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WO2016031264A1 - Agent d'augmentation du volume des muscles squelettiques et son utilisation - Google Patents

Agent d'augmentation du volume des muscles squelettiques et son utilisation Download PDF

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Publication number
WO2016031264A1
WO2016031264A1 PCT/JP2015/053580 JP2015053580W WO2016031264A1 WO 2016031264 A1 WO2016031264 A1 WO 2016031264A1 JP 2015053580 W JP2015053580 W JP 2015053580W WO 2016031264 A1 WO2016031264 A1 WO 2016031264A1
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WO
WIPO (PCT)
Prior art keywords
meclizine
congenital
syndrome
muscle
skeletal muscle
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PCT/JP2015/053580
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English (en)
Japanese (ja)
Inventor
欽司 大野
石黒　直樹
哲朗 飛田
松下　雅樹
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国立大学法人名古屋大学
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Application filed by 国立大学法人名古屋大学 filed Critical 国立大学法人名古屋大学
Publication of WO2016031264A1 publication Critical patent/WO2016031264A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • the present invention relates to a skeletal muscle bulking agent and use thereof.
  • the skeletal muscle bulking agent of the present invention is used, for example, for the treatment of sarcopenia.
  • Muscle loss such as sarcopenia
  • Muscle loss that causes a decrease in skeletal muscle mass is considered to be one of the causes of reduced mobility, falling fractures, and vulnerability in the elderly.
  • the treatment is seen as a trump card for maintaining a healthy life expectancy.
  • There is no fundamental cure for sarcopenia and exercise therapy, nutrition therapy, and pharmacotherapy have been attempted, but there are still no effective treatments due to adherence and side effects.
  • the causes of sarcopenia include various factors such as changes in age-related hormone balance, age-related changes in muscles and nerves, changes in disuse due to other diseases and social factors, and inadequate intake of amino acids and vitamins due to undernutrition. Predisposing factors are considered to be involved in multiple ways. Therefore, the fundamental treatment is difficult, and the development of a new treatment method is required.
  • skeletal muscle loss is the main cause or cause of various diseases in addition to sarcopenia and other muscle loss. Many of these diseases have not yet been established as appropriate treatments, and there is a need to provide new treatments.
  • a main problem of the present invention is to provide a novel treatment strategy for a disease whose main cause or part of the etiology is skeletal muscle loss.
  • the present inventors tried to find a low molecular weight compound effective for increasing the amount of skeletal muscle from among already approved drugs.
  • FDA-approved drug library Prestwick ⁇ Chemicals
  • 320 types that can be clinically applied in Japan and that can be administered for a long period of time are selected, and a sub-library is created to screen for effective compounds. did.
  • meclizine has a cell proliferation promoting effect and a differentiation inhibiting effect. It was. That is, meclizine was selected as a very promising compound.
  • the therapeutic agent according to [3], wherein the disease is sarcopenia.
  • the above-mentioned diseases include muscle damage due to trauma or surgery, disuse muscular atrophy, disuse syndrome, easy fall, neurogenic muscular atrophy, osteoporosis, osteoarthritis, osteoarthritis, scoliosis and posterior Spinal deformity such as mania, obesity, rheumatoid arthritis, dermatomyositis, polymyositis, myositis associated with autoimmune diseases, locomotive syndrome, metabolic syndrome, motor organ instability, dynapenia, flail, rhabdomyolysis, It is a disease selected from the group consisting of cachexia due to muscular dystrophy, congenital myopathy, congenital myasthenia syndrome, congenital hypoplasia, congenital metabolic disorders, impaired glucose tolerance or diabetes or cancer, [3 ] The therapeutic agent as described in.
  • a method for treating bone system diseases comprising a step of administering to a patient with cachexia due to cancer or
  • a method for treating muscular dystrophy comprising the step of administering meclizine or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient with muscular dystrophy.
  • a physical training or physical exercise supplement containing a meclizine or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a skeletal muscle bulking agent and use thereof.
  • the present invention is based on a result of finding a novel effect of meclizine, that is, an effect of increasing skeletal muscle mass.
  • meclizine promotes myoblast proliferation while reversibly inhibiting its differentiation is worthy of special mention.
  • the skeletal muscle bulking agent of the present invention contains meclizine or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Meclizine is a compound of the substance name 1-[(4-chlorophenyl) phenylmethyl] -4-[(3-methylphenyl) methyl] piperazine and is known as a kind of antihistamine.
  • Meclizine is sold as an over-the-counter (OTC) as a motion sickness medicine.
  • OTC over-the-counter
  • Meclizine is sometimes referred to as meclozine.
  • meclizine and the term “meclozin” are used interchangeably.
  • a pharmacologically acceptable salt of meclizine may be used as the active ingredient of the skeletal muscle bulking agent of the present invention.
  • Commercial meclizine preparations are often formulated in the form of meclizine hydrochloride. Therefore, the hydrochloride is also preferably used in the present invention.
  • the “pharmacologically acceptable salt” is not limited to this, and various salts such as an acid addition salt and an amino acid addition salt are assumed.
  • acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, acetate, maleate, fumarate, citrate, benzenesulfonate, Organic acid salts such as benzoate, malate, oxalate, methanesulfonate, and tartrate are listed.
  • amino acid addition salts include glycine addition salts, phenylalanine addition salts, lysine addition salts, aspartic acid addition salts, and glutamic acid addition salts.
  • Muscles are roughly classified into skeletal muscles, smooth muscles and myocardium. Skeletal muscle is composed of muscle cells (muscle fibers) and connective tissue. Skeletal muscles are also called voluntary muscles and are histologically striated muscles. In addition to the role of moving the body, skeletal muscle has various roles such as maintaining posture, stabilizing joints, generating heat, and protecting blood vessels and organs.
  • the skeletal muscle bulking agent of the present invention can be applied to the treatment or prevention of diseases whose main cause or part of the pathogenesis is skeletal muscle loss. That is, the present invention also provides a therapeutic agent for the disease (containing a skeletal muscle bulking agent).
  • “Therapeutic agent” refers to a drug that exhibits a therapeutic or prophylactic effect on a target disease or condition.
  • Therapeutic effects include alleviation of symptoms or concomitant symptoms characteristic of the target disease / pathology (lightening), prevention or delay of worsening of symptoms, and the like.
  • the latter can be regarded as one of the preventive effects in terms of preventing the seriousness.
  • the therapeutic effect and the preventive effect are partially overlapping concepts, and it is difficult to clearly distinguish them from each other, and there is little benefit in doing so.
  • a typical preventive effect is to prevent or delay the recurrence of symptoms characteristic of the target disease / pathology.
  • it shows some therapeutic effect or preventive effect with respect to a target disease / pathology, or both, it corresponds to the therapeutic agent with respect to a target disease / pathology.
  • a disease in which a decrease in skeletal muscle is the main cause or a part of the etiology is, for example, sarcopenia typified by sarcopenia.
  • Other spinal deformities such as muscle damage due to trauma and surgery, disuse muscle atrophy, disuse syndrome, easy fall, neurogenic muscle atrophy, osteoporosis, osteoarthritis, osteoarthritis, scoliosis and kyphosis , Obesity, rheumatoid arthritis, dermatomyositis, polymyositis, myositis associated with autoimmune disease, locomotive syndrome, metabolic syndrome, motor organ instability, dynapenia, flail, rhabdomyolysis, muscular dystrophy, congenital
  • the therapeutic agent of the present invention can also be applied to myopathy, congenital myasthenia syndrome, congenital hypoplasia, congenital metabolic disorders, impaired glucose tolerance or cachexia due to diabetes or cancer.
  • the preparation of the therapeutic agent of the present invention can be performed according to a conventional method.
  • other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological Saline solution and the like.
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • the dosage form for formulation is not particularly limited. Examples of dosage forms are tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories.
  • the therapeutic agent of the present invention is administered orally or parenterally (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, or intraperitoneal injection, transdermal, nasal, transmucosal, etc.) depending on the dosage form.
  • Applies to Systemic and local administration are also indicated by the subject. These administration routes are not mutually exclusive, and two or more arbitrarily selected can be used in combination (for example, intravenous injection or the like is performed simultaneously with oral administration or after a predetermined time has elapsed).
  • the therapeutic agent of the present invention contains an active ingredient in an amount necessary for obtaining an expected therapeutic effect (that is, a therapeutically effective amount).
  • the amount of the active ingredient in the therapeutic agent of the present invention generally varies depending on the dosage form, but the amount of the active ingredient is set, for example, within the range of about 0.1 wt% to about 99 wt% so as to achieve a desired dose.
  • the dosage of the therapeutic agent of the present invention is set so as to obtain the expected therapeutic effect.
  • symptoms symptoms, patient age, sex, weight, etc. are generally considered.
  • a person skilled in the art can set an appropriate dose in consideration of these matters.
  • the dose can be set so that the amount of active ingredient per day is 1 mg to 500 mg, preferably 5 mg to 300 mg, particularly preferably 10 mg to 200 mg.
  • the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted. In preparing the administration schedule, the patient's medical condition and the duration of effect of the active ingredient can be taken into consideration.
  • treatment with another medicine for example, existing therapeutic agent
  • the existing therapeutic technique may be combined with the treatment with the therapeutic agent of the present invention.
  • the present application is intended for diseases mainly caused by skeletal muscle loss (muscle loss such as sarcopenia, muscle damage due to trauma or surgery, disuse muscle atrophy, disuse syndrome, Falls, neurogenic muscle atrophy, osteoporosis, osteoarthritis, osteoarthritis, spinal deformity such as scoliosis and kyphosis, obesity, rheumatoid arthritis, dermatomyositis, polymyositis, myositis associated with autoimmune diseases, Locomotive syndrome, metabolic syndrome, motor organ instability, dynapenia, flail, rhabdomyolysis, muscular dystrophy, congenital myopathy, congenital myasthenia syndrome, congenital hypoplasia, congenital metabolic disorders, There is also provided a therapeutic method characterized by administering a therapeutically effective amount of the therapeutic agent of the present invention to a patient with impaired glucose tolerance or cachexia due to diabetes or cancer.
  • skeletal muscle loss muscle loss
  • disuse muscle atrophy disuse muscle
  • the skeletal muscle bulking agent of the present invention can also be used as a supplementary nutrient for physical training / physical exercise for the purpose of increasing or strengthening muscles.
  • the “supplementary nutrient” used herein is used to promote the effects of physical training / physical exercise, and has a higher effect than when it is not used.
  • a supplementary nutritional supplement it can also be provided in the form of a food composition containing it in addition to the form (dosage form) similar to the therapeutic agent.
  • a food composition for example, it is provided in the form of powder, granule powder, tablet, paste, liquid or the like as a dietary supplement (supplement, nutrition drink, etc.).
  • the food composition of the present invention preferably contains an active ingredient in such an amount that a desired effect, that is, an increase in muscle can be expected.
  • the addition amount can be determined in consideration of the age, physique (height, weight, etc.), gender, etc. of the subject (user) in which it is used.
  • the skeletal muscle bulking agent of the present invention is also useful in the fields of animal husbandry, pets (animals) and aquaculture.
  • livestock cattle, pig, horse, sheep, etc.
  • poultry chicken, duck, goose, turkey, quail
  • Pheasants, etc. fish
  • fish una, red sea bream, yellowtail, etc.
  • the present invention can also be used as a meat volume increasing agent. It is also possible to use the skeletal muscle bulking agent of the present invention for maintaining the health and body shape of pets.
  • Tannic acid facilitates expression of the polypyrimidine tract binding protein and alleviates deleterious inclusion of CHRNA1 exon P3A due to an hnRNP H-disrupting mutation in congenital myasthenic syndrome. Hum. Mol. Genet., 18, 1229-1237.).
  • Hu5 / KD3 cell line (distributed by National Longevity Medical Research Center, Director Yasuhiro Hashimoto) is a cell line in which telomerase is continuously expressed in human myoblasts. Differentiate into myotubes with induction medium (Shiomi K et al. Gene Ther. 2011; 18: 857-866). Two types of media are used for culturing the Hu5 / KD3 cell line.
  • pmGM (20% fetal bovine serum (FBS, Thermo Scientific), 2% Ultroser G (Biosepra, PALL), penicillin G (100 u / ml) and streptomycin sulfate (100 ⁇ g / ml)
  • Penstrep Dulbecco's Modified Eagle's Medium
  • pmDM 2% horse serum, 1% insulin-transferrin-selenate (ITS, Invitrogen)
  • penicillin G 100 u / ml
  • streptomycin sulfate 100 ⁇ g / ml
  • the cultured cells were buffered (50 mM HEPES pH 7.0, 150 mM NaCl, 10% glycerol, 1% TritonX-100, 1.5 mM MgCl2, 1 mM EGTA, 100 mM NaF, 10 mM sodium pyrophosphate, 1 ⁇ g / ⁇ l aprotinin, 1 ⁇ g / ⁇ l leupeptin, 1 ⁇ g / ⁇ l pepstatin A, 1 mM PMSF, 1 mM sodium orthovanadate). All proteins were dissolved in 1 ⁇ laemmli buffer, separated by SDS-PAGE (10% or 7.5% gel), and transferred to a PVDF membrane (Immobilon-P, Millipore).
  • All proteins were dissolved in 1 ⁇ laemmli buffer, separated by SDS-PAGE (10% or 7.5% gel), and transferred to a PVDF membrane (Immobilon-P, Millipore).
  • the transferred membrane was washed with a Tris buffer containing 0.05% Tween 20 (TBS-T) and then blocked with TBS-T containing 3% bovine serum albumin (room temperature, 1 hour). Subsequently, the treated membrane was reacted with mouse anti-MYH monoclonal antibody (H-300, Santa Cruz Biotechnology, dilution 1: 200) or anti-GAPDH antibody (G9545, Sigma-Aldrich, dilution 1: 600) (4 ° C overnight. The membrane was washed three times and then reacted with a secondary antibody (HRP-labeled goat anti-rabbit IgG antibody (GE Healthcare, 1: 6000)) (room temperature, 1 hour). Detection was performed using Amersham ECL Western blotting detection reagents (GE Healthcare), and quantification was performed using the ImageJ program.
  • TBS-T Tris buffer containing 0.05% Tween 20
  • TBS-T Tris buffer containing 0.05% bovine serum albumin
  • the BrdU assay is a method for quantifying cell division and is used to evaluate cell proliferation in the same manner as the MTS assay. Also in the BrdU assay, meclizine showed a cell growth promoting action (FIG. 3).
  • the morphology of cells on differentiation induction day 7 was compared with and without meclizine (control) (FIG. 4).
  • control meclizine
  • formation of myotube myotube
  • myotubes are not observed in cells administered with meclizine.
  • Differentiation is suppressed by meclizine, which is a morphologically undifferentiated state.
  • MYH myosin heavy chain protein
  • Myosin heavy chain protein is a structural protein of muscle expressed at the end of differentiation.
  • DAPI nuclear staining was used as a control for cell number.
  • meclizine suppressed the expression of myosin heavy chain protein (FIG. 5).
  • Western blot analysis also showed that meclizine suppressed the expression of myosin heavy chain protein (MYH) in cells on day 7 of differentiation induction (FIG. 6).
  • the gene expression level of myosin heavy chain protein (MYH) was compared by quantitative RT-PCR. Evaluation by quantitative RT-PCR was performed as follows. First, total RNA was isolated from cells using Trizol (Life Technologies). First strand cDNA was synthesized with ReverTra Ace (Toyobo). Using LightCycler 480 Real-Time PCR (Roche) and SYBR Green (Takara), mRNA expression levels of myosin heavy chain 1 (MYH1), myosin heavy chain 7 (MYH7), myogenin (MYOG), Pax7 and dystrophin (DMD) It was measured. The mRNA level was corrected by the expression level of GAPDH.
  • MYH1 myosin heavy chain 1
  • MYH7 myosin heavy chain 7
  • MYOG myogenin
  • DMD dystrophin
  • Method C57BL / 6J mice were fed a special feed (meclizine-containing feed (4 g / 10 kg) or control feed) from the 16th day of birth (0w) and reared in a cage. On the 23rd day after birth (1w), the 30th day after birth (2w) and the 37th day after birth (3w), body weight was measured. The animals were sacrificed on the 37th day after birth, and X-ray photography and micro CT measurement were performed. Micro CT measurement was performed according to the following procedure. First, the whole body of the mouse was scanned with a 35 ⁇ m wide slice in a cross section perpendicular to the body axis.
  • the mouse sacroiliac joint was Merckmar, and the vertebral body with the sacroiliac joint was the first sacrum.
  • the fourth lumbar vertebral body was identified starting from the first sacrum.
  • the body axis cross-sectional image data at the fourth and fifth lumbar intervertebral intervertebral discs were taken into the image analysis software.
  • the muscle cross-sectional area of the paraspinal muscles (vertical spine and multifidus) was measured with image analysis software (FIG. 16). Three slice images were measured per intervertebral space.
  • MDX mice muscle dystrophy model mice
  • a special feed meclizine-containing feed (4g / 10kg) or control feed
  • 21st day (0w) to the 49th day (4w) after birth. Reared in The body weight was measured on the 28th day after birth (1w), the 35th day after birth (2w), the 42nd day after birth (3w), and the 49th day after birth (4w).
  • the meclizine-administered mouse had a larger paraspinal muscle cross-sectional area than the control (FIG. 17).
  • the results are shown as a ratio to the control.
  • meclizine was found to increase body weight and paraspinal muscle cross-sectional area in normal mice.
  • ⁇ Summary> Meclizine inhibited human myoblast differentiation and promoted proliferation in a dose-dependent manner. ⁇ The differentiation inhibitory effect of meclizine was reversible. • Mice receiving meclizine increased body weight and muscle cross-sectional area. ⁇ Meclizine also increased body weight in muscular dystrophy model mice. For muscular dystrophy, meclodin administration is expected to increase muscle mass and weight.
  • the skeletal muscle bulking agent of the present invention contains meclizine, which is an already approved drug, as an active ingredient. Meclizine has an antihistamine effect and is marketed as an OTC (over-the-counter). It has been used safely for more than 50 years and has established safety such as optimal dose, side effects and contraindications. This fact is a great merit for clinical application.
  • the therapeutic strategy using the skeletal muscle bulking agent of the present invention is not limited to sarcopenia and other disease groups (muscle damage caused by trauma or surgery, disuse).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention se rapporte au problème visant à fournir une nouvelle stratégie thérapeutique pour une affection de laquelle la perte de muscle squelettique est la cause principale ou partielle. L'invention concerne un agent d'augmentation du volume des muscles squelettiques contenant de la méclizine ou un sel pharmaceutiquement acceptable de celle-ci en tant que substance active.
PCT/JP2015/053580 2014-08-29 2015-02-10 Agent d'augmentation du volume des muscles squelettiques et son utilisation WO2016031264A1 (fr)

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JP2014-176248 2014-08-29
JP2014176248 2014-08-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024029173A1 (fr) * 2022-08-03 2024-02-08 国立大学法人東海国立大学機構 Agent pour la prévention ou l'amélioration de l'ostéoporose

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013032761A1 (fr) * 2011-09-01 2013-03-07 Kraft Foods Global Brands Llc Gomme à mâcher pouvant être dégradée et procédé pour sa fabrication

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013032761A1 (fr) * 2011-09-01 2013-03-07 Kraft Foods Global Brands Llc Gomme à mâcher pouvant être dégradée et procédé pour sa fabrication

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
MATSUSHITA M ET AL., PLOS ONE, vol. 8, no. 12, 2013, pages e81569 *
MUCHIR A ET AL., SKELETAL MUSCLE, vol. 3, no. 17, 2013 *
PRADO CMM ET AL., BRITISH JOURNAL OF CANCER, vol. 106, 2012, pages 1583 - 1586 *
ROBERTS PJ ET AL., ONCOGENE, vol. 26, 2007, pages 3291 - 3310 *
STROBEL S ET AL., ARTHRITIS RESEARCH & THERAPY, vol. 12, no. 2, 2010, pages R34 *
TANNAPFEL A ET AL., GUT, vol. 52, 2003, pages 706 - 712 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024029173A1 (fr) * 2022-08-03 2024-02-08 国立大学法人東海国立大学機構 Agent pour la prévention ou l'amélioration de l'ostéoporose

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