WO2013118773A1 - 特発性炎症性筋疾患の予防又は治療剤 - Google Patents
特発性炎症性筋疾患の予防又は治療剤 Download PDFInfo
- Publication number
- WO2013118773A1 WO2013118773A1 PCT/JP2013/052730 JP2013052730W WO2013118773A1 WO 2013118773 A1 WO2013118773 A1 WO 2013118773A1 JP 2013052730 W JP2013052730 W JP 2013052730W WO 2013118773 A1 WO2013118773 A1 WO 2013118773A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- muscle
- idiopathic inflammatory
- myopathy
- valine
- leucine
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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 a prophylactic or therapeutic agent for idiopathic inflammatory myopathy associated with idiopathic inflammatory myopathy and steroid myopathy, and more specifically, idiopathic inflammatory muscle containing isoleucine, leucine and valine as active ingredients.
- the present invention relates to a preventive or therapeutic agent for idiopathic inflammatory myopathy associated with diseases and steroid myopathy.
- Idiopathic inflammatory myopathy refers to polymyositis, dermatomyositis, dermatomyositis without myopathies, pediatric dermatomyositis, myositis associated with malignant tumors, myositis associated with other collagen diseases, according to Olsen and Wartmann's disease type classification It is a general term for myopathy classified as inclusion body myositis. Inflammatory cell infiltration into muscle tissue and pathological findings of large and small muscle fibers associated with muscle fiber necrosis and atrophy. Inflammation of muscle tissue results in symptoms of generalized weakness, possibly due to muscle pain and muscle atrophy.
- idiopathic inflammatory myopathy is a symptom that greatly affects the patient's QOL and prognosis, and is a symptom to be treated along with the calming of inflammation and prevention of complications.
- steroid drugs are mainly used as first-line drugs, and immunosuppressants are often used in combination.
- treatment centering on the administration of steroid drugs such as pulse therapy using a large amount of steroid drugs, is being performed.
- These treatment methods are effective in reducing inflammation in muscle tissue, but are poor in improving muscle atrophy and muscle weakness.
- steroid drugs have muscular atrophy as a side effect, and may cause symptoms of muscle weakness called steroid myopathy.
- Steroid myopathy develops in patients who use steroid drugs for a long time or in large quantities, and there is no way to deal with it other than steroid drug reduction or withdrawal to avoid it.
- steroid drug weight loss in the treatment of idiopathic inflammatory myopathy increases the risk of exacerbated inflammation and recurrence. Even if the drug can be reduced, the patient can only wait for the natural recovery of the lost muscle strength while moving the body in daily life, and it takes a long time to recover completely.
- idiopathic inflammatory myopathy there is a problem that there is no therapeutic agent or treatment that can achieve both anti-inflammation and muscular strength improvement effects.
- the muscle weakness continues after the inflammation has subsided, causing a significant loss of QOL.
- valine in a branched chain amino acid (hereinafter also referred to as “BCAA”) composition may enhance the effects of steroid drugs and immunosuppressive agents. It has been suggested (Patent Document 1). However, this document merely evaluates the efficacy of limb swelling as a joint score, and does not directly indicate the presence or absence of anti-inflammatory action of valine itself. Furthermore, there is no description that valine is effective for idiopathic inflammatory myopathy.
- branched-chain amino acids act on muscle, it is mainly an improvement of muscle fatigue (Patent Document 2), and it is known that itself is useful for idiopathic inflammatory myopathy.
- Patent Document 2 branched chain amino acids suppress muscle atrophy caused by steroid drugs and improve muscle strength, that is, useful for the prevention and treatment of steroid myopathy.
- Patent Document 3 Non-Patent Document 3
- Non-patent Document 1 Non-patent Document 1
- Non-patent Document 2 An IL-1 receptor antagonist Anakinra has also not been found to have an anti-inflammatory effect on polymyositis and dermatomyositis (Non-patent Document 2).
- the present condition is that the effective drug for the treatment of idiopathic inflammatory myopathy and idiopathic inflammatory myopathy which is accompanied by steroid myopathy during treatment has not been obtained.
- An object of the present invention is to provide a preventive or therapeutic agent for idiopathic inflammatory myopathy and idiopathic inflammatory myopathy associated with steroid myopathy during treatment.
- idiopathic inflammatory in which idiopathic inflammatory myopathy and steroid myopathy are combined. It is effective in the prevention or treatment of muscular diseases. In particular, it suppresses (seduces) the inflammation of muscle tissue in idiopathic inflammatory myopathy combined with idiopathic inflammatory myopathy and steroid myopathy. It has been found that it has the effect of suppressing and improving muscle strength. As a result of further studies based on these findings, the present inventors have completed the present invention.
- a preventive or therapeutic agent for idiopathic inflammatory myopathy comprising isoleucine, leucine and valine as active ingredients;
- Idiopathic inflammatory myopathy from polymyositis, dermatomyositis, dermatomyositis without muscular symptoms, childhood dermatomyositis, myositis associated with malignant tumors, myositis associated with other collagen diseases, and inclusion body myositis
- the agent according to [1] selected from the group consisting of: [3] The agent according to [1] or [2], which suppresses inflammation of muscle tissue; [4] The agent according to any one of [1] to [3], which improves muscle atrophy and / or muscle weakness; [5] The agent according to any one of [1] to [4], wherein the weight ratio of isoleucine, leucine and valine is 1: 1 to 3: 0.5 to 2.0; [6] The agent according to any one of [
- the agent or composition containing isoleucine, leucine and valine as active ingredients provided by the present invention is particularly useful for idiopathic inflammatory myopathy and idiopathic inflammatory myopathy combined with steroid myopathy. Because of its superior effects in both inflammation suppression and muscle strength improvement, it can be effectively administered to patients with idiopathic inflammatory myopathy and idiopathic inflammatory myopathy combined with steroid myopathy. Can be prevented or treated.
- steroid drugs In the treatment of idiopathic inflammatory myopathy, steroid drugs have been used from the viewpoint of anti-inflammation, and immunosuppressants are used in combination when the effect is insufficient.
- none of the drugs has an effective muscle strength improving action. Therefore, having both an inflammation-inhibiting action and a muscular strength-improving action in muscle tissue is a unique effect in the agent of the present invention.
- it is effective in improving muscular strength without steroid drug reduction or withdrawal, which is unique in the agent of the present invention. It is an effect.
- branched chain amino acids of isoleucine, leucine and valine are substances having established safety, prevention of idiopathic inflammatory muscle disease of the present invention and idiopathic inflammatory myopathy combined with steroid myopathy or
- the therapeutic agent can be provided as highly safe and with few side effects.
- FIG. 1 is a comparison of inflammation scores of a BCAA administration group, a prednisolone (PSL) administration group and a vehicle administration group, and a control (Ctrl) mouse in the normal group and the adjuvant immunization group in a C-protein induced mouse myositis model (CIM mouse). It is a graph which shows. The vertical axis of the graph represents the inflammation score of the mouse.
- FIG. 2 is a graph showing comparison of muscle weights of quadriceps femoris, flexor flexors and triceps surae muscles of BCAA administration group, PSL administration group and Vehicle administration group in CIM mice, and normal group and adjuvant immunization group in Ctrl mice. It is.
- FIG. 3 is a graph showing comparison of forelimb muscle strength measurements of BCAA administration group, PSL administration group and Vehicle administration group in CIM mice, and normal group and adjuvant immunization group in Ctrl mice.
- the vertical axis of the graph represents the measured value (g) of the forelimb muscle strength of the mouse.
- FIG. 4 is a graph showing a comparison of the distribution of fast muscle fiber cross-sectional areas of BCAA administration group, PSL administration group and Vehicle administration group in CIM mice, and normal group and adjuvant immunization group in Ctrl mice.
- FIG. 5 is a graph showing a comparison of inflammation scores of a BCAA + PSL combined administration group and a PSL single administration group in CIM mice, and a normal group and a vehicle administration group in Ctrl mice.
- the vertical axis of the graph represents the inflammation score of the mouse.
- FIG. 6 is a graph showing a comparison of the muscle weights of the quadriceps femoris, flexor flexors and triceps surae muscles in the BCIM + PSL combined administration group, the PSL single administration group and the vehicle administration group in CIM mice, and the normal group in Ctrl mice. .
- the vertical axis of the graph represents the weight (mg) of various muscles.
- FIG. 7 is a graph showing comparison of forelimb muscle strength measurements of BCAA + PSL combined administration group, PSL single administration group and Vehicle administration group in CIM mice, and normal group in Ctrl mice.
- the vertical axis of the graph represents the measured value (g) of the forelimb muscle strength of the mouse.
- the present invention provides a preventive or therapeutic agent for idiopathic inflammatory muscle disease and idiopathic inflammatory myopathy combined with steroid myopathy, which contains isoleucine, leucine and valine as active ingredients (in the present specification) , Sometimes referred to as “agent of the present invention”).
- the idiopathic inflammatory myopathy refers to a disease in which mononuclear cell infiltration is observed in the skeletal muscles of the extremities or trunk and causes muscle disorders such as inflammation and degeneration.
- Symptoms of idiopathic inflammatory myopathy include inflammation of muscle tissue and muscle weakness as described above, as well as other skin symptoms (eg, heliotrophic eruption, Gottron sign etc.), joint symptoms (eg, joint pain, Arthritis, etc.), Raynaud's phenomenon, respiratory symptoms (eg, interstitial pneumonia, etc.), cardiac symptoms (eg, arrhythmia, heart failure, etc.), systemic symptoms (eg, fever, general malaise, etc.), etc.
- the agent of the present invention has an effect of suppressing inflammation of muscle tissue and an effect of improving muscle strength, and may have an effect of improving the above-mentioned other symptoms together with or through these effects.
- “prophylaxis” of idiopathic inflammatory myopathy and steroid myopathy associated with idiopathic inflammatory myopathy and steroid myopathy refers to idiopathic inflammatory myopathy or steroid myopathy as described above. It means preventing the manifestation of symptoms in an individual who does not show symptoms (including prevention of recurrence), and “treatment” refers to idiopathic inflammatory muscles associated with idiopathic inflammatory myopathy and steroid myopathy. In an individual who exhibits symptoms of a disease, this means reducing the symptoms or preventing or delaying the worsening of the symptoms.
- Idiopathic inflammatory myopathy can be classified in more detail according to the above clinical symptoms and examination findings such as needle electromyogram.
- classified idiopathic inflammatory myopathy include polymyositis, dermatomyositis, pediatric dermatomyositis, myositis associated with malignant tumors, other collagen diseases (for example, SLE (systemic lupus erythematosus), scleroderma, etc. ), Myositis, and inclusion body myositis.
- SLE systemic lupus erythematosus
- scleroderma etc.
- Myositis myositis
- inclusion body myositis inclusion body myositis.
- many patients are diagnosed with polymyositis, dermatomyositis, or inclusion body myositis, and among them, many patients are diagnosed with polymyositis or dermatomyositis.
- the agent of the present invention is useful for any of the above diseases (myositis), but is particularly suitable for polymyositis and dermatomyositis, and most suitable for polymyositis. .
- the agent of the present invention is useful for dermatomyositis without muscular symptoms from the viewpoint of further improving mild muscular symptoms or preventing muscular symptoms that may occur in the future. .
- Infiltrating inflammatory cells are, for example, T lymphocytes, B lymphocytes, NK cells, macrophages, dendritic cells, and the like.
- the agent of the present invention is useful for both polymyositis and dermatomyositis, the three branched chain amino acids of isoleucine, leucine and valine are either directly or directly on the molecules involved in the mechanism of action as described above. It can act indirectly and promote or suppress their activity.
- isoleucine, leucine and valine may be for inhibiting inflammatory cell infiltration in muscle tissue.
- Whether or not inflammatory cells are infiltrated can be examined by sectioning a muscle tissue collected by biopsy or the like and observing the muscle section by staining with hematoxylin and eosin (HE staining). If the amount of inflammatory cells observed by HE staining is lower than that before administration of the branched chain amino acid, it can be determined that infiltration of inflammatory cells is suppressed.
- HE staining hematoxylin and eosin
- isoleucine, leucine and valine may be for improving muscle atrophy and / or muscle weakness.
- muscle fiber staining can also be performed using an antibody against myosin heavy chain (MHC), laminin, and the like, which are muscle fiber constituent proteins.
- MHC myosin heavy chain
- muscle cells are collected from muscle tissue, and the expression level of muscle atrophy-related genes (eg, atrogon-1, MuRF-1 etc.) in the cells is measured to examine the improvement of muscle atrophy. You can also.
- the gene is atrogon-1 or MuRF-1, it can be determined that the muscle fiber is improved if the expression level is lower than that before administration of the branched chain amino acid.
- Whether or not the muscle weakness has been improved can be examined by using a commercially available muscle strength measuring device such as a grip strength meter. If the muscular strength is improved compared to before administration of the branched chain amino acid, it can be determined that the decrease in muscular strength is improved.
- the anti-inflammatory action and the muscular strength improving action of the muscle tissue possessed by the agent of the present invention may be independent and independent actions.
- Isoleucine, leucine and valine contained as active ingredients in the agent of the present invention can be used in any of L-form, D-form and DL-form, preferably L-form and DL-form. More preferred is the L-form.
- isoleucine, leucine and valine for example, those obtained from hydrolysis of natural proteins derived from animals or plants can be used, or those obtained by fermentation or chemical synthesis can be used.
- Isoleucine, leucine and valine can be used not only in free form but also in salt form.
- the salt form include acid addition salts and base addition salts, but any form can be adopted as long as it is a chemically acceptable salt.
- the salt form is preferably a pharmaceutically acceptable salt.
- Examples of pharmaceutically acceptable salts include salts with acids and salts with bases.
- acids that are added to isoleucine, leucine, or valine to form pharmaceutically acceptable salts include inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, Organic acids such as tartaric acid, maleic acid, fumaric acid or monomethyl sulfuric acid can be mentioned.
- bases that form pharmaceutically acceptable salts by adding to isoleucine, leucine, or valine, respectively include metal hydroxides such as sodium and potassium, metal carbonates such as calcium, and inorganic such as ammonia. Examples include bases, organic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine.
- the compounding ratio (weight ratio) of isoleucine, leucine and valine contained in the agent of the present invention is such that the agent of the present invention can prevent idiopathic inflammatory myopathy associated with desired activity or idiopathic inflammatory myopathy and steroid myopathy. Or it can adjust suitably in the range which has a therapeutic effect.
- the blending ratio of three types of branched chain amino acids is usually 1: 1 to 3: 0.5 to 2.0, preferably 1: 1.5 to 2 as a weight ratio.
- the agent of the present invention contains an isoleucine salt, a leucine salt, or a valine salt
- the calculation of the weight ratio should be carried out after all the branched chain amino acid salts are converted to free form. To do.
- the weight ratio of isoleucine, leucine and valine is within the above range, an effective preventive or therapeutic effect can be obtained for idiopathic inflammatory myopathy and idiopathic inflammatory myopathy combined with steroid myopathy.
- the agent of the present invention is useful as a medicine, and its application target includes mammals (for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
- mammals for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.
- the subject of application of the agent of the present invention is preferably a human.
- the intake of the agent of the present invention may be appropriately adjusted according to the body weight or size of the animal.
- the administration method when the agent of the present invention is used as a medicine may be either oral administration or parenteral administration.
- the dosage form for oral administration include liquids such as powders, granules, capsules, tablets, chewables and the like, liquids such as solutions and syrups, and parenteral dosage forms include injections. , Infusion agents, nasal / pulmonary sprays, and the like.
- the agent of the present invention can be prepared by using an appropriate pharmaceutically acceptable carrier such as an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, a suspension, as required in the preparation. It can be formulated as a pharmaceutical composition by blending agents, emulsifiers, isotonic agents, stabilizers, soothing agents, preservatives, antioxidants, flavoring agents, coloring agents, etc. It may be referred to as “the composition of the invention”). The agent of the present invention can be formulated into a dosage form as shown above by an ordinary method.
- an appropriate pharmaceutically acceptable carrier such as an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, a suspension, as required in the preparation. It can be formulated as a pharmaceutical composition by blending agents, emulsifiers, isotonic agents, stabilizers, soothing agents, preservatives, antioxidants, flavoring agents
- composition of the present invention it is preferable that all active ingredients of isoleucine, leucine and valine are all contained in the same composition from the viewpoint that they can be administered easily.
- Each of the amino acids may be contained alone or in any combination in the plurality of compositions.
- excipients examples include sugars such as lactose, glucose, D-mannitol, organic excipients such as starches and celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin.
- a lubricant pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.
- fatty acid salts such as stearic acid and stearate, talc, silicates, etc., purified water, physiological saline, etc.
- Cellulose and starch, etc. used as a solubilizer include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like.
- a tonicity agent sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium and the like, polysorbates, polyoxyethylene hydrogenated castor oil, etc.
- Sodium chloride, potassium chloride, sugars, glycerin, urea, etc., and stabilizers such as polyethylene glycol, sodium dextran sulfate, and other amino acids.
- stabilizers such as polyethylene glycol, sodium dextran sulfate, and other amino acids.
- glucose, calcium gluconate, procaine hydrochloride, etc. and as preservatives, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are antioxidants.
- the agent include sulfite and ascorbic acid
- examples of the flavoring agent include sweeteners and fragrances that are commonly used in the pharmaceutical field
- coloring agent include colorants that are commonly used in the pharmaceutical field. It is done.
- the content of branched chain amino acids (isoleucine, leucine, and valine) contained in the composition of the present invention can be appropriately set according to the form of the preparation.
- the content of branched chain amino acids is usually 5 to 50% by weight, preferably 10 to 30% by weight, based on the entire composition.
- the content of branched chain amino acids is usually 50 to 100% by weight, preferably 90 to 100% by weight, based on the whole composition.
- the “content” indicates the ratio of the total weight of the three types of branched chain amino acids in the weight of the composition of the present invention.
- the content thereof is a ratio of the total weight of three kinds of branched chain amino acids in the weight of the composition.
- the content is the total weight of the three branched chain amino acids in the total weight of each composition Is the ratio.
- the “weight ratio” indicates the weight ratio of each branched chain amino acid contained in the composition of the present invention.
- each active ingredient of isoleucine, leucine and valine is included in one composition Is the ratio of the content of individual branched-chain amino acids, and when each of the active ingredients is contained alone or in any combination in a plurality of compositions, each of the active ingredients contained in each composition It is the ratio of weight.
- Preferred examples of the agent or composition of the present invention include isoleucine, leucine and valine in a weight ratio of 1: 2: 1.2 (isoleucine: 0.952 g, leucine: 1.904 g, valine: 1.144 g).
- the branched chain amino acid preparation Rebact (registered trademark) granules (Ajinomoto Co., Inc.) (orally administered) can be mentioned.
- Suitable parenteral administration agents include aminic high-concentration amino acid infusions ((registered trademark) intravenous infusion (Ajinomoto Pharmaceutical Co., Ltd.)) and morihepamine ((registered trademark) intravenous infusion (Ajinomoto Pharmaceutical Co., Ltd.)). Can be mentioned.
- the dose (intake) of the agent or composition of the present invention to humans varies depending on the age, body weight, disease state, administration method, etc. of the subject patient, but usually 1 to 30 g isoleucine per person, 1 leucine 1 -30 g, valine 1-30 g. In the case of general adults, preferably per day, 2-10 g of isoleucine, 4-20 g of leucine, 2-10 g of valine, more preferably 2.5-3.0 g of isoleucine, 5.0-7.0 g of leucine.
- the valine content is 3.0 to 4.0 g.
- the daily dose for an adult is usually about 3 to 90 g, preferably about 3 to 20 g as the total amount of the three kinds of branched chain amino acids.
- the dose is calculated after all the branched-chain amino acid salts are converted to free form.
- the timing of administration is not particularly limited, and may be any time before meals, between meals, and after meals. Also, the administration period is not particularly limited.
- the above calculation as the active ingredient of a drug used for the purpose of treatment, prevention, etc. of the disease targeted by the present invention As the range is determined, it is necessary to include this in the calculation for branched-chain amino acids that are ingested or administered for other purposes, for example, due to the need for a normal diet or for the treatment of another disease There is no. For example, it is not necessary to calculate by subtracting the amount of branched chain amino acids per day taken from a normal diet from the daily dose of the active ingredient in the present invention.
- the actual dose ratio is a ratio of a single dose or a daily dose of each active ingredient per administration subject (ie, patient).
- the weight ratio corresponds to the dose ratio.
- the ratio of the total amount of each active ingredient in each preparation administered once or daily corresponds to the dose ratio.
- Isoleucine, leucine, and valine have already been widely used in the pharmaceutical and food fields, and safety has been established.
- the present invention contains these branched chain amino acids in a ratio of 1: 2: 1.2.
- the acute toxicity (LD50) in these agents and compositions is 10 g / kg or more in the oral administration of mice.
- the agent or composition of the present invention is useful for the prevention or treatment of idiopathic inflammatory myopathy and idiopathic inflammatory myopathy combined with steroid myopathy, but idiopathic inflammation that has been used for a long time. It can also be used in combination with a prophylactic or therapeutic agent for sexual muscular disease.
- the term “combination” means the use before, simultaneously with, or after the administration of a preventive or therapeutic agent for idiopathic inflammatory myopathy, which has been used for a long time, and as a combination of both This includes the use of.
- Examples of the prophylactic or therapeutic agent for idiopathic inflammatory myopathy that can be used in combination with the agent or composition of the present invention include, but are not limited to, steroid drugs and immunosuppressants.
- Examples of the steroid drug include prednisolone, methylprednisolone, hydrocortisone, cortisone acetate, dexamethasone, triamcinolone, betamethasone and the like.
- Examples of the immunosuppressant include azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolic acid, various antibody drugs, ⁇ globulin, and the like.
- agents may be used alone or in combination with the agent or composition of the present invention, or two or more thereof may be used in combination.
- the dose, administration period, and administration interval of the drug used in combination with the agent or composition of the present invention can be appropriately set according to the disease state, the subject patient, and the like.
- the agent or composition of the present invention in the prevention and treatment of idiopathic inflammatory myopathy, can enhance the effects of steroid drugs and immunosuppressive agents. This is useful in that the therapeutic effect can be enhanced and side effects can be reduced as compared with the case where a steroid drug or immunosuppressant is used alone.
- the steroid drug and the immunosuppressant include the above drugs, and a steroid drug (eg, prednisolone) is preferable.
- the dose, administration period, and administration interval of the drug used in combination with the agent or composition of the present invention can be appropriately set according to the disease state, the subject patient, and the like.
- Steroids are often used as a first-line drug for the treatment of idiopathic inflammatory myopathy, and if muscle weakness is observed during the course of treatment, steroid myopathy may be due to deterioration of the underlying disease. It is difficult to judge whether the muscular strength is reduced due to the merger.
- the agent or composition of the present invention improves both inflammation and muscle weakness due to the primary disease of idiopathic inflammatory myopathy when used in combination with the start of steroid therapy in idiopathic inflammatory myopathy.
- steroid drugs may have to be reduced for treatment aimed at improving muscular strength.
- the agent or the pharmaceutical composition of the present invention the treatment can be continued and the sufficient muscular strength can be improved without reducing the dose of the steroid drug during the treatment due to the combination of steroid myopathy.
- Example 1 Inhibitory Effect of BCAA on Muscle Tissue Inflammation in C-protein Induced Mouse Myositis Model Effect of BCAA on inflammation in muscle tissue using C-protein-induced Myositis model (CIM) It was investigated.
- CCM C-protein-induced Myositis model
- the hindlimb is composed of 200 ⁇ g C-protein and 100 ⁇ g Mycobacterium butyricum, and an adjuvant containing Complete Freund's adjuvant (CFA) CFA without C-protein was injected intradermally into the plantar and ridge, and intraperitoneal injection of 0.25 ⁇ g pertussis toxin (Pertussis toxin).
- CFA Complete Freund's adjuvant
- Adjuvant controls not immunized with antigen were injected intradermally with CFA at the same site.
- Oral administration was made into a BCAA administration group and a PSL administration group, respectively.
- 0.5% methylcellulose and 5% ⁇ cyclodextrin were orally administered instead of BCAA, etc., to obtain a vehicle administration group.
- the high inflammation score observed in the vehicle administration group of the C-protein induced mouse myositis model was significantly suppressed in the PSL administration group and the BCAA administration group. Thereby, it was shown that BCAA has an anti-inflammatory action. Since the CIM mouse is considered as a model mouse for polymyositis, it was suggested that BCAA is useful for the treatment of polymyositis and the like.
- Example 4 Effect of BCAA on improving muscle fiber atrophy in CIM mice Since steroid myopathy occurs predominantly in fast muscle fibers (MHC IIB positive fibers), the muscle fiber atrophy of CIM mice is measured by measuring the muscle fiber cross-sectional area. evaluated. Fast muscle fibers and myofiber boundary portions of the triceps section collected 21 days after immunization were labeled by immunofluorescence staining using anti-MHC IIB antibody and anti-Laminin antibody (Sigma), and MHC IIB positive The muscle fiber cross-sectional area was measured using Image J software (NIH). The distribution of the muscle fiber area is shown as a histogram in FIG.
- Example 5 Dose Response of BCAA to Inhibition of Muscle Tissue Inflammation
- 0.25 g / kg BCAA + 20 mg / kg PSL, 0.75 g / kg BCAA + 20 mg / kg PSL, 2.25 g / kg BCAA + 20 mg / kg PSL (each BCAA is orally administered with isoleucine, leucine and valine (mixture of isoleucine: leucine: valine 1: 2: 1.2) by weight) or 20 mg / kg PSL daily, each in the PSL single administration group And PSL + BCAA combination administration group.
- Example 6 Dose responsiveness of BCAA to inhibition of muscle atrophy Quadriceps femoris, flexors and triceps were collected from CIM mice and control mice (Ctrl) 21 days after immunization in Example 5, and muscle weight was measured. did. The results are shown in FIG. In the PSL single administration group, no increase in muscle weight was observed, whereas in the BCAA + PSL combination administration group, an increase in muscle weight was observed depending on the dose.
- Example 7 Dose responsiveness of BCAA to muscle strength improvement 20 days after immunization in Example 5, the forelimb muscle strength of each mouse was measured using an animal grip force meter MK-380CM / R (Muromachi Kikai). The measurement was performed 6 times for each individual, and the average value was obtained. The results are shown in FIG. In the PSL single administration group, no increase in forelimb muscle strength was observed, whereas in the BCAA + PSL combination administration group, an increase in forelimb muscle strength was observed depending on the dose.
- the branched chain amino acids of isoleucine, leucine and valine have idiopathic inflammatory myopathy because when combined, they suppress inflammation in muscle tissue and further improve muscle strength by suppressing the symptoms of muscle atrophy. It is possible to effectively treat such diseases by administering it to patients who have the disease.
- steroid myopathy cannot be improved by a single steroid, whereas the branched chain amino acids of isoleucine, leucine and valine can improve muscle strength when used in combination with steroid drugs. It is possible to effectively treat such diseases by administering to patients with idiopathic inflammatory myopathy. Therefore, the present invention is useful as a medicament for the prevention or treatment of idiopathic inflammatory myopathy and idiopathic inflammatory myopathy associated with steroid myopathy during treatment.
Abstract
Description
[1]イソロイシン、ロイシンおよびバリンを有効成分として含有する、特発性炎症性筋疾患の予防又は治療剤;
[2]特発性炎症性筋疾患が、多発性筋炎、皮膚筋炎、筋症状のない皮膚筋炎、小児皮膚筋炎、悪性腫瘍に合併する筋炎、他の膠原病に合併する筋炎、及び封入体筋炎からなる群より選択される、[1]に記載の剤;
[3]筋組織の炎症を抑制することを特徴とする、[1]又は[2]に記載の剤;
[4]筋萎縮および/または筋力低下を改善することを特徴とする、[1]~[3]のいずれかに記載の剤;
[5]イソロイシン、ロイシンおよびバリンの重量比が、1:1~3:0.5~2.0である、[1]~[4]のいずれかに記載の剤;
[6]ヒトに対する1日あたりの投与量が、イソロイシン、ロイシンおよびバリンの合計量として3~90gである、[1]~[5]のいずれかに記載の剤;
[7][1]~[6]のいずれかに記載の剤、及び薬学的に許容される担体を含む、医薬組成物;
[8]イソロイシン、ロイシンおよびバリンからなる、特発性炎症性筋疾患の予防又は治療剤;
[9][8]に記載の剤、及び薬学的に許容される担体からなる医薬組成物;
[10]イソロイシン、ロイシンおよびバリンを有効成分として含有する組成物を、投与対象に投与することを含む、特発性炎症性筋疾患の予防又は改善方法;
[11]イソロイシン、ロイシンおよびバリンを有効成分として含有する組成物を、投与対象に投与することを含む、筋組織の炎症を抑制することを特徴とする、「10」に記載の方法;
[12]イソロイシン、ロイシンおよびバリンを有効成分として含有する組成物を、投与対象に投与することを含む、筋萎縮および/または筋力低下を改善することを特徴とする、[10]に記載の方法;
[13]イソロイシン、ロイシンおよびバリンの重量比が1:1~3:0.5~2.0である、[10]~[12]のいずれかに記載の方法;
[14]ヒトに対する1日あたりの投与量が、イソロイシン、ロイシンおよびバリンの合計量として3~90gである、[10]~[13]のいずれかに記載の方法;
[15]特発性炎症性筋疾患が、治療中にステロイドミオパチーを合併する特発性炎症性筋疾患である、[1]~[6]のいずれかに記載の剤;
[16][15]に記載の剤、及び薬学的に許容される担体を含む、医薬組成物;
[17]特発性炎症性筋疾患が、治療中にステロイドミオパチーを合併する特発性炎症性筋疾患である、[8]に記載の剤;
[18][17]に記載の剤、及び薬学的に許容される担体を含む、医薬組成物;
[19]特発性炎症性筋疾患が、治療中にステロイドミオパチーを合併する特発性炎症性筋疾患である、[10]~[14]のいずれかに記載の方法。
C-protein誘導型マウス筋炎モデル(C-protein-induced Myositis:CIM)を用いて、筋組織の炎症に与えるBCAAの効果を検討した。C57BL/6マウス(メス、8週齢)に抗原免疫を行うため、200μg C-proteinと100μg結核死菌(Mycobacterium butyricum)とを含み、Complete Freund’s adjuvant(CFA)を成分とするアジュバントを後肢足底および尾根部に、C-proteinを含まないCFAを前肢根部に皮内注射し、0.25μgの百日咳毒素(Pertussis toxin)を腹腔内注射した。抗原を免疫しないAdjuvant controlには、CFAを同じ部位に皮内注射した。免疫3日後より、0.75g/kg BCAA(イソロイシン、ロイシンおよびバリン(重量比としてイソロイシン:ロイシン:バリン=1:2:1.2)の配合物)、又は20mg/kg Prednisolone(PSL)を連日経口投与し、それぞれBCAA投与群、PSL投与群とした。また、BCAA等の代わりに0.5%メチルセルロース及び5%γシクロデキストリンを経口投与し、Vehicle投与群とした。免疫21日後に筋肉を採取し、大腿四頭筋および屈筋の炎症の程度を炎症スコアにより評価した。炎症スコアは、HE染色した筋切片内で炎症細胞の浸潤と筋線維壊死とを認める領域の筋線維数を以下の基準に従ってスコア化し、大腿四頭筋と屈筋とのスコアの平均値として求めた。
スコア化方法:Grade 0 = 浸潤なし, Grade 1 = 1線維, Grade 2 = 2-5線維, Grade 3 = 6-15線維, Grade 4 = 16-30線維, Grade 5 =31-100線維, Grade 6 = 101線維以上。同一筋肉内の複数部位に同スコアの浸潤が見られた場合は、スコアに0.5を加えた。
結果を図1に示す。C-protein誘導型マウス筋炎モデル(CIMマウス)のVehicle投与群で見られる高い炎症スコアは、PSL投与群とBCAA投与群にて有意に抑制された。これにより、BCAAは抗炎症作用を有することが示された。CIMマウスは多発性筋炎のモデルマウスと考えられていることから、BCAAは多発性筋炎の治療等に対して有用であることが示唆された。
免疫21日後のCIMマウス及びコントロールマウス(Ctrl)から大腿四頭筋、屈筋、および上腕三頭筋を採取し、筋重量を測定した。結果を図2に示す。いずれの筋肉もCtrl群に比較してCIMマウスのVehicle投与群にて筋重量の低下が見られ、PSL投与群では改善が見られないものの、BCAA投与群では改善された。
免疫20日後に動物用握力計MK-380CM/R(室町機械)を用いて各マウスの前肢筋力を測定した。測定は各個体につき6回行い、その平均値を求めた。結果を図3に示す。Ctrl群に比べてCIMマウスのVehicle投与群では筋力の低下が見られ、PSL投与群では改善効果が弱いが、BCAA投与群ではほぼ正常レベルまで改善された。
ステロイド筋症は速筋線維(MHC IIB陽性線維)に優位に生じることから、CIMマウスの