WO2010098475A1 - Agent de prévention et de traitement de troubles de la nutrition - Google Patents

Agent de prévention et de traitement de troubles de la nutrition Download PDF

Info

Publication number
WO2010098475A1
WO2010098475A1 PCT/JP2010/053175 JP2010053175W WO2010098475A1 WO 2010098475 A1 WO2010098475 A1 WO 2010098475A1 JP 2010053175 W JP2010053175 W JP 2010053175W WO 2010098475 A1 WO2010098475 A1 WO 2010098475A1
Authority
WO
WIPO (PCT)
Prior art keywords
serine
group
pharmaceutically acceptable
administration
eating disorders
Prior art date
Application number
PCT/JP2010/053175
Other languages
English (en)
Japanese (ja)
Inventor
泰秀 井上
隆雪 清水
Original Assignee
株式会社大塚製薬工場
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 株式会社大塚製薬工場 filed Critical 株式会社大塚製薬工場
Publication of WO2010098475A1 publication Critical patent/WO2010098475A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the present invention relates to an agent for preventing and treating eating disorders.
  • Eating disorders 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.
  • 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.
  • 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.
  • bulimia ie, bulimia nervosa
  • psychotherapy and nutritional guidance are difficult to implement because patients themselves often refuse treatment, and any drug used in drug therapy has side effects.
  • 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.
  • 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. 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. 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. 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.
  • 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. The use according to Item 10, wherein the eating disorder is anorexia nervosa.
  • 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.
  • 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.
  • 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.
  • 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.
  • D-serine a pharmaceutically acceptable derivative thereof
  • a pharmaceutically acceptable salt thereof as an active ingredient.
  • the eating disorder preventive and therapeutic agent of the present invention may contain a pharmaceutically acceptable derivative of D-serine as an active ingredient.
  • a pharmaceutically acceptable derivative of D-serine as an active ingredient.
  • pharmaceutically acceptable derivatives pharmaceutically acceptable derivatives that can be used in place of D-serine in pharmaceutical applications can be widely used.
  • 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:
  • 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.
  • 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.
  • 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.
  • D-serine derivative 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.
  • 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.
  • the hydrogen atom of the hydroxyl group constituting D-serine may be substituted with a methyl group
  • one hydrogen atom in the amino group may be substituted with a t-butoxycarbonyl group.
  • the compound corresponds to N- (t-butoxycarbonyl) -O-methyl-D-serine.
  • 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.
  • 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.
  • 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.
  • alkylated D-serine examples include D-serine substituted with a linear or branched alkyl group having 1 to 6 carbon atoms.
  • 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).
  • esterified D-serine examples 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.
  • 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.
  • amidated D-serine examples 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.
  • N-acetyl-D-serine N-benzyloxycarbonyl-D-serine, N- (t-butoxycarbonyl) -D-serine, N-carbobenzoxy-D-serine, etc.
  • N-acetyl-D-serine N-benzyloxycarbonyl-D-serine, N- (t-butoxycarbonyl) -D-serine, N-carbobenzoxy-D-serine, etc.
  • D-serine bonded to other amino acids through peptide bonds examples 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.
  • a compound in which the hydrogen atom of the hydroxyl group constituting D-serine is substituted with a phosphono group 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable carrier used in the composition include diluents, excipients and the like that are usually used.
  • 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.
  • 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.
  • 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; lubric
  • 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.
  • a tablet can be made into a double tablet and a multilayer tablet.
  • 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.
  • 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.
  • 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.
  • emulsions, suspensions, etc. 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.
  • blood 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.
  • an aqueous preparation is preferred.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the administration method can employ
  • 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.
  • 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.
  • a high-calorie infusion Neopalen No. 1: Otsuka Pharmaceutical Co., Ltd.
  • 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 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.
  • MK-801 is a compound represented by the following structural formula.
  • (+)-MK-801-hydrogen-maleate (sigma-aldrich) was used for administration of MK-801.
  • an MK-801 solution in which (+)-MK-801 hydrogen maleate was dissolved in physiological saline was used.
  • 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.
  • physiological saline was administered at a dose of 2 mL / kg.
  • 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).
  • 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.
  • 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.
  • D-serine manufactured by Wako Pure Chemical Industries, Ltd.
  • 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.
  • Nembutal injection (Dainippon Sumitomo Pharma Co., Ltd.) was used.
  • 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.
  • JMS syringe pump JMS syringe pump
  • the feed was changed to powdered feed CRF-1 and reared under free drinking.
  • 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.
  • Serine concentrations in the plasma and brain obtained as described above were measured by liquid chromatography.
  • 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 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.
  • 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.
  • MK-801 administration and D-serine administration for preparing an eating disorder model are performed in parallel in the test group.
  • 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.
  • D-serine manufactured by Wako Pure Chemical Industries, Ltd.
  • 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.
  • an MK-801 solution (0.25 mg / mL) in which (+)-MK-801 hydrogen maleate was dissolved in physiological saline was used.
  • Nembutal injection (Dainippon Sumitomo Pharma Co., Ltd.) was used.
  • 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).
  • the feed was changed to powdered feed CRF-1 and reared under free drinking.
  • 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.
  • the cells were grouped by stratified randomization (standard group: 10 animals, control group: 10 animals, test group: 10 animals).
  • 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.
  • 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.
  • MK-801 or physiological saline
  • 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.
  • 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.
  • 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 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.
  • 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.
  • an ointment containing antibiotics (terramycin ointment (Yoshindo Co., Ltd.) and isodine gel (Meiji Seika Co., Ltd.) was applied to the surgical site.
  • terramycin ointment Yoshindo Co., Ltd.
  • isodine gel Meiji Seika Co., Ltd.
  • 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.
  • 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.
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur un agent de prévention et de traitement de troubles de la nutrition, montrant des effets préventifs et curatifs excellents sur des troubles de la nutrition sans avoir d'effets secondaires. L'invention porte spécifiquement sur un agent de prévention et de traitement de troubles de la nutrition, contenant, en tant qu'ingrédient actif, au moins une substance choisie dans un groupe constitué par la D-sérine, des promédicaments pharmaceutiquement acceptables et des dérivés de celle-ci, des sels pharmaceutiquement acceptables de la D-sérine, des promédicaments et des dérivés.
PCT/JP2010/053175 2009-02-27 2010-02-26 Agent de prévention et de traitement de troubles de la nutrition WO2010098475A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-046884 2009-02-27
JP2009046884 2009-02-27

Publications (1)

Publication Number Publication Date
WO2010098475A1 true WO2010098475A1 (fr) 2010-09-02

Family

ID=42665679

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/053175 WO2010098475A1 (fr) 2009-02-27 2010-02-26 Agent de prévention et de traitement de troubles de la nutrition

Country Status (1)

Country Link
WO (1) WO2010098475A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7467138B2 (ja) 2020-01-30 2024-04-15 株式会社 資生堂 腸管バリア改善剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CONTREAS, P. C., NEUROPHARMACOLOGY, vol. 29, no. 3, 1990, pages 291 - 293 *
TORU NISHIKAWA ET AL., ANNUAL REPORT OF THE PHARMACOPSYCHIATRY RESEARCH FOUNDATION, vol. 23, 1992, pages 213 - 220 *
TORU NISHIKAWA, NO NO KAGAKU, vol. 21, 1999, pages 757 - 763 *
YVAUPEL, D. B. ET AL., PHARMACOLOGY BIOCHEMISTRY & BEHAVIOR, vol. 17, 1982, pages 539 - 545 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7467138B2 (ja) 2020-01-30 2024-04-15 株式会社 資生堂 腸管バリア改善剤

Similar Documents

Publication Publication Date Title
EP3704108B1 (fr) Inhibiteur d'irak4 en combinaison avec un inhibiteur de bcl-2 pour utilisation dans le traitement du cancer
EP2433932A1 (fr) Agent prophylactique et/ou thérapeutique contre l'hyperlipidémie
TW201136916A (en) New uses
US20020048612A1 (en) GABA substrate and the use thereof for treating cognitive and emotional disorders
CN115304593B (zh) 苯并异噻唑化合物及其药物组合物和应用
WO2002060431A1 (fr) Medicaments therapeutiques/prophylactiques contre des maladies inflammatoires
TW516959B (en) Composition containing ascorbic acid
WO2006064744A1 (fr) Composition medicinale pour le traitement du diabete
EP4331583A1 (fr) Agent augmentant la carnitine sanguine
CN111067900B (zh) 治疗或预防肥胖或其相关疾病的化合物及其应用
WO2010098475A1 (fr) Agent de prévention et de traitement de troubles de la nutrition
JPWO2007069744A1 (ja) メタボリックシンドローム予防・改善用組成物
JP2007070253A (ja) 肥満、糖尿病の予防・治療剤
TWI590823B (zh) Cancerous anemia to improve, prevention agent
JP5557243B2 (ja) 睡眠の改善剤
JP2018177738A (ja) Ｔｒｐｖ４活性抑制剤
WO2010098298A1 (fr) Composition pharmaceutique contenant une combinaison d'un composé possédant une activité inhibitrice de la digestion/absorption des nutriments et d'un dérivé de cyclohexanecarboxamide
JP5376786B2 (ja) 神経細胞賦活組成物
JP2020115853A (ja) ホスホジエステラーゼ３阻害用組成物及び血小板凝集抑制用組成物
JP5376785B2 (ja) 医薬組成物
WO2014148136A1 (fr) Composé ayant une activité anti-allergique et son utilisation
US20240216342A1 (en) Blood carnitine-increasing agent
JP2021520403A (ja) 糖尿病予防・治療用の医薬品組成物及びその用途
JP6807423B2 (ja) ガロカテキンの使用
JPWO2009054360A1 (ja) 内臓脂肪特異的低減剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10746354

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10746354

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP