WO2014199935A1 - Obesity preventative used to prevent body weight increase or obesity being drug side effect, by suppressing endoplasmic reticulum stress signal - Google Patents

Obesity preventative used to prevent body weight increase or obesity being drug side effect, by suppressing endoplasmic reticulum stress signal Download PDF

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WO2014199935A1
WO2014199935A1 PCT/JP2014/065186 JP2014065186W WO2014199935A1 WO 2014199935 A1 WO2014199935 A1 WO 2014199935A1 JP 2014065186 W JP2014065186 W JP 2014065186W WO 2014199935 A1 WO2014199935 A1 WO 2014199935A1
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endoplasmic reticulum
obesity
reticulum stress
drug
agent
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French (fr)
Japanese (ja)
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中島　利博
聡子 荒谷
千恵 臼井
嘉久 山野
健弥 西岡
英俊 藤田
尚子 八木下
伊藤　健司
郁朗 中村
西岡　久寿樹
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株式会社エム・エス・エス
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    • 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
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an anti-obesity agent used to prevent weight gain and obesity as side effects of a predetermined drug by suppressing an endoplasmic reticulum stress signal.
  • an object of the present invention is to provide a preventive or therapeutic agent for weight gain and obesity which are side effects caused by an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia.
  • the present invention also includes a drug comprising an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and a preventive or therapeutic agent for weight gain and obesity that are side effects caused by the drug.
  • a drug comprising an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and a preventive or therapeutic agent for weight gain and obesity that are side effects caused by the drug.
  • An object is to provide a pharmaceutical kit.
  • the present invention is basically based on the following knowledge. In other words, the mechanisms of weight gain and obesity described above have not been clarified, and no specific method for improving these side effects has been proposed.
  • the present invention verifies adipocyte differentiation and endoplasmic reticulum stress signals using antidepressants, antipsychotic agents, pain treatment agents, and fibromyalgia treatment agents. It was found that the endoplasmic reticulum stress signal was enhanced.
  • the above-mentioned drugs cause obesity in patients by enhancing adipocyte differentiation and endoplasmic reticulum stress signals. By utilizing this mechanism, obesity, which is a side effect of a given drug, can be effectively prevented and symptoms can be improved. This will improve the patient's QOL.
  • the first aspect of the present invention relates to a therapeutic or preventive agent for weight gain or obesity comprising an endoplasmic reticulum stress inhibitor as an active ingredient.
  • the weight gain or obesity is a side effect caused by a drug including one or more of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a fibromyalgia therapeutic agent.
  • a preferred example of a therapeutic or prophylactic agent for this aspect is that the drug causing weight gain or obesity as a side effect is from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin.
  • the drug causing weight gain or obesity as a side effect is from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin.
  • One or more selected agents is selected agents.
  • a preferred example of a therapeutic or prophylactic agent for this aspect is an endoplasmic reticulum stress inhibitor, Pramipexole, a pharmaceutically acceptable salt of pramipexole, or a pharmaceutically acceptable solvate of pramipexole, Ropinirole, a pharmaceutically acceptable salt of ropinirole, or a pharmaceutically acceptable solvate of ropinirole.
  • the second aspect of the present invention relates to a pharmaceutical kit.
  • the pharmaceutical kit includes an agent containing any one or more of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and an endoplasmic reticulum stress inhibitor.
  • the endoplasmic reticulum stress inhibitor is a therapeutic or preventive agent for weight gain or obesity as a side effect caused by the drug.
  • a preferred example of this aspect is one or more agents selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin.
  • weight gain and obesity caused by a given drug are partly due to endoplasmic reticulum stress and adipocyte differentiation.
  • weight gain and obesity which are side effects associated with taking a predetermined drug, are prevented or treated.
  • FIG. 1 is a list of antipsychotics and antidepressants.
  • FIG. 2A and FIG. 2B are graphs replaced with drawings showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered.
  • FIG. 3 is a photograph replacing a drawing showing differentiation into fat cells.
  • FIG. 4 is a photograph replacing a drawing showing differentiation into fat cells.
  • FIG. 5 is a photograph replacing a drawing showing differentiation into fat cells.
  • FIG. 6 is a photograph replacing a drawing showing differentiation into fat cells.
  • FIG. 7 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered.
  • FIG. 8 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered.
  • the first aspect of the present invention relates to a therapeutic or preventive agent for weight gain or obesity comprising an endoplasmic reticulum stress inhibitor as an active ingredient.
  • the weight gain or obesity is a side effect caused by a drug including one or more of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a fibromyalgia therapeutic agent.
  • ER stress is related to the accumulation of abnormal proteins in the ER. Abnormal proteins accumulated in the endoplasmic reticulum are extracted into the cytoplasm and degraded by endoplasmic reticulum-related degradation (ERAD: ER-associated degradation). It is known that apoptosis (cell death) is induced when endoplasmic reticulum stress becomes excessive.
  • ESD endoplasmic reticulum-related degradation
  • Endoplasmic reticulum stress inhibitors are known.
  • known endoplasmic reticulum stress inhibitors can be appropriately used.
  • Specific examples of endoplasmic reticulum stress inhibitors are: Disclosed in Japanese Patent No. 3934399, “An endoplasmic reticulum stress-inhibiting composition containing, as an active ingredient, a fat-soluble extractable component obtained by continuously extracting fruit bodies of Yamabushidatake with ethanol, acetone and chloroform” , "Dilinoleoylphosphatidylethanolamine” disclosed in Japanese Patent No.
  • ASK1 inhibitory substance for example, host cell transformed with ASK1 dominant negative body, ASK1 dominant negative body expression recombinant vector or ASK1 dominant negative body expression recombinant vector
  • Table No. 02/038179 “A fat-soluble extract component derived from mulberry yellow (for example, Meshimakobu, Mushroom, Mushroom, Matsumatsukatake)” disclosed in JP-A-2006-342077 “Yokukan, Sankawa Kyu or Shiba” disclosed in Japanese Patent Application Laid-Open No. 2011-037722.
  • endoplasmic reticulum stress inhibitors are active ingredients for preventing the above-described weight gain and obesity. And the effective amount of an endoplasmic reticulum stress inhibitor can be made into the same grade as what was indicated by the above-mentioned gazette, for example.
  • the content of the active ingredient is 1 milligram or more and 100 milligrams or less, and is administered 1 to 3 times a day, 1 milligram or more and 500 grams or less per day. Since the endoplasmic reticulum stress inhibitor is well-known, it can be manufactured according to a well-known method.
  • the endoplasmic reticulum stress inhibitor is generally a tablet, but may be an injection or a liquid. Tablets can be produced by tableting with known additives. Injections and solutions can be produced by dissolving the active ingredients together with solvents and additives in ampoules.
  • an endoplasmic reticulum stress inhibitor (pramipexole (pramipexole hydrochloride hydrate)) or ropinirole (ropinirole hydrochloride)
  • ropinirole hydrochloride ropinirole hydrochloride
  • Pramipexole is an active ingredient of Biciflor (registered trademark).
  • the general name of pramipexole hydrochloride hydrate is (S) -2-Amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole monohydrohydrate ((S) -2-amino-4,5,6,7- Tetrahydro-6-propylaminobenzothiazole dihydrochloride monohydrate).
  • Additives contained in Bi-Siflor® are corn starch, light anhydrous silicic acid, povidone K25, magnesium stearate, D-mannitol.
  • pramipexole As an active ingredient, pramipexole (pramipexol hydrochloride hydrate) is administered at the initial dose of 0.125 mg twice a day, and a maximum of 4.5 mg per day can be administered. Therefore, when pramipexole, a salt thereof, or a solvate thereof (for example, pramipexole hydrochloride hydrate) is used as an endoplasmic reticulum stress inhibitor of the present invention, 0.05 mg to 3 mg per dose is once a day or more. It is preferable to administer 4 times or less, and 0.1 mg or more and 2 mg or less may be administered once or more and 3 times or less per day.
  • Ropinirole is an active ingredient of Lekip (registered trademark) tablets.
  • the generic name for ropinirole hydrochloride is 4- [2- (dipropylamino) ethyl] -2-indolinone monohydrochloride.
  • Lequip contains croscarmellose sodium, magnesium stearate, lactose hydrate, crystalline cellulose, hypromellose, macrogol 400, polysorbate 80, and titanium oxide as additives.
  • REQUIP® is an adult dose of ropinirole, starting at 0.25 mg once a day, 3 times a day (0.75 mg daily), increasing by 0.75 mg daily for 4 weeks. The daily dose should be 3mg.
  • ropinirole, a salt thereof, or a solvate thereof for example, ropinirole hydrochloride
  • 0.1 mg or more and 3 mg or less is used once a day or more and 4 times a day. It is preferable to administer below, and 0.2 mg or more and 2 mg or less per administration may be administered once or more and 3 times or less per day.
  • Preferred examples of the therapeutic or prophylactic agent of this aspect include one or more kinds selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin. It is an agent. That is, a preferred aspect of the present invention is to prevent or treat weight gain or obesity caused by any of olanzapine, quetiapine, mirtazapine, and gabapentin. That is, when these drugs are administered (or before and after), endoplasmic reticulum stress inhibitors can be administered to suppress endoplasmic reticulum stress caused by these drugs, resulting in weight gain and obesity ( (Adipogenesis) can be effectively prevented.
  • pregabalin olanzapine
  • quetiapine quetiapine
  • mirtazapine mirtazapine
  • gabapentin gabapentin
  • a preferred embodiment of the present invention relates to a method for treating or preventing weight gain or obesity, which is a side effect of the aforementioned drug, comprising the step of administering the aforementioned drug and an endoplasmic reticulum stress inhibitor to a patient. Because these drugs are commercially available, patients should be inoculated with these drugs according to the marketed dosage and usage.
  • the dose and frequency of administration of the endoplasmic reticulum stress inhibitor may be appropriately adjusted according to the type and the subject.
  • Antidepressants, antipsychotics, pain treatments, and fibromyalgia treatments are commercially available.
  • the antidepressant, antipsychotic agent, pain treatment agent, and fibromyalgia which are agents in the present invention, are commercially available and those that are commercially available are modified within the obvious range of those skilled in the art. Can be used as appropriate. That is, these active ingredients, the amount of active ingredients, the administration method, and the formulation method can be appropriately modified as necessary based on these commercially available ones.
  • Pregabalin is sold as Lyrica (registered trademark) in Japan.
  • the chemical name of pregabalin is (3S) -3- (aminomethyl) -5-methylhexanoic acid ((3S) -3- (Aminomethyl) -5-methylhexanoic acid).
  • pregabalin is orally administered as an initial dose of 150 mg twice a day as an initial dose to adults, followed by one day over one week. The dose is gradually increased to 300 mg and then maintained at 300 to 450 mg. The maximum daily dose should not exceed 450 mg, and both are to be administered orally in two divided doses per day.
  • Zyplexa registered trademark
  • Zydis registered trademark
  • Zyprexa® Zydis® is initiated by oral administration of 5-10 mg of olanzapine once daily to adults. As a maintenance dose, 10 mg is orally administered once a day. The dose may be adjusted according to age and symptoms. However, the daily dose does not exceed 20 mg.
  • Zyprexa® Zydis® includes gelatin, D-mannitol, aspartame (L-phenylalanine compound), methyl sodium paraoxybenzoate, and propyl sodium paraoxybenzoate as attachments.
  • Seroquel which is an antipsychotic drug, has an active ingredient of quetiapine (quetiapine fumarate) and is administered twice or three times a day at a dose of 25 mg (quetiapine equivalent). And this drug is added as crystalline cellulose, lactose hydrate, calcium hydrogen phosphate hydrate, povidone, sodium starch glycolate, magnesium stearate, hypromellose, macrogol, titanium oxide, yellow ferric oxide, And iron sesquioxide.
  • Reflex which is an antidepressant
  • Reflex® contains mirtazapine as an active ingredient.
  • Reflex® is given to adults as mirtazapine at an initial dose of 15 mg / day and 15-30 mg orally once daily before going to bed. The dose may be adjusted according to age and symptoms within a range not exceeding 45 mg / day, but the dose should be increased to 15 mg / day at intervals of 1 week or longer.
  • Reflex® includes corn starch, hydroxypropyl cellulose, magnesium stearate, light anhydrous silicic acid, lactose hydrate, hypromellose, macrogol 6000, titanium oxide, and yellow ferric oxide.
  • gabapentin an antipsychotic drug and a therapeutic agent for fibromyalgia
  • the daily dose is 600 mg on the first day as gabapentin.
  • the daily dose of 1200 mg is orally administered in 3 divided doses.
  • the daily dose of 1200 mg to 1800 mg is orally administered in divided doses in 3 doses.
  • the dose may be adjusted according to the symptoms, but the maximum daily dose is 2400 mg.
  • Gabapen® contains talc, hydroxypropylcellulose, hypromellose, triacetin, propylene glycol, copolyvidone, polyoxyethylene polyoxypropylene glycol, and magnesium stearate as additives.
  • the second aspect of the present invention relates to a pharmaceutical kit.
  • the pharmaceutical kit includes an agent containing any one or more of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and an endoplasmic reticulum stress inhibitor.
  • the endoplasmic reticulum stress inhibitor is a therapeutic or preventive agent for weight gain or obesity as a side effect caused by the drug.
  • a preferred example of this aspect is one or more agents selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin.
  • any one of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia and an endoplasmic reticulum stress inhibitor may be present separately.
  • one tablet may contain any of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia and an endoplasmic reticulum stress inhibitor.
  • the present invention comprises a step of administering any of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a fibromyalgia therapeutic agent (drug) to a subject (eg, a human or a non-human mammal)
  • a subject eg, a human or a non-human mammal
  • the present invention also provides a method for treating and preventing weight gain or obesity as a side effect caused by a drug, including a step of administering an endoplasmic reticulum stress inhibitor.
  • an endoplasmic reticulum stress suppressant When the patient is inoculated with the drug at the same time or with the drug and an endoplasmic reticulum stress suppressant is inoculated, weight gain or obesity caused by the drug can be prevented or treated.
  • the drug and endoplasmic reticulum stress suppressor may be inoculated simultaneously or separately.
  • Fig. 1 is a list of antipsychotics and antidepressants.
  • the left column is the product name
  • the middle column is the generic name
  • the right column is the description of each drug.
  • 293 cells that induce endoplasmic reticulum stress were seeded at 5 ⁇ 10 4 / well on a 24 well plate. After 24 hours, 4 x ERSE Luc 50 ng and pRL-TK 1 ng were transfected using Lipofectamine 2000. One group added DMSO. The remaining croup was supplemented with 2 ⁇ g / ml tunicamycin to induce endoplasmic reticulum stress.
  • FIG. 2 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered.
  • the vertical axis represents the amount of light emission.
  • the amount of luminescence of control cells in which endoplasmic reticulum stress was not induced by tunicamycin was set to 1. It shows that the ERSE gene expression level increases as the amount of luminescence increases (that is, endoplasmic reticulum stress is induced).
  • endoplasmic reticulum stress is induced when a specific antipsychotic is administered (particularly Quetiapine). Furthermore, when an antipsychotic was administered to cells in which endoplasmic reticulum stress was induced by tunicamycin, endoplasmic reticulum stress was further induced as compared to when tunicamycin alone was administered (especially Olanzapine, Quetiapine, Mirtapine, Gabapentin). From these results, it was shown that some antipsychotic drugs induce endoplasmic reticulum stress or promote the action of tunicamycin (inhibition of glycosylation on proteins).
  • 3T3-L1 cells were confluent with DMEM (10% FBS, Hihg Glucose) and then cultured for 3 days. Differentiation was induced by adding 500 microM IBMX, 1 microM Dexamethasone, 5 microg / ml Insulin. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose). After culturing for 3 days, 3T3-L1 cells were washed with PBS ( ⁇ ), and then fixed with 10% formalin.
  • DMEM 50% FBS, Hihg Glucose
  • FIG. 3 is a photograph replacing a drawing showing differentiation into adipocytes.
  • the two figures on the left of FIG. 3 show control cells in which differentiation has not been induced.
  • the two figures on the right of FIG. 3 show cells in which differentiation has been induced.
  • FIG. 3 was observed at a magnification of 4 times (upper) and at a magnification of 10 times (lower). It was confirmed that the differentiation of 3T3-L1 cells was promoted by IBMX / dex / Insulin, and lipid droplets were increased by the Oil Red O dyeing color as compared to the control cells.
  • 3T3-L1 cells were cultured for 3 days after reaching confluence with DMEM (10% FBS, Hihg Glucose). Differentiation was induced by adding 500 microM IBMX, 1 microM Dexamethasone, 5 ⁇ g / ml Insulin. At the same time, 100 micro M Quetiapine (seroquel) or DMSO was added. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin, and the drug was added in the same manner. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose), cultured for 3 days, and then Oil Red O staining was performed.
  • DMEM 50% FBS, Hihg Glucose
  • FIG. 4 is a photograph replacing a drawing showing differentiation into fat cells.
  • the upper four diagrams in FIG. 4 are control cells (with DMEM added), and the lower four diagrams are photographs replacing the drawings showing cells to which 3T3-L1 cells have been differentiated and to which quetiapine has been administered.
  • An increase in lipid droplets was observed compared to control cells. From the above, it was shown that Quetiapine is involved in promoting differentiation of adipocytes.
  • 3T3-L1 cells were cultured for 3 days after reaching confluence with DMEM (10% FBS, Hihg Glucose).
  • DMEM 50% FBS, Hihg Glucose
  • 500 micro M IBMX, 1 micro M Dexamethasone, 5 micro g / ml Insulin were added to induce differentiation.
  • 30 micro g / ml Gabapentin, 100 or 200 micro M Olanzapine (Zyprexa), 100 micro M Mirazapine (Reflex) or DMSO was added.
  • the medium was replaced with a medium containing 4 microg / ml Insulin, and the drug was added in the same manner.
  • DMEM 10% FBS, Hihg Glucose
  • oil red O staining was performed.
  • FIG. 5 is a photograph replacing a drawing showing differentiation into fat cells. From FIG. 5, it was shown that when Gabapentin, Olanzapine (Zyprexa), and Mirazapine were administered, lipid droplets increased as compared to control cells (DMEM addition). In particular, when 200 microM Olanzapine was administered, the number of fat droplets increased significantly.
  • 3T3-L1 cells were cultured for 3 days after reaching confluence with DMEM (10% FBS, Hihg Glucose). Differentiation was induced by adding 500 microM IBMX, 1 microM Dexamethasone, 5 microg / ml Insulin. At the same time, 20 micro M Pramipoleole, 100 micro M Ropinirole, 50 micro M L-DOPA, or DMSO was added. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin, and the drug was added in the same manner. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose), cultured for 3 days, and then Oil Red O staining was performed.
  • DMEM 50% FBS, Hihg Glucose
  • FIG. 6 is a photograph replacing a drawing showing differentiation into fat cells. As shown in FIG. 6, no significant increase in lipid droplets was observed even when Pramipexole, Ropinirole, or L-DOPA was administered to 3T3-L1 cells in which differentiation was induced, compared to control cells (DMEM addition). .
  • Synoviolin is one of the E3 ubiquitin ligases that govern substrate recognition for ubiquitination. So far, it has been reported that synoviolin knockout mice have decreased body weight and white adipose tissue, and synoviolin has been reported to be involved in the body weight control system. Synoviolin has also been reported to suppress the function of PGC-1 ⁇ (a molecule involved in mitochondrial biogenesis and energy metabolism and involved in obesity suppression).
  • endoplasmic reticulum stress response When endoplasmic reticulum stress occurs, the endoplasmic reticulum stress response is normally avoided by the function of the endoplasmic reticulum stress response, but if the endoplasmic reticulum stress response fails for some reason, apoptosis (cell death) occurs. Be guided. Specifically, an abnormal protein is polyubiquitinated by E3 ubiquitin ligase by the endoplasmic reticulum stress response, and is degraded by the proteasome, thereby maintaining the homeostasis of the endoplasmic reticulum. Insulin resistance has been observed in mice that have knocked out genes involved in the endoplasmic reticulum stress response so far, suggesting that obesity is induced when the response mechanism to endoplasmic reticulum stress fails.
  • FIG. 7 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when DMSO or pregabalin is administered in tunicamycin administered (right) and not (left).
  • Pregabalin is a prescription drug used for neuropathic pain, marketed as Lyrica®.
  • FIG. 7 shows that pregabalin induces endoplasmic reticulum stress and enhances the action of tunicamycin.
  • Grp78 forward: TTCAGGAGCAAATGTCTTTGTTT (SEQ ID NO: 1), Reverse: AGTTCTTGCCGTTCAAGGTG (SEQ ID NO: 2)), XBP-1 (forward: GGAGTTAAGACAGCGCTTGG (SEQ ID NO: 3), Reverse: CACTGGCCTCACTTCATTC (SEQ ID NO: 4)), GAPDH (forward: GAGGTGGGGAAGGGGTATAA (SEQ ID NO: 5), reverse: ATCTTCTCCAGCCCAGCA (SEQ ID NO: 6)).
  • PCR was performed according to the description of the above-mentioned description of the PCR system, and the following conditions were adopted as PCR cycles. 40 cycles of heat denaturation (95 ° C. for 10 seconds), annealing and elongation reaction (60 ° C. for 30 seconds) as one cycle were performed. The result is shown in FIG.
  • FIG. 8 shows that in patients with fibromyalgia, the expression of genes Grp78 and XBP-1 activated by endoplasmic reticulum stress is increased in patients taking a therapeutic agent for fibromyalgia. That is, by administering a therapeutic agent or preventive agent for weight gain or obesity containing an endoplasmic reticulum stress inhibitor as an active ingredient, it is caused by endoplasmic reticulum stress of a patient taking or taking a therapeutic agent for fibromyalgia. It turns out that weight gain and obesity can be prevented.
  • Sequence number 1 Primer Sequence number 2: Primer Sequence number 3: Primer Sequence number 4: Primer Sequence number 5: Primer Sequence number 6: Primer

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Abstract

[Problem] To provide a prophylactic or treatment agent for body weight increase or obesity being a side effect of antidepressants, antipsychotic drugs, analgesics, or treatment agents for fibromyalgia. [Solution] A prophylactic or treatment agent for body weight increase or obesity, including as an effective component thereof an endoplasmic reticulum stress suppressant, said body weight increase or obesity being a side effect of drugs including at least one among antidepressants, antipsychotic drugs, analgesics, and treatment agents for fibromyalgia. Example endoplasmic reticulum stress suppressants are pramipexole, a pharmacologically acceptable salt of pramipexole, a pharmacologically acceptable solvate of pramipexole, ropinirole, a pharmacologically acceptable salt of ropinirole, and a pharmacologically acceptable solvate of ropinirole.

Description

小胞体ストレスシグナルを抑制することによる，薬剤の副作用としての体重増加や肥満を防止するために用いられる肥満防止剤Anti-obesity agent used to prevent weight gain and obesity as side effects of drugs by suppressing endoplasmic reticulum stress signal
　本発明は，小胞体ストレスシグナルを抑制することによる，所定の薬剤の副作用としての体重増加や肥満を防止するために用いられる肥満防止剤に関する。 The present invention relates to an anti-obesity agent used to prevent weight gain and obesity as side effects of a predetermined drug by suppressing an endoplasmic reticulum stress signal.
　抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤の多くは，副作用として体重増加や肥満を惹き起こす。複数の薬剤の添付文書にもこれらの副作用が明記されている。例えば，線維筋肉痛症の患者には女性が多い。特に女性の患者にとって体重増加や肥満といった副作用は大きなストレスをもたらす。 Many of antidepressants, antipsychotics, pain treatments, and fibromyalgia treatments cause weight gain and obesity as side effects. These side effects are also specified in package inserts for several drugs. For example, there are many women with fibromyalgia. Particularly for female patients, side effects such as weight gain and obesity cause great stress.
　しかしながら，上記した体重増加や肥満のメカニズムが明らかにされておらず，これらの副作用の具体的な改善方法は提案されていなかった。 However, the mechanisms of weight gain and obesity described above have not been clarified, and no specific method for improving these side effects has been proposed.
　そこで本発明は，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤によってもたらされる副作用である体重増加や肥満の予防剤又は治療剤を提供することを目的とする。 Therefore, an object of the present invention is to provide a preventive or therapeutic agent for weight gain and obesity which are side effects caused by an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia.
　本発明はまた，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤からなる薬剤と，薬剤によってもたらされる副作用である体重増加や肥満の予防剤又は治療剤とを含む医薬キットを提供することを目的とする。 The present invention also includes a drug comprising an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and a preventive or therapeutic agent for weight gain and obesity that are side effects caused by the drug. An object is to provide a pharmaceutical kit.
　本発明は，基本的には，以下の知見に基づく。すなわち，従来，上記した体重増加や肥満のメカニズムが明らかにされておらず，これらの副作用の具体的な改善方法は提案されていなかった。本発明は，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤を用いて，脂肪細胞分化及び小胞体ストレスシグナルについて検証を行い，これらの薬剤は，脂肪細胞分化及び小胞体ストレスシグナルを亢進することを見出した。また，実施例に基づいて，上記した薬剤は，脂肪細胞分化及び小胞体ストレスシグナルを亢進することにより，患者に肥満をもたらすことも明らかとなった。このメカニズムを利用することで，所定の薬剤の副作用である肥満を効果的に予防することや，症状を改善することができる。これにより患者のＱＯＬが向上することとなる。 The present invention is basically based on the following knowledge. In other words, the mechanisms of weight gain and obesity described above have not been clarified, and no specific method for improving these side effects has been proposed. The present invention verifies adipocyte differentiation and endoplasmic reticulum stress signals using antidepressants, antipsychotic agents, pain treatment agents, and fibromyalgia treatment agents. It was found that the endoplasmic reticulum stress signal was enhanced. In addition, based on the examples, it has also been clarified that the above-mentioned drugs cause obesity in patients by enhancing adipocyte differentiation and endoplasmic reticulum stress signals. By utilizing this mechanism, obesity, which is a side effect of a given drug, can be effectively prevented and symptoms can be improved. This will improve the patient's QOL.
　また，上記のとおり，所定の薬剤が肥満を惹き起こすメカニズムが明らかになった。このため，小胞体ストレス抑制剤を所定の薬剤とともに患者に投与することで，薬剤の副作用である肥満を効果的に予防又は治療することができることとなる。 Also, as described above, the mechanism by which certain drugs cause obesity has been clarified. For this reason, by administering an endoplasmic reticulum stress inhibitor together with a predetermined drug to a patient, obesity that is a side effect of the drug can be effectively prevented or treated.
　本発明の第１の側面は，小胞体ストレス抑制剤を有効成分として含む，体重増加又は肥満の治療剤又は予防剤に関する。そして，この体重増加又は肥満は，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれか１種又は２種以上を含む薬剤により惹き起こされる副作用である。 The first aspect of the present invention relates to a therapeutic or preventive agent for weight gain or obesity comprising an endoplasmic reticulum stress inhibitor as an active ingredient. The weight gain or obesity is a side effect caused by a drug including one or more of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a fibromyalgia therapeutic agent.
　この側面の治療剤又は予防剤の好ましい例は，副作用として体重増加又は肥満をもたらす薬剤が，プレガバリン，オランザピン（Olanzapine），クエチアピン（Quetiapine），ミルタザピン（Mirtazapine），及びガバペンチン（Gabapentin）からなる群から選ばれる１又は２種以上の剤である。 A preferred example of a therapeutic or prophylactic agent for this aspect is that the drug causing weight gain or obesity as a side effect is from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin. One or more selected agents.
　この側面の治療剤又は予防剤の好ましい例は小胞体ストレス抑制剤が，
　　プラミペキソール，プラミペキソールの薬学的に許容される塩，又はプラミペキソールの薬学的に許容される溶媒和物であるか，
　　ロピニロール，ロピニロールの薬学的に許容される塩，又はロピニロールの薬学的に許容される溶媒和物である。 A preferred example of a therapeutic or prophylactic agent for this aspect is an endoplasmic reticulum stress inhibitor,
Pramipexole, a pharmaceutically acceptable salt of pramipexole, or a pharmaceutically acceptable solvate of pramipexole,
Ropinirole, a pharmaceutically acceptable salt of ropinirole, or a pharmaceutically acceptable solvate of ropinirole.
　本発明の第２の側面は，医薬キットに関する。この医薬キットは，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれか１種又は２種以上を含む薬剤と，小胞体ストレス抑制剤とを含む。小胞体ストレス抑制剤は，前記薬剤により惹き起こされる副作用としての体重増加又は肥満の治療剤又は予防剤である。 The second aspect of the present invention relates to a pharmaceutical kit. The pharmaceutical kit includes an agent containing any one or more of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and an endoplasmic reticulum stress inhibitor. The endoplasmic reticulum stress inhibitor is a therapeutic or preventive agent for weight gain or obesity as a side effect caused by the drug.
　この側面の好ましい例は，薬剤が，プレガバリン，オランザピン（Olanzapine），クエチアピン（Quetiapine），ミルタザピン（Mirtazapine），及びガバペンチン（Gabapentin）からなる群から選ばれる１又は２種以上の剤である。 A preferred example of this aspect is one or more agents selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin.
　実施例により実証された通り，所定の薬剤がもたらす体重増加や肥満は，小胞体ストレスやそれによる脂肪細胞の分化が一因である。このため，実施例により実証された通り，小胞体ストレス抑制剤を用いることで，所定の薬剤を摂取したことに伴う副作用である体重増加や肥満が予防又は治療される。 As demonstrated by the examples, weight gain and obesity caused by a given drug are partly due to endoplasmic reticulum stress and adipocyte differentiation. For this reason, as demonstrated by the examples, by using an endoplasmic reticulum stress suppressant, weight gain and obesity, which are side effects associated with taking a predetermined drug, are prevented or treated.
図１は，抗精神薬と抗うつ薬の一覧である。FIG. 1 is a list of antipsychotics and antidepressants. 図２Ａ及び図２Ｂは，所定の薬剤を投与した際の小胞体ストレス応答エレメント（ＥＲＳＥ）遺伝子発現量を示す図面に替わるグラフである。FIG. 2A and FIG. 2B are graphs replaced with drawings showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered. 図３は，脂肪細胞への分化を示す図面に替わる写真である。FIG. 3 is a photograph replacing a drawing showing differentiation into fat cells. 図４は，脂肪細胞への分化を示す図面に替わる写真である。FIG. 4 is a photograph replacing a drawing showing differentiation into fat cells. 図５は，脂肪細胞への分化を示す図面に替わる写真である。FIG. 5 is a photograph replacing a drawing showing differentiation into fat cells. 図６は，脂肪細胞への分化を示す図面に替わる写真である。FIG. 6 is a photograph replacing a drawing showing differentiation into fat cells. 図７は，所定の薬剤を投与した際の小胞体ストレス応答エレメント（ＥＲＳＥ）遺伝子発現量を示す図面に替わるグラフである。FIG. 7 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered. 図８は，所定の薬剤を投与した際の小胞体ストレス応答エレメント（ＥＲＳＥ）遺伝子発現量を示す図面に替わるグラフである。FIG. 8 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered.
　本発明の第１の側面は，小胞体ストレス抑制剤を有効成分として含む，体重増加又は肥満の治療剤又は予防剤に関する。そして，この体重増加又は肥満は，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれか１種又は２種以上を含む薬剤により惹き起こされる副作用である。 The first aspect of the present invention relates to a therapeutic or preventive agent for weight gain or obesity comprising an endoplasmic reticulum stress inhibitor as an active ingredient. The weight gain or obesity is a side effect caused by a drug including one or more of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a fibromyalgia therapeutic agent.
　小胞体ストレスは，小胞体に異常なタンパク質が蓄積されることに関連する。小胞体内に蓄積した異常タンパク質は，小胞体関連分解（ＥＲＡＤ：ＥＲ－ａｓｓｏｃｉａｔｅｄ　ｄｅｇｒａｄａｔｉｏｎ）によって，細胞質に引き出されて分解される。小胞体ストレスが過度になると，アポトーシス（細胞死）が誘導されることが知られている。 ER stress is related to the accumulation of abnormal proteins in the ER. Abnormal proteins accumulated in the endoplasmic reticulum are extracted into the cytoplasm and degraded by endoplasmic reticulum-related degradation (ERAD: ER-associated degradation). It is known that apoptosis (cell death) is induced when endoplasmic reticulum stress becomes excessive.
　小胞体ストレス抑制剤は，公知である。本発明においては，公知の小胞体ストレス抑制剤を適宜用いることができる。
　具体的な小胞体ストレス抑制剤の例は，
　特許第３９４３３９９号公報に開示された，「ヤマブシダケの子実体を，エタノール，アセトン及びクロロホルムで連続的に抽出することによって得られる脂溶性抽出成分を有効成分として含有する小胞体ストレス抑制性組成物」，
　特許４６１９６６６号公報に開示された「ジリノレオイルホスファチジルエタノールアミン」，
　再表０２／０３８１７９号公報に開示された「ＡＳＫ１阻害物質（例えば，ＡＳＫ１ドミナントネガティブ体，ＡＳＫ１ドミナントネガティブ体発現組換えベクターまたはＡＳＫ１ドミナントネガティブ体発現組換えベクターにより形質転換された宿主細胞）」，
　特開２００６－３４２０７７号公報に開示された「桑黄（例えば，メシマコブ，キコブタケ，エゾキコブタケ，マツノカタワタケ）由来の脂溶性抽出成分」，
　特開２０１１－０３７７２２号公報に開示された「抑肝，散川きゅう又は柴胡」である。 Endoplasmic reticulum stress inhibitors are known. In the present invention, known endoplasmic reticulum stress inhibitors can be appropriately used.
Specific examples of endoplasmic reticulum stress inhibitors are:
Disclosed in Japanese Patent No. 3934399, “An endoplasmic reticulum stress-inhibiting composition containing, as an active ingredient, a fat-soluble extractable component obtained by continuously extracting fruit bodies of Yamabushidatake with ethanol, acetone and chloroform” ,
"Dilinoleoylphosphatidylethanolamine" disclosed in Japanese Patent No. 4619666,
"ASK1 inhibitory substance (for example, host cell transformed with ASK1 dominant negative body, ASK1 dominant negative body expression recombinant vector or ASK1 dominant negative body expression recombinant vector)" disclosed in Table No. 02/038179,
“A fat-soluble extract component derived from mulberry yellow (for example, Meshimakobu, Mushroom, Mushroom, Matsumatsukatake)” disclosed in JP-A-2006-342077
“Yokukan, Sankawa Kyu or Shiba” disclosed in Japanese Patent Application Laid-Open No. 2011-037722.
　これらの小胞体ストレス抑制剤は，上記した体重増加や肥満を防止するための有効成分となる。そして，小胞体ストレス抑制剤の有効量は，たとえば，上記した公報に開示されたものと同程度とすることができる。通常，有効成分の含有量は，１ミリグラム以上１００ミリグラム以下であり，１日１回から３回，１日当たり１ミリグラム以上５００グラム以下投与される。小胞体ストレス抑制剤は，公知であるので，公知の方法に従って製造できる。小胞体ストレス抑制剤は，一般的には錠剤であるが，注射剤や液剤であってもよい。錠剤は，公知の添加物とともに打錠することで製造できる。注射剤や液剤はアンプルに溶媒や添加物とともに有効成分を溶解させることにより製造できる。 These endoplasmic reticulum stress inhibitors are active ingredients for preventing the above-described weight gain and obesity. And the effective amount of an endoplasmic reticulum stress inhibitor can be made into the same grade as what was indicated by the above-mentioned gazette, for example. Usually, the content of the active ingredient is 1 milligram or more and 100 milligrams or less, and is administered 1 to 3 times a day, 1 milligram or more and 500 grams or less per day. Since the endoplasmic reticulum stress inhibitor is well-known, it can be manufactured according to a well-known method. The endoplasmic reticulum stress inhibitor is generally a tablet, but may be an injection or a liquid. Tablets can be produced by tableting with known additives. Injections and solutions can be produced by dissolving the active ingredients together with solvents and additives in ampoules.
　一方，後述する実施例により実証された小胞体ストレス抑制剤（プラミペキソール（プラミペキソール塩酸塩水和物））又はロピニロール（ロピニロール塩酸塩））は，本発明の好ましい小胞体ストレス抑制剤である。 On the other hand, an endoplasmic reticulum stress inhibitor (pramipexole (pramipexole hydrochloride hydrate)) or ropinirole (ropinirole hydrochloride)) demonstrated by the examples described later is a preferred endoplasmic reticulum stress inhibitor of the present invention.
　プラミペキソール（プラミペキソール塩酸塩水和物）は，ビ・シフロール（登録商標）の有効成分である。プラミペキソール塩酸塩水和物の一般名は，（Ｓ）－２－Ａｍｉｎｏ－４,５,６,７－ｔｅｔｒａｈｙｄｒｏ－６－ｐｒｏｐｙｌａｍｉｎｏｂｅｎｚｏｔｈｉａｚｏｌｅ　ｄｉｈｙｄｒｏｃｈｌｏｒｉｄｅ　ｍｏｎｏｈｙｄｒａｔｅ　（（Ｓ）－２－アミノ－４,５,６,７－テトラヒドロ－６－プロピルアミノベンゾチアゾール　二塩酸塩一水和物）である。ビ・シフロール（登録商標）に含まれる添加物は，トウモロコシデンプン，軽質無水ケイ酸，ポビドンＫ２５，ステアリン酸マグネシウム，Ｄ－マンニトールである。有効成分としてのプラミペキソール（プラミペキソール塩酸塩水和物）は，初日0.１25mgを１日2回投与され，最大で１日当たり４．５ｍｇ投与可能である。このため，本発明の小胞体ストレス抑制剤としてプラミペキソール，その塩，又はその溶媒和物（たとえば，プラミペキソール塩酸塩水和物）を用いる場合，１回あたり０．０５ｍｇ以上３ｍｇ以下を１日１回以上４回以下投与することが好ましく，１回あたり０．１ｍｇ以上２ｍｇ以下を１日１回以上３回以下投与するものであってもよい。 Pramipexole (pramipexole hydrochloride hydrate) is an active ingredient of Biciflor (registered trademark). The general name of pramipexole hydrochloride hydrate is (S) -2-Amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole monohydrohydrate ((S) -2-amino-4,5,6,7- Tetrahydro-6-propylaminobenzothiazole dihydrochloride monohydrate). Additives contained in Bi-Siflor® are corn starch, light anhydrous silicic acid, povidone K25, magnesium stearate, D-mannitol. As an active ingredient, pramipexole (pramipexol hydrochloride hydrate) is administered at the initial dose of 0.125 mg twice a day, and a maximum of 4.5 mg per day can be administered. Therefore, when pramipexole, a salt thereof, or a solvate thereof (for example, pramipexole hydrochloride hydrate) is used as an endoplasmic reticulum stress inhibitor of the present invention, 0.05 mg to 3 mg per dose is once a day or more. It is preferable to administer 4 times or less, and 0.1 mg or more and 2 mg or less may be administered once or more and 3 times or less per day.
　ロピニロール（ロピニロール塩酸塩）は，レキップ（登録商標）錠の有効成分である。ロピニロール塩酸塩の一般名は，４－［２－（ジプロピルアミノ）エチル］－２－インドリノン一塩酸塩である。レキップ（登録商標）は，クロスカルメロースナトリウム，ステアリン酸マグネシウム，乳糖水和物，結晶セルロース，ヒプロメロース，マクロゴール400，ポリソルベート８０，酸化チタンを添加物として含む。レキップ（登録商標）は，成人にはロピニロールとして１回０．２５ｍｇ，１日3回（１日量０．７５ｍｇ）から始め，１週毎に１日量として０．７５ｍｇずつ増量し，4週目に１日量を3mgとする。以後経過観察しながら，必要に応じ，１日量として１．５ｍｇずつ１週間以上の間隔で増量し，維持量（標準１日量３－９ｍｇ）を定める。いずれの投与量の場合も１日3回に分け，経口投与する。このため，本発明の小胞体ストレス抑制剤としてロピニロール，その塩，又はその溶媒和物（たとえば，ロピニロール塩酸塩）を用いる場合，１回あたり０．１ｍｇ以上３ｍｇ以下を１日１回以上４回以下投与することが好ましく，１回あたり０．２ｍｇ以上２ｍｇ以下を１日１回以上３回以下投与するものであってもよい。 Ropinirole (Ropinirole hydrochloride) is an active ingredient of Lekip (registered trademark) tablets. The generic name for ropinirole hydrochloride is 4- [2- (dipropylamino) ethyl] -2-indolinone monohydrochloride. Lequip (registered trademark) contains croscarmellose sodium, magnesium stearate, lactose hydrate, crystalline cellulose, hypromellose, macrogol 400, polysorbate 80, and titanium oxide as additives. REQUIP® is an adult dose of ropinirole, starting at 0.25 mg once a day, 3 times a day (0.75 mg daily), increasing by 0.75 mg daily for 4 weeks. The daily dose should be 3mg. Thereafter, follow-up, and if necessary, increase the daily dose by 1.5 mg at intervals of 1 week or longer, and determine the maintenance dose (standard daily dose: 3-9 mg). In any case, divide 3 times a day and administer orally. Therefore, when ropinirole, a salt thereof, or a solvate thereof (for example, ropinirole hydrochloride) is used as the endoplasmic reticulum stress inhibitor of the present invention, 0.1 mg or more and 3 mg or less is used once a day or more and 4 times a day. It is preferable to administer below, and 0.2 mg or more and 2 mg or less per administration may be administered once or more and 3 times or less per day.
　この側面の治療剤又は予防剤の好ましい例は，薬剤が，プレガバリン，オランザピン（Olanzapine），クエチアピン（Quetiapine），ミルタザピン（Mirtazapine），及びガバペンチン（Gabapentin）からなる群から選ばれる１又は２種以上の剤である。すなわち，本発明の好ましい側面は，オランザピン（Olanzapine），クエチアピン（Quetiapine），ミルタザピン（Mirtazapine），及びガバペンチン（Gabapentin）のいずれかによって惹き起こされる体重の増加又は肥満を予防又は治療するものである。すなわち，これらの薬剤を投与する際（またはその前後）に，小胞体ストレス抑制剤を投与することで，これらの薬剤によって惹き起こされる小胞体ストレスを抑制でき，その結果体重の増加や肥満化（脂肪細胞化）を効果的に防止することができる。すなわち，本発明の好ましい態様は，上記した薬剤と小胞体ストレス抑制剤とを患者に投与する工程を含む，上記した薬剤の副作用である体重増加又は肥満の治療又は予防方法に関する。これらの薬剤は市販されているため，患者は，市販された用量及び用法に従ってこれらの薬剤を接種すればよい。 Preferred examples of the therapeutic or prophylactic agent of this aspect include one or more kinds selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin. It is an agent. That is, a preferred aspect of the present invention is to prevent or treat weight gain or obesity caused by any of olanzapine, quetiapine, mirtazapine, and gabapentin. That is, when these drugs are administered (or before and after), endoplasmic reticulum stress inhibitors can be administered to suppress endoplasmic reticulum stress caused by these drugs, resulting in weight gain and obesity ( (Adipogenesis) can be effectively prevented. That is, a preferred embodiment of the present invention relates to a method for treating or preventing weight gain or obesity, which is a side effect of the aforementioned drug, comprising the step of administering the aforementioned drug and an endoplasmic reticulum stress inhibitor to a patient. Because these drugs are commercially available, patients should be inoculated with these drugs according to the marketed dosage and usage.
　小胞体ストレス抑制剤の投与量や投与回数は，その種類や対象に応じて適宜調整すればよい。 The dose and frequency of administration of the endoplasmic reticulum stress inhibitor may be appropriately adjusted according to the type and the subject.
　抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤は市販されている。このため，本発明における薬剤である抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症は，市販されているもの及び市販されているものから当業者が自明な範囲で変更を加えたものを適宜用いることができる。すなわち，これらの有効成分，有効成分の量，投与方法，製剤化の方法は，これらの市販されているものを基準として必要に応じて適宜修正したものを採用できる。 Antidepressants, antipsychotics, pain treatments, and fibromyalgia treatments are commercially available. For this reason, the antidepressant, antipsychotic agent, pain treatment agent, and fibromyalgia, which are agents in the present invention, are commercially available and those that are commercially available are modified within the obvious range of those skilled in the art. Can be used as appropriate. That is, these active ingredients, the amount of active ingredients, the administration method, and the formulation method can be appropriately modified as necessary based on these commercially available ones.
　プレガバリンは，日本ではリリカ（登録商標）として販売されている。プレガバリンの化学名は，（３Ｓ）－３－（アミノメチル）－５－メチルヘキサン酸（（３Ｓ）－３－（Ａｍｉｎｏｍｅｔｈｙｌ）－５－ｍｅｔｈｙｌｈｅｘａｎｏｉｃ　ａｃｉｄ）である。プレガバリンの添付文章によれば，線維筋痛症に伴う疼痛に対して，成人には初期用量としてプレガバリン１日日150mgを1日2回に分けて経口投与し、その後１週間以上かけて１日用量として300mgまで漸増した後，300～450mgで維持する。１日最高用量は450mgを超えないこととし，いずれも1日2回に分けて経口投与するとされている。 Pregabalin is sold as Lyrica (registered trademark) in Japan. The chemical name of pregabalin is (3S) -3- (aminomethyl) -5-methylhexanoic acid ((3S) -3- (Aminomethyl) -5-methylhexanoic acid). According to the pregabalin attachment, for pain associated with fibromyalgia, pregabalin is orally administered as an initial dose of 150 mg twice a day as an initial dose to adults, followed by one day over one week. The dose is gradually increased to 300 mg and then maintained at 300 to 450 mg. The maximum daily dose should not exceed 450 mg, and both are to be administered orally in two divided doses per day.
　たとえば，抗精神病薬であるジプレキサ（登録商標）ザイディス（登録商標）は，その有効成分がオランザピンである。ジプレキサ（登録商標）ザイディス（登録商標）は，成人にはオランザピンとして５～１０ｍｇを１日１回経口投与により開始する。維持量として１日１回１０ｍｇ経口投与する。なお，年齢，症状により適宜増減する。ただし，１日量は20mgを超えない。ジプレキサ（登録商標）ザイディス（登録商標）は，添付物として，ゼラチン，Ｄ－マンニトール，アスパルテーム（Ｌ－フェニルアラニン化合物），パラオキシ安息香酸メチルナトリウム，及びパラオキシ安息香酸プロピルナトリウムを含む。 For example, Zyplexa (registered trademark) Zydis (registered trademark), which is an antipsychotic drug, has an active ingredient olanzapine. Zyprexa® Zydis® is initiated by oral administration of 5-10 mg of olanzapine once daily to adults. As a maintenance dose, 10 mg is orally administered once a day. The dose may be adjusted according to age and symptoms. However, the daily dose does not exceed 20 mg. Zyprexa® Zydis® includes gelatin, D-mannitol, aspartame (L-phenylalanine compound), methyl sodium paraoxybenzoate, and propyl sodium paraoxybenzoate as attachments.
　たとえば，抗精神病薬剤であるセロクエル（登録商標）は，その有効成分がクエチアピン（クエチアピンフマル酸塩）であり，１回２５ｍｇ（クエチアピン当量）で１日２回又は３回投与する。そして，この薬剤は，添加物として，結晶セルロース，乳糖水和物，リン酸水素カルシウム水和物，ポビドン，デンプングリコール酸ナトリウム，ステアリン酸マグネシウム，ヒプロメロース，マクロゴール，酸化チタン，黄色三二酸化鉄，及び三二酸化鉄を含む。 For example, Seroquel (registered trademark), which is an antipsychotic drug, has an active ingredient of quetiapine (quetiapine fumarate) and is administered twice or three times a day at a dose of 25 mg (quetiapine equivalent). And this drug is added as crystalline cellulose, lactose hydrate, calcium hydrogen phosphate hydrate, povidone, sodium starch glycolate, magnesium stearate, hypromellose, macrogol, titanium oxide, yellow ferric oxide, And iron sesquioxide.
　たとえば，抗うつ剤であるリフレックス（登録商標）は，ミルタザピンを有効成分として含む。リフレックス（登録商標）は，成人にはミルタザピンとして１日１5mgを初期用量とし，１５～３０ｍｇを１日１回就寝前に経口投与する。なお，年齢，症状に応じ１日45mgを超えない範囲で適宜増減するが，増量は１週間以上の間隔をあけて１日用量として１5mgずつ行う。リフレックス（登録商標）は，添加物として，トウモロコシデンプン，ヒドロキシプロピルセルロース，ステアリン酸マグネシウム，軽質無水ケイ酸，乳糖水和物，ヒプロメロース，マクロゴール６０００，酸化チタン，及び黄色三二酸化鉄を含む。 For example, Reflex (registered trademark), which is an antidepressant, contains mirtazapine as an active ingredient. Reflex® is given to adults as mirtazapine at an initial dose of 15 mg / day and 15-30 mg orally once daily before going to bed. The dose may be adjusted according to age and symptoms within a range not exceeding 45 mg / day, but the dose should be increased to 15 mg / day at intervals of 1 week or longer. Reflex® includes corn starch, hydroxypropyl cellulose, magnesium stearate, light anhydrous silicic acid, lactose hydrate, hypromellose, macrogol 6000, titanium oxide, and yellow ferric oxide.
　たとえば，抗精神病薬剤及び線維筋痛症の治療剤であるガバペン（登録商標）は，その有効成分がガバペンチンであり，成人及び１３歳以上の小児にはガバペンチンとして初日１日量600mg，２日目１日量１２００mgをそれぞれ３回に分割経口投与する。３日目以降は，維持量として１日量１２００ｍｇ～１８００ｍｇを３回に分割経口投与する。なお，症状により適宜増減するが，１日最高投与量は２４００ｍｇまでとする。ガバペン（登録商標）は，添加物として，タルク，ヒドロキシプロピルセルロース，ヒプロメロース，トリアセチン，プロピレングリコール，コポリビドン，ポリオキシエチレンポリオキシプロピレングリコール，及びステアリン酸マグネシウムを含む。 For example, gabapentin, an antipsychotic drug and a therapeutic agent for fibromyalgia, has an active ingredient of gabapentin. For adults and children aged 13 years and over, the daily dose is 600 mg on the first day as gabapentin. The daily dose of 1200 mg is orally administered in 3 divided doses. After the third day, the daily dose of 1200 mg to 1800 mg is orally administered in divided doses in 3 doses. The dose may be adjusted according to the symptoms, but the maximum daily dose is 2400 mg. Gabapen® contains talc, hydroxypropylcellulose, hypromellose, triacetin, propylene glycol, copolyvidone, polyoxyethylene polyoxypropylene glycol, and magnesium stearate as additives.
　本発明の第２の側面は，医薬キットに関する。この医薬キットは，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれか１種又は２種以上を含む薬剤と，小胞体ストレス抑制剤とを含む。小胞体ストレス抑制剤は，前記薬剤により惹き起こされる副作用としての体重増加又は肥満の治療剤又は予防剤である。 The second aspect of the present invention relates to a pharmaceutical kit. The pharmaceutical kit includes an agent containing any one or more of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia, and an endoplasmic reticulum stress inhibitor. The endoplasmic reticulum stress inhibitor is a therapeutic or preventive agent for weight gain or obesity as a side effect caused by the drug.
　この側面の好ましい例は，薬剤が，プレガバリン，オランザピン（Olanzapine），クエチアピン（Quetiapine），ミルタザピン（Mirtazapine），及びガバペンチン（Gabapentin）からなる群から選ばれる１又は２種以上の剤である。 A preferred example of this aspect is one or more agents selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin.
　この医薬キットは，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれかと，小胞体ストレス抑制剤とが別々に存在してもよい。一方，たとえば一つの錠剤に，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれかと，小胞体ストレス抑制剤とが含まれてもよい。 In this pharmaceutical kit, any one of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia and an endoplasmic reticulum stress inhibitor may be present separately. On the other hand, for example, one tablet may contain any of an antidepressant, an antipsychotic agent, a pain therapeutic agent, and a therapeutic agent for fibromyalgia and an endoplasmic reticulum stress inhibitor.
　本発明は，対象（例えばヒト又はヒト以外の哺乳動物）に，抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤（薬剤）のいずれかを投与する工程と，小胞体ストレス抑制剤を投与する工程とを含む，薬剤により惹き起こされる副作用としての体重増加又は肥満の治療方法及び予防方法をも提供する。薬剤と同時又は薬剤を患者が接種するとともに小胞体ストレス抑制剤を接種した場合，薬剤が惹き起こす体重増加又は肥満を予防又は治療することができる。薬剤と小胞体ストレス抑制剤とは同時に接種してもよいし，別々に接種しても良い。 The present invention comprises a step of administering any of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a fibromyalgia therapeutic agent (drug) to a subject (eg, a human or a non-human mammal) The present invention also provides a method for treating and preventing weight gain or obesity as a side effect caused by a drug, including a step of administering an endoplasmic reticulum stress inhibitor. When the patient is inoculated with the drug at the same time or with the drug and an endoplasmic reticulum stress suppressant is inoculated, weight gain or obesity caused by the drug can be prevented or treated. The drug and endoplasmic reticulum stress suppressor may be inoculated simultaneously or separately.
　図１は，抗精神薬と抗うつ薬の一覧である。左欄は商品名，中欄は一般名，右欄は各薬の説明である。 Fig. 1 is a list of antipsychotics and antidepressants. The left column is the product name, the middle column is the generic name, and the right column is the description of each drug.
　抗精神薬は小胞体ストレスを誘導する
　293細胞を５　ｘ　１０４／ｗｅｌｌずつ２４　ｗｅｌｌ　ｐｌａｔｅに播種した。２４時間後，４　ｘ　ＥＲＳＥ　Ｌｕｃ　５０　ｎｇ，ｐＲＬ－ＴＫ　１　ｎｇをＬｉｐｏｆｅｃｔｒａｍｉｎｅ　２０００を用いてトランスフェクションした。一方のグループはＤＭＳＯを添加した。残りのクループは２μｇ／ｍｌツニカマイシン（ｔｕｎｉｃａｍｙｃｉｎ）を添加し小胞体ストレスを誘導した。その後，１００μＭ　オランザピン（Ｏｌａｎｚａｐｉｎｅ）　（Ｚｙｐｒｅｘａ），アリピプラゾール（Ａｒｉｐｉｐｒａｚｏｌｅ），１００μＭ　クエチアピン（Ｑｕｅｔｉａｐｉｎｅ）　（ｓｅｒｏｑｕｅｌ），１００　μＭ　ミルタザピン（Ｍｉｒｔａｚａｐｉｎｅ）（Ｒｅｆｌｅｘ），０．１　ｍｇ/ｍｌ　ガバペンチン（Ｇａｂａｐｅｎｔｉｎ）　（ＧＢＰ），３または１０μＭリスペリドン（Ｒｉｓｐｅｒｉｄｏｎｅ）　（Ｒｉｓｐｅｒｄａｌ）をツニカマイシンと同時に添加し３７℃で培養した。２４　時間後細胞を回収しＰａｓｓｉｖｅ　Ｌｙｓｉｓ　Ｂｕｆｆｅｒに溶解し，ルミノメーターによりＥＲＳＥ遺伝子の発現量を測定した。各実験は３連で行い，Ｄｕａｌ　Ｌｕｓｉｆｅｒａｓｅ法により補正した。 As an antipsychotic, 293 cells that induce endoplasmic reticulum stress were seeded at 5 × 10 4 / well on a 24 well plate. After 24 hours, 4 x ERSE Luc 50 ng and pRL-TK 1 ng were transfected using Lipofectamine 2000. One group added DMSO. The remaining croup was supplemented with 2 μg / ml tunicamycin to induce endoplasmic reticulum stress. Later, 100 μM Olanzapine (Zyprexa), Aripiprazole (Aripiprazole), 100 μM Quetiapine (seroquel), 100 μM Mirazapine (G), B Alternatively, 10 μM risperidone (Risperdal) was added simultaneously with tunicamycin and cultured at 37 ° C. After 24 hours, the cells were collected, dissolved in Passive Lysis Buffer, and the expression level of the ERSE gene was measured with a luminometer. Each experiment was performed in triplicate and corrected by the Dual Lusiferase method.
　測定結果を図２に示す。図２は，所定の薬剤を投与した際の小胞体ストレス応答エレメント（ＥＲＳＥ）遺伝子発現量を示す図面に替わるグラフである。図２において縦軸は発光量を示す。ｔｕｎｉｃａｍｙｃｉｎにより小胞体ストレスが誘導されていないコントロール細胞の発光量を１とした。発光量が多くなるほど，ＥＲＳＥ遺伝子発現量が上昇している（すなわち，小胞体ストレスが誘導されている）ことを示している。 The measurement results are shown in FIG. FIG. 2 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when a predetermined drug is administered. In FIG. 2, the vertical axis represents the amount of light emission. The amount of luminescence of control cells in which endoplasmic reticulum stress was not induced by tunicamycin was set to 1. It shows that the ERSE gene expression level increases as the amount of luminescence increases (that is, endoplasmic reticulum stress is induced).
　図２の左部分のグラフから，特定の抗精神薬を投与すると小胞体ストレスが誘導されることがわかる（特にＱｕｅｔｉａｐｉｎｅ）。さらにｔｕｎｉｃａｍｙｃｉｎにより小胞体ストレスが誘導された細胞に抗精神薬を投与すると，ｔｕｎｉｃａｍｙｃｉｎのみを投与した時に比べてさらに小胞体ストレスが誘導された（特にＯｌａｎｚａｐｉｎｅ，Ｑｕｅｔｉａｐｉｎｅ，Ｍｉｒｔａｚａｐｉｎｅ，Ｇａｂａｐｅｎｔｉｎ）。以上のことからいくつかの抗精神薬は，小胞体ストレスを誘導するか，又はｔｕｎｉｃａｍｙｃｉｎの作用（タンパク質への糖鎖修飾を阻害）を促進することが示された。 2 It can be seen from the graph in the left part of FIG. 2 that endoplasmic reticulum stress is induced when a specific antipsychotic is administered (particularly Quetiapine). Furthermore, when an antipsychotic was administered to cells in which endoplasmic reticulum stress was induced by tunicamycin, endoplasmic reticulum stress was further induced as compared to when tunicamycin alone was administered (especially Olanzapine, Quetiapine, Mirtapine, Gabapentin). From these results, it was shown that some antipsychotic drugs induce endoplasmic reticulum stress or promote the action of tunicamycin (inhibition of glycosylation on proteins).
　一方，図２の右部分のグラフに示されるとおり，Ｒｉｓｐｅｒｉｄｏｎｅを投与しても小胞体ストレスが誘導されなかった。一方，ｔｕｎｉｃａｍｙｃｉｎにより誘導された細胞にＲｉｓｐｅｒｉｄｏｎｅを投与した場合，投与量に比例して小胞体ストレスが抑制された。以上のことから，Ｒｉｓｐｅｒｉｄｏｎｅはｔｕｎｉｃａｍｙｃｉｎの作用を抑制することが示された。 On the other hand, as shown in the graph in the right part of FIG. 2, no endoplasmic reticulum stress was induced even when Risperidone was administered. On the other hand, when Risperidone was administered to cells induced by tunicamycin, endoplasmic reticulum stress was suppressed in proportion to the dose. From the above, it was shown that Risperidone suppresses the action of tunicamycin.
　脂肪細胞の分化検証
　３Ｔ３－Ｌ１細胞（脂肪前駆細胞）をＤＭＥＭ（１０%ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）でコンフルエントに達した後，３日間培養した。５００マイクロＭ　ＩＢＭＸ，１　マイクロＭ　Ｄｅｘａｍｅｔｈａｓｏｎｅ，５マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎを添加し分化を誘導した。３　日間培養後，４マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎを含む培地に置換した。３日間培養後，ＤＭＥＭ（１０　％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）に置換し3日間培養後，３Ｔ３－Ｌ１細胞をＰＢＳ（－）で洗ったのち，１０　％　ホルマリン（ｆｏｒｍａｌｉｎ）で固定した。固定後，ＰＢＳ（－）で洗浄し６０　％　Ｉｓｏｐｒｏｐａｎｏｌに置換した。１８　ｍｇ/ｍｌ　Ｏｉｌ　Ｒｅｄ　Ｏ/Ｉｓｏｐｒｏｐａｎｏｌで２０分染色し，６０％Ｉｓｏｐｒｏｐａｎｏｌ及びＰＢＳ（－）で洗浄し顕微鏡で観察した（Ｏｉｌ　Ｒｅｄ　Ｏ染色）。脂肪細胞は分化すると線維芽細胞の鋭角的な形態から丸い形になり，細胞内に微細な多くの脂肪滴が見られるようになる。 Verification of Adipocyte Differentiation 3T3-L1 cells (preadipocytes) were confluent with DMEM (10% FBS, Hihg Glucose) and then cultured for 3 days. Differentiation was induced by adding 500 microM IBMX, 1 microM Dexamethasone, 5 microg / ml Insulin. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose). After culturing for 3 days, 3T3-L1 cells were washed with PBS (−), and then fixed with 10% formalin. After fixation, the plate was washed with PBS (−) and replaced with 60% Isopropanol. It was stained with 18 mg / ml Oil Red O / Isopropanol for 20 minutes, washed with 60% Isopropanol and PBS (−), and observed with a microscope (Oil Red O staining). When adipocytes differentiate, they become round from the acute shape of fibroblasts, and many fine lipid droplets can be seen in the cells.
　図３は，脂肪細胞への分化を示す図面に替わる写真である。図３左の２つの図は分化が誘導されていないコントロール細胞を示す。図３右の２つの図は分化が誘導された細胞を示す。図３は，倍率４倍（上），及び倍率１０倍（下）でそれぞれ観察したものである。ＩＢＭＸ/ｄｅｘ/Ｉｎｓｕｌｉｎにより３Ｔ３－Ｌ１細胞の分化が促進され，Ｏｉｌ　Ｒｅｄ　Ｏ染め色によりコントロール細胞に比べて脂肪滴が増加したことが確認された。 FIG. 3 is a photograph replacing a drawing showing differentiation into adipocytes. The two figures on the left of FIG. 3 show control cells in which differentiation has not been induced. The two figures on the right of FIG. 3 show cells in which differentiation has been induced. FIG. 3 was observed at a magnification of 4 times (upper) and at a magnification of 10 times (lower). It was confirmed that the differentiation of 3T3-L1 cells was promoted by IBMX / dex / Insulin, and lipid droplets were increased by the Oil Red O dyeing color as compared to the control cells.
　３Ｔ３－Ｌ１細胞をＤＭＥＭ　（１０　％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）でコンフルエントに達した後３日間培養した。５００　マイクロＭ　ＩＢＭＸ，１　マイクロＭ　Ｄｅｘａｍｅｔｈａｓｏｎｅ，５　μｇ/ｍｌ　Ｉｎｓｕｌｉｎを添加し分化を誘導した。同時に１００　マイクロＭ　Ｑｕｅｔｉａｐｉｎｅ　（ｓｅｒｏｑｕｅｌ）又はＤＭＳＯを添加した。３日間培養後，４　マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎ　を含む培地に置換し同様に薬剤を添加した。３日間培養後，ＤＭＥＭ　（　１０　％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）　に置換し3日間培養後，Ｏｉｌ　Ｒｅｄ　Ｏ　染色を行った。 3T3-L1 cells were cultured for 3 days after reaching confluence with DMEM (10% FBS, Hihg Glucose). Differentiation was induced by adding 500 microM IBMX, 1 microM Dexamethasone, 5 μg / ml Insulin. At the same time, 100 micro M Quetiapine (seroquel) or DMSO was added. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin, and the drug was added in the same manner. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose), cultured for 3 days, and then Oil Red O staining was performed.
　その結果を図４に示す。図４は，脂肪細胞への分化を示す図面に替わる写真である。図４上の４つの図がコントロール細胞（ＤＭＥＭ添加），下の４つの図が３Ｔ３－Ｌ１細胞の分化を促進させた後Ｑｕｅｔｉａｐｉｎｅを投与した細胞を示す図面に替わる写真である。コントロール細胞と比較して脂肪滴の増加が観察された。以上のことから，Ｑｕｅｔｉａｐｉｎｅは脂肪細胞の分化促進に関与していることが示された。 The result is shown in FIG. FIG. 4 is a photograph replacing a drawing showing differentiation into fat cells. The upper four diagrams in FIG. 4 are control cells (with DMEM added), and the lower four diagrams are photographs replacing the drawings showing cells to which 3T3-L1 cells have been differentiated and to which quetiapine has been administered. An increase in lipid droplets was observed compared to control cells. From the above, it was shown that Quetiapine is involved in promoting differentiation of adipocytes.
　３Ｔ３－Ｌ１細胞をＤＭＥＭ　（　１０　％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）でコンフルエントに達した後３日間培養した。５００　マイクロＭ　ＩＢＭＸ，１　マイクロＭ　Ｄｅｘａｍｅｔｈａｓｏｎｅ，５　マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎ　を添加し分化を誘導した。同時に３０　マイクロｇ/ｍｌ　Ｇａｂａｐｅｎｔｉｎ，１００又は２００　マイクロＭ　Ｏｌａｎｚａｐｉｎｅ　（Ｚｙｐｒｅｘａ），１００　マイクロＭ　Ｍｉｒｔａｚａｐｉｎｅ　（Ｒｅｆｌｅｘ）もしくはＤＭＳＯを添加した。３日間培養後，４　マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎを含む培地に置換し同様に薬剤を添加した。３日間培養後，ＤＭＥＭ　（１０　％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）に置換し３日間培養後，オイルレッドＯ染色を行った。 3T3-L1 cells were cultured for 3 days after reaching confluence with DMEM (10% FBS, Hihg Glucose). 500 micro M IBMX, 1 micro M Dexamethasone, 5 micro g / ml Insulin were added to induce differentiation. At the same time, 30 micro g / ml Gabapentin, 100 or 200 micro M Olanzapine (Zyprexa), 100 micro M Mirazapine (Reflex) or DMSO was added. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin, and the drug was added in the same manner. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose), and after culturing for 3 days, oil red O staining was performed.
　その結果を図５に示す。図５は，脂肪細胞への分化を示す図面に替わる写真である。図５から，Ｇａｂａｐｅｎｔｉｎ，Ｏｌａｎｚａｐｉｎｅ　（Ｚｙｐｒｅｘａ），Ｍｉｒｔａｚａｐｉｎｅを投与したところコントロール細胞（ＤＭＥＭ添加）に比べて脂肪滴が増加することが示された。特に２００　マイクロＭ　Ｏｌａｎｚａｐｉｎｅを投与したときに，脂肪滴の数が有意に増加した。 The result is shown in FIG. FIG. 5 is a photograph replacing a drawing showing differentiation into fat cells. From FIG. 5, it was shown that when Gabapentin, Olanzapine (Zyprexa), and Mirazapine were administered, lipid droplets increased as compared to control cells (DMEM addition). In particular, when 200 microM Olanzapine was administered, the number of fat droplets increased significantly.
　３Ｔ３－Ｌ１細胞をＤＭＥＭ（１０　％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）でコンフルエントに達した後3日間培養した。５００マイクロＭ　ＩＢＭＸ，１　マイクロＭ　Ｄｅｘａｍｅｔｈａｓｏｎｅ，５マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎを添加し分化を誘導した。同時に２０マイクロＭ　Ｐｒａｍｉｐｅｘｏｌｅ，１００　マイクロＭ　Ｒｏｐｉｎｉｒｏｌｅ，５０マイクロＭ　Ｌ－ＤＯＰＡ，もしくはＤＭＳＯ　を添加した。3日間培養後，４マイクロｇ/ｍｌ　Ｉｎｓｕｌｉｎを含む培地に置換し同様に薬剤を添加した。３日間培養後，ＤＭＥＭ（１０％　ＦＢＳ,　Ｈｉｈｇ　Ｇｌｕｃｏｓｅ）に置換し３日間培養後，Ｏｉｌ　Ｒｅｄ　Ｏ染色を行った。 3T3-L1 cells were cultured for 3 days after reaching confluence with DMEM (10% FBS, Hihg Glucose). Differentiation was induced by adding 500 microM IBMX, 1 microM Dexamethasone, 5 microg / ml Insulin. At the same time, 20 micro M Pramipoleole, 100 micro M Ropinirole, 50 micro M L-DOPA, or DMSO was added. After culturing for 3 days, the medium was replaced with a medium containing 4 microg / ml Insulin, and the drug was added in the same manner. After culturing for 3 days, it was replaced with DMEM (10% FBS, Hihg Glucose), cultured for 3 days, and then Oil Red O staining was performed.
　その結果を図６に示す。図６は，脂肪細胞への分化を示す図面に替わる写真である。図６に示すとおり，分化が誘導された３Ｔ３－Ｌ１細胞にＰｒａｍｉｐｅｘｏｌｅ，Ｒｏｐｉｎｉｒｏｌｅ，Ｌ－ＤＯＰＡをそれぞれ投与しても，コントロール細胞（ＤＭＥＭ添加）と比べて有意に脂肪滴の増加は観察されなかった。 The result is shown in FIG. FIG. 6 is a photograph replacing a drawing showing differentiation into fat cells. As shown in FIG. 6, no significant increase in lipid droplets was observed even when Pramipexole, Ropinirole, or L-DOPA was administered to 3T3-L1 cells in which differentiation was induced, compared to control cells (DMEM addition). .
　シノビオリンはユビキチン化の基質認識を司るＥ３ユビキチンリガーゼの１つである。これまでにシノビオリンノックアウトマウスにおいて体重と白脂肪組織が減少することが報告されており，シノビオリンは体重コントロールシステムに関与していることが報告されている。また，シノビオリンはＰＧＣ－１β（ミトコンドリア生合成とエネルギー代謝に関与しており，肥満抑制に関与している分子）の機能を抑制していることが報告されている。 Synoviolin is one of the E3 ubiquitin ligases that govern substrate recognition for ubiquitination. So far, it has been reported that synoviolin knockout mice have decreased body weight and white adipose tissue, and synoviolin has been reported to be involved in the body weight control system. Synoviolin has also been reported to suppress the function of PGC-1β (a molecule involved in mitochondrial biogenesis and energy metabolism and involved in obesity suppression).
　小胞体ストレスが発生すると，通常は小胞体ストレス応答（ｕｎｆｏｌｄｅｄ　ｐｒｏｔｅｉｎ　ｒｅｓｐｏｎｓｅ）が機能することにより小胞体ストレスが回避されるが，何らかの理由で小胞体ストレス応答が機能しなくなるとアポトーシス（細胞死）が誘導される。具体的には小胞体ストレス応答により異常タンパク質はＥ３ユビキチンリガーゼによりポリユビキチン化され，プロテアソームによって分解され，小胞体の恒常性が保たれる。これまでに小胞体ストレス応答に関与している遺伝子をノックアウトしたマウスでインスリン抵抗性が見られたことから，小胞体ストレスへの応答メカニズムが破綻すると肥満が誘導されることが示唆されている。 When endoplasmic reticulum stress occurs, the endoplasmic reticulum stress response is normally avoided by the function of the endoplasmic reticulum stress response, but if the endoplasmic reticulum stress response fails for some reason, apoptosis (cell death) occurs. Be guided. Specifically, an abnormal protein is polyubiquitinated by E3 ubiquitin ligase by the endoplasmic reticulum stress response, and is degraded by the proteasome, thereby maintaining the homeostasis of the endoplasmic reticulum. Insulin resistance has been observed in mice that have knocked out genes involved in the endoplasmic reticulum stress response so far, suggesting that obesity is induced when the response mechanism to endoplasmic reticulum stress fails.
　精神病を患っており，薬剤（オランザピン（Ｏｌａｎｚａｐｉｎｅ），クエチアピン（Ｑｕｅｔｉａｐｉｎｅ），又はミルタザピン（Ｍｉｒｔａｚａｐｉｎｅ））の投与により体重増加や肥満の傾向が見られた２４名の患者を投与された薬剤に応じた３つのグループに分けた。一方，線維筋痛症に罹患し疼痛を訴えるとともに，ガバペンチン（Ｇａｂａｐｅｎｔｉｎ）が投与されたことに伴う体重増加や肥満の傾向を訴える８名の患者を最後のグループとした。 24 patients who suffered from psychosis and were prone to weight gain or obesity with administration of drugs (Olanzapine, Quetiapine, or mirtazapine) 3 Divided into two groups. On the other hand, eight patients who suffered from fibromyalgia and complained of pain and complained of weight gain and obesity associated with the administration of gabapentin were taken as the last group.
　それぞれのグループの２名の患者に，上記した薬剤とともに，ビ・シフロール（登録商標）を１回当たりプラミペキソール塩酸塩水和物当量で０．２ｍｇ摂取させた。すると投与計画後１週間でいずれ体重の増加や肥満に顕著な改善が見られた。また，それぞれのグループの２名の患者に，上記した薬剤とともに，レキップ（登録商標）錠を１回当たりロピニロール塩酸塩当量で０．２ｍｇ摂取させた。すると投与計画後１週間でいずれも体重の増加や肥満に顕著な改善が見られた。 Two patients in each group were given 0.2 mg of pipipexol hydrochloride hydrate equivalent per dose of Bi-Siflor (registered trademark) together with the above-mentioned drugs. Then, in one week after the administration schedule, the body weight gain and obesity were remarkably improved. Two patients in each group received 0.2 mg of Ropinirole hydrochloride equivalent each time together with the above-mentioned drugs. Then, in one week after the administration schedule, weight gain and obesity were remarkably improved in all cases.
　また，それぞれのグループの残りの２名の患者に，上記した薬剤と合わせて小胞体ストレス抑制剤を投与したところ，有意に体重の増加や肥満に改善が見られた。 Moreover, when the endoplasmic reticulum stress inhibitor was administered to the remaining 2 patients in each group together with the above-mentioned drugs, weight gain and obesity were significantly improved.
