[go: up one dir, main page]

WO2014199935A1 - Agent de prévention utilisé pour prévenir l'augmentation de la masse corporelle ou l'obésité en tant qu'effet indésirable d'un médicament, par la suppression du signal de stress du réticulum endoplasmique - Google Patents

Agent de prévention utilisé pour prévenir l'augmentation de la masse corporelle ou l'obésité en tant qu'effet indésirable d'un médicament, par la suppression du signal de stress du réticulum endoplasmique Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
endoplasmic reticulum
obesity
reticulum stress
drug
agent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2014/065186
Other languages
English (en)
Japanese (ja)
Inventor
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSS KK
Original Assignee
MSS KK
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 MSS KK filed Critical MSS KK
Publication of WO2014199935A1 publication Critical patent/WO2014199935A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le problème décrit par la présente invention est de fournir un agent prophylactique ou de traitement contre l'augmentation de la masse corporelle ou de l'obésité en tant qu'effet indésirable de la prise d'antidépresseurs, de médicaments antipsychotiques, d'analgésiques ou d'agents de traitement de la fibromyalgie. La solution selon l'invention consiste à fournir un agent prophylactique ou de traitement contre l'augmentation de la masse corporelle ou de l'obésité, incluant en tant que composant efficace un suppresseur du signal de stress du réticulum endoplasmique, ladite obésité ou augmentation de la masse corporelle étant un effet indésirable de médicaments dont un au moins parmi les antidépresseurs, les médicaments antipsychotiques, les analgésiques et les agents de traitement de la fibromyalgie. Des exemples de suppresseurs du stress du réticulum endoplasmique sont le pramipexole, un sel pharmacologiquement acceptable du pramipexole, un solvate pharmacologiquement acceptable du pramipexole, le ropinirole, un sel pharmacologiquement acceptable du ropinirole et un solvate pharmacologiquement acceptable du ropinirole.
PCT/JP2014/065186 2013-06-10 2014-06-09 Agent de prévention utilisé pour prévenir l'augmentation de la masse corporelle ou l'obésité en tant qu'effet indésirable d'un médicament, par la suppression du signal de stress du réticulum endoplasmique Ceased WO2014199935A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2013-121694 2013-06-10
JP2013121694 2013-06-10
JP2013-206486 2013-10-01
JP2013206486 2013-10-01

Publications (1)

Publication Number Publication Date
WO2014199935A1 true WO2014199935A1 (fr) 2014-12-18

Family

ID=52022231

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2014/065186 Ceased WO2014199935A1 (fr) 2013-06-10 2014-06-09 Agent de prévention utilisé pour prévenir l'augmentation de la masse corporelle ou l'obésité en tant qu'effet indésirable d'un médicament, par la suppression du signal de stress du réticulum endoplasmique

Country Status (1)

Country Link
WO (1) WO2014199935A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008530050A (ja) * 2005-02-10 2008-08-07 ビオプロジェ １−［３−［３−（４−クロロフェニル）プロポキシ］プロピル］−ピペリジン一塩酸塩
WO2009035473A2 (fr) * 2007-09-13 2009-03-19 Sanfilippo Louis C Procédé de traitement de la frénésie alimentaire, de l'obésité causée par un comportement de frénésie alimentaire et des troubles dépressifs
JP2009528999A (ja) * 2006-02-21 2009-08-13 アンプラ ファーマシューティカルズ インコーポレイテッド Ｃｂ１アンタゴニストおよび逆アゴニスト
JP2011502175A (ja) * 2007-11-05 2011-01-20 マッキントッシュ、ダイアン 非定型抗精神病薬の使用に関連した体重増加を遅延させるための方法および組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008530050A (ja) * 2005-02-10 2008-08-07 ビオプロジェ １−［３−［３−（４−クロロフェニル）プロポキシ］プロピル］−ピペリジン一塩酸塩
JP2009528999A (ja) * 2006-02-21 2009-08-13 アンプラ ファーマシューティカルズ インコーポレイテッド Ｃｂ１アンタゴニストおよび逆アゴニスト
WO2009035473A2 (fr) * 2007-09-13 2009-03-19 Sanfilippo Louis C Procédé de traitement de la frénésie alimentaire, de l'obésité causée par un comportement de frénésie alimentaire et des troubles dépressifs
JP2011502175A (ja) * 2007-11-05 2011-01-20 マッキントッシュ、ダイアン 非定型抗精神病薬の使用に関連した体重増加を遅延させるための方法および組成物

