as confirmed in Example 1, D-serine is an eating disorder. It was strongly supported that it was useful for treatment.

Claims (15)

An agent for preventing and treating eating disorders containing, as an active ingredient, at least one selected from the group consisting of D-serine, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof. The agent for preventing and treating eating disorders according to claim 1, wherein the pharmaceutically acceptable derivative of D-serine is a prodrug of D-serine. The agent for preventing and treating eating disorders according to claim 1 or 2, wherein the pharmaceutically acceptable derivative of D-serine is O-benzyl-D-serine or N-glycyl-D-serine. The preventive and therapeutic agent for eating disorders according to any one of claims 1 to 3, wherein the eating disorder is anorexia nervosa. The agent for preventing and treating eating disorders according to any one of claims 1 to 4, which is applied as a preparation for intravenous administration. 6. The preventive and therapeutic agent for eating disorders according to any one of claims 1 to 5, which is formulated such that 0.01 to 2 g / kg (body weight) is administered per day in terms of D-serine content. An effective amount selected from the group consisting of D-serine, a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable salt thereof is administered to an eating disordered person. Eating disorder treatment method. The method of treating eating disorders according to claim 7, wherein the eating disorder person is anorexia nervosa. The method for treating eating disorders according to claim 7 or 8, wherein the administration route is intravenous. Use of at least one selected from the group consisting of D-serine, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof for the production of an eating disorder preventive and therapeutic agent. The use according to claim 10, wherein the eating disorder is anorexia nervosa. The use according to claim 10 or 11, wherein the eating disorder preventive and therapeutic agent is in the form of a preparation for intravenous administration. At least one compound selected from the group consisting of D-serine, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof for use in a method for preventing and treating eating disorders. 14. A compound according to claim 13, wherein the eating disorder is anorexia nervosa. 15. A compound according to claim 13 or 14, wherein the compound is administered intravenously.

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