　２９３細胞を５×１０４／ｗｅｌｌずつ２４ウェルプレートに播種した。２４時間後４ｘＥＲＳＥ　Ｌｕｃ　５０ｎｇ、ｐＲＬ－ＴＫ １ｎｇをインビロトジェン社製Ｌｉｐｏｆｅｃｔａｍｉｎｅ（リポフェクトアミン）２０００を用いてトランスフェクションした。ＤＭＳＯもしくは２μｇ／/ｍｌツニカマイシン（Ｔｕｎｉｃａｍｙｃｉｎ）を添加し，小胞体ストレスを誘導した。ＤＭＳＯもしくは１,１０μＭプレガバリン（Ｐｒｅｇａｂａｌｉｎ）を添加し３７℃で２４ 時間培養した。細胞をＰａｓｓｉｖｅ Ｌｙｓｉｓ Ｂｕｆｆｅｒ（パッシブライシスバッファー）に溶解し、ルミノメーターにより活性を測定した。各実験は３連で行い、Ｄｕａｌ Ｌｕｓｉｆｅｒａｓｅ（デュアルルシフェラーゼ）法により補正した。その結果を図７に示す。図７は，ツニカマイシンを投与したもの（右）としないもの（左）における，ＤＭＳＯ又はプレガバリンを投与した際の小胞体ストレス応答エレメント（ＥＲＳＥ）遺伝子発現量を示す図面に替わるグラフである。プレガバリンは，リリカ（登録商標）として販売されている，神経障害性疼痛に用いられる処方箋医薬品である。図７から，プレガバリンは小胞体ストレスを誘導し，ツニカマイシンの作用を高めることがわかる。 293 cells were seeded at 5 × 10 4 / well in a 24-well plate. After 24 hours, 4 × ERSE Luc 50 ng and pRL-TK 1 ng were transfected using Lipofectamine (Lipofectamine) 2000 manufactured by Inbirotogen. DMSO or 2 μg // ml tunicamycin was added to induce endoplasmic reticulum stress. DMSO or 1,10 μM pregabalin was added and cultured at 37 ° C. for 24 hours. The cells were lysed in Passive Lysis Buffer (passive lysis buffer), and the activity was measured with a luminometer. Each experiment was performed in triplicate and corrected by the Dual Lusiferase method. The result is shown in FIG. FIG. 7 is a graph instead of a drawing showing the endoplasmic reticulum stress response element (ERSE) gene expression level when DMSO or pregabalin is administered in tunicamycin administered (right) and not (left). Pregabalin is a prescription drug used for neuropathic pain, marketed as Lyrica®. FIG. 7 shows that pregabalin induces endoplasmic reticulum stress and enhances the action of tunicamycin.
　線維筋痛症患者由来の末梢血単核球ＲＮＡの調整および小胞体ストレス関連因子の発現解析
　プレガバリン処方前および処方１ヶ月後の線維筋痛症患から採取した血液から、Ｐａｎｃａｌｌ　ｄｅｎｓｉｔｙ　１．０７７ｇ／ｍｌ　（ＰＡＮ　ＢＩＯＴＥＣＨ）を用いて比重分離法により末梢血単核球を調整した。末梢血単核球からＲＮｅａｓｙ　ｋｉｔ（キアゲン社製）を用いてｔｏｔａｌ　ＲＮＡを精製し、逆転写酵素反応によりｃＤＮＡを合成した。ＳｔｅｐＯｎｅＰｌｕｓリアルタイムＰＣＲシステム（Ｌｉｆｅ　Ｔｅｃｈｎｏｌｏｇｉｅｓ社製）を用いて小胞体ストレスにより活性化される遺伝子Ｇｒｐ７８，ＸＢＰ－１のプレガバリン処方前後での発現量の変化を測定した。 Preparation of peripheral blood mononuclear RNA from fibromyalgia patients and analysis of expression of endoplasmic reticulum stress-related factors From blood collected from patients with fibromyalgia before and 1 month after pregabalin prescription, 1.075 g of pancall density Peripheral blood mononuclear cells were prepared by specific gravity separation using ml (PAN BIOTECH). Total RNA was purified from peripheral blood mononuclear cells using RNeasy kit (Qiagen), and cDNA was synthesized by reverse transcriptase reaction. Using a StepOnePlus real-time PCR system (manufactured by Life Technologies), changes in the expression levels of the genes Grp78 and XBP-1 activated by endoplasmic reticulum stress before and after pregabalin prescription were measured.
　それぞれの遺伝子の発現量は内部コントロールＧＡＰＤＨの値により補正した。ＰＣＲ反応には以下のプライマーを用いた。
　Ｇｒｐ７８（フォワード：TTCAGGAGCAAATGTCTTTGTTT（配列番号１），
　リバース：AGTTCTTGCCGTTCAAGGTG（配列番号２）），
　ＸＢＰ－１（フォワード：GGAGTTAAGACAGCGCTTGG（配列番号３），
　リバース：CACTGGCCTCACTTCATTC（配列番号４）），
　ＧＡＰＤＨ（フォワード：GAGGTGGGGAAGGGGTATAA（配列番号５），リバース： ATCTTCTCCAGCCCAGCA（配列番号６））。
　また，ＰＣＲは，上記したＰＣＲシステムの解説書の記載に従って行い，ＰＣＲサイクルとして以下の条件を採用した。
　　熱変性（９５℃１０秒），アニーリング及び伸長反応（６０℃３０秒）を１サイクルとするするサイクルを４０サイクル行った。
　その結果を図８に示す。 The expression level of each gene was corrected by the value of the internal control GAPDH. The following primers were used for the PCR reaction.
Grp78 (forward: TTCAGGAGCAAATGTCTTTGTTT (SEQ ID NO: 1),
Reverse: AGTTCTTGCCGTTCAAGGTG (SEQ ID NO: 2)),
XBP-1 (forward: GGAGTTAAGACAGCGCTTGG (SEQ ID NO: 3),
Reverse: CACTGGCCTCACTTCATTC (SEQ ID NO: 4)),
GAPDH (forward: GAGGTGGGGAAGGGGTATAA (SEQ ID NO: 5), reverse: ATCTTCTCCAGCCCAGCA (SEQ ID NO: 6)).
Moreover, PCR was performed according to the description of the above-mentioned description of the PCR system, and the following conditions were adopted as PCR cycles.
40 cycles of heat denaturation (95 ° C. for 10 seconds), annealing and elongation reaction (60 ° C. for 30 seconds) as one cycle were performed.
The result is shown in FIG.
　図８から，線維筋痛症患者において，線維筋痛症の治療剤を摂取した患者において，小胞体ストレスにより活性化される遺伝子Ｇｒｐ７８，ＸＢＰ－１の発現が増加していることがわかる。すなわち，小胞体ストレス抑制剤を有効成分として含む体重増加又は肥満の治療剤又は予防剤を投与することで，線維筋痛症の治療剤を摂取する患者又は摂取した患者の小胞体ストレスに起因する体重増加や肥満を防止できることがわかる。 FIG. 8 shows that in patients with fibromyalgia, the expression of genes Grp78 and XBP-1 activated by endoplasmic reticulum stress is increased in patients taking a therapeutic agent for fibromyalgia. That is, by administering a therapeutic agent or preventive agent for weight gain or obesity containing an endoplasmic reticulum stress inhibitor as an active ingredient, it is caused by endoplasmic reticulum stress of a patient taking or taking a therapeutic agent for fibromyalgia. It turns out that weight gain and obesity can be prevented.
　配列番号１：プライマー
　配列番号２：プライマー
　配列番号３：プライマー
　配列番号４：プライマー
　配列番号５：プライマー
　配列番号６：プライマー Sequence number 1: Primer Sequence number 2: Primer Sequence number 3: Primer Sequence number 4: Primer Sequence number 5: Primer Sequence number 6: Primer

Claims (6)

  1. 　小胞体ストレス抑制剤を有効成分として含む，
    　抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれか１種又は２種以上を含む薬剤により惹き起こされる副作用としての体重増加又は肥満の治療剤又は予防剤。     Containing endoplasmic reticulum stress inhibitor as an active ingredient,
    A therapeutic or preventive agent for weight gain or obesity as a side effect caused by a drug comprising one or more of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a therapeutic agent for fibromyalgia.
  2. 　請求項１に記載の治療剤又は予防剤であって，
    　前記薬剤が，プレガバリン，オランザピン，クエチアピン，ミルタザピン，及びガバペンチンからなる群から選ばれる１又は２種以上の剤を含む，
    　治療剤又は予防剤。     The therapeutic or prophylactic agent according to claim 1,
    The drug comprises one or more agents selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin,
    A therapeutic or prophylactic agent.
  3. 　請求項１又は２に記載の治療剤又は予防剤であって，
    　前記小胞体ストレス抑制剤が，
    　　プラミペキソール，プラミペキソールの薬学的に許容される塩，又はプラミペキソールの薬学的に許容される溶媒和物であるか，
    　　ロピニロール，ロピニロールの薬学的に許容される塩，又はロピニロールの薬学的に許容される溶媒和物である，
    　治療剤又は予防剤。     The therapeutic agent or prophylactic agent according to claim 1 or 2,
    The endoplasmic reticulum stress inhibitor is
    Pramipexole, a pharmaceutically acceptable salt of pramipexole, or a pharmaceutically acceptable solvate of pramipexole,
    Ropinirole, a pharmaceutically acceptable salt of ropinirole, or a pharmaceutically acceptable solvate of ropinirole,
    A therapeutic or prophylactic agent.
  4. 　抗うつ剤，抗精神病薬剤，疼痛治療剤，及び線維筋痛症の治療剤のいずれか１種又は２種以上を含む薬剤と，
    　小胞体ストレス抑制剤と，を含む，
    　医薬キット。     A drug comprising one or more of an antidepressant, an antipsychotic drug, a pain therapeutic agent, and a therapeutic agent for fibromyalgia,
    Endoplasmic reticulum stress inhibitor,
    Pharmaceutical kit.
  5. 　請求項４に記載の医薬キットであって，
    　前記薬剤が，プレガバリン，オランザピン，クエチアピン，ミルタザピン，及びガバペンチンからなる群から選ばれる１又は２種以上の剤を含む，
    　医薬キット。     A pharmaceutical kit according to claim 4, wherein
    The drug comprises one or more agents selected from the group consisting of pregabalin, olanzapine, quetiapine, mirtazapine, and gabapentin,
    Pharmaceutical kit.
  6. 　請求項４に記載の医薬キットであって，
    　前記小胞体ストレス抑制剤は，前記薬剤により惹き起こされる副作用としての体重増加又は肥満の治療剤又は予防剤である，
    　医薬キット。     A pharmaceutical kit according to claim 4, wherein
    The endoplasmic reticulum stress inhibitor is a therapeutic or preventive agent for weight gain or obesity as a side effect caused by the drug,
    Pharmaceutical kit.
PCT/JP2014/065186 2013-06-10 2014-06-09 Obesity preventative used to prevent body weight increase or obesity being drug side effect, by suppressing endoplasmic reticulum stress signal WO2014199935A1 (en)

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