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Ko Tenkanzai Gabapen Tablets 200mg Gabapen Tablets 300mg Gabapen Tablets 400mg", IRYO-YO IYAKUHIN TENPU BUNSHO, 2013, pages 1 - 6, Retrieved from the Internet <URL:http://www.info.pmda.go.jp/downfiles/ph/PDF/671450_1139007F1022_2_05.pdf> [retrieved on 20140813] *
"Totsu Chiryozai ( Shinkei Shogaisei Totsu . Sen'ikintsusho) Lyrica Capsules 25mg Lyrica Capsules 75mg Lyrica Capsules 150mg", IRYO-YO IYAKUHIN TENPU BUNSHO, 2013, pages 1 - 8, Retrieved from the Internet <URL:http://www.info.pmda.go.jp/downfiles/ ph/PDF/671450_1190017M1028_1_11.pdf> [retrieved on 20140813] *
HIROSHI OKA ET AL.: "Totsu Shikkan Sen'ikintsusho", CLIN NEUROSCI., vol. 27, no. 5, 2009, pages 548 - 549 *
MAKOTO SUEISHI ET AL.: "Toin ni Okeru Sen'ikintsusho (FM) Chiryo Keiken", THE 55TH ANNUAL GENERAL ASSEMBLY AND SCIENTIFIC MEETING OF JAPAN COLLEGE OF RHEUMATOLOGY/THE 20TH INTERNATIONAL RHEUMATOLOGY SYMPOSIUM PROGRAM SHOROKUSHU, 2011, pages 247 *
MASANORI FUKUSHIMA, MERCK MANUAL, 10 December 1999 (1999-12-10), pages 1538 - 1539 *
OZASA R ET AL.: "The antipsychotic olanzapine induces apoptosis in insulin-secreting pancreatic beta cells by blocking PERK-mediated translational attenuation.", CELL STRUCT FUNCT., vol. 38, no. 2, 2013, pages 183 - 195 *
ZAREBA G.: "New treatment options in the management of fibromyalgia: role of pregabalin.", NEUROPSYCHIATR DIS TREAT., vol. 4, no. 6, 2008, pages 1193 - 1201 *

Similar Documents

Publication Publication Date Title
EP2579879B1 (fr) Dérivés de triazine pour retarder l&#39;apparition du diabète de type 1
EP3240538B1 (fr) Utilisation de masitinib pour le traitement d&#39;une sous-population de patients atteints de sclérose latérale amyotrophique
US20220184075A1 (en) Pharmaceutical composition containing hdac6 inhibitor as active ingredient for prevention or treatment of itching
EP2523557B1 (fr) Méthodes permettant de faire perdre du poids à des patients souffrant d&#39;une dépression sévère
US12364672B2 (en) Esketamine for use in treating major depressive disorder
CN112384220A (zh) sGC刺激剂治疗线粒体障碍的用途
KR20130083895A (ko) 2형 당뇨병의 치료
WO2015165948A2 (fr) Compositions, procédés et utilisations pour le traitement de neuropathies diabétiques
JP2018514556A (ja) 肝疾患の予防および治療のための薬物の調製におけるトリメタジジンの使用
KR101516677B1 (ko) 지방성 간 질환의 치료용 의약 조성물
EP2614821B1 (fr) Composition pharmaceutique pour le traitement d&#39;un trouble de l&#39;anxiété, contenant de la n-acétyl-l-cystéine ou un dérivé de celle-ci
CN104013638B (zh) 当药黄素及其衍生物的用途
CN118354769A (zh) 治疗激越和其它痴呆症相关的行为症状的方法
WO2014199935A1 (fr) Agent de prévention utilisé pour prévenir l&#39;augmentation de la masse corporelle ou l&#39;obésité en tant qu&#39;effet indésirable d&#39;un médicament, par la suppression du signal de stress du réticulum endoplasmique
EP4420660A1 (fr) Utilisation d&#39;édaravone dans le traitement d&#39;un trouble du spectre de l&#39;autisme
EA019194B1 (ru) Применение 4-циклопропилметокси-n-(3,5-дихлор-1-оксидопиридин-4-ил)-5-(метокси)пиридин-2-карбоксамида для лечения моторных нарушений, связанных с болезнью паркинсона
RU2391095C1 (ru) Фармацевтическая композиция, включающая холина альфосцерат и гопантеновую кислоту (или ее соль), для лечения недостаточности кровообращения мозга и эректильной дисфункции
CZ301210B6 (cs) Použití desoxypeganinu k ošetrování klinické deprese
US10426836B2 (en) Compositions and methods for treating stress-related disorders
CN112437661A (zh) 苯甲酸或其盐用于预防或治疗抗n-甲基-d-天冬氨酸受体脑炎的用途
CN104411308A (zh) 通过给予某些合成化合物治疗阿尔茨海默病的方法
CN110384705B (zh) 山楂酸在制备治疗2型糖尿病胰岛细胞损伤药物中的应用
CN102670597A (zh) 5-(4-羟基-3-甲氧基苯亚甲基)罗丹宁在制备治疗帕金森氏病药物中的用途
JP2025087929A (ja) うつ病および／またはうつ状態の治療および／または予防用医薬
WO2023076936A1 (fr) Utilisation d&#39;auranofine en tant qu&#39;inhibiteur de protéine kinase c atypique pour le traitement de troubles neurodégénératifs

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: 14811241

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: 14811241

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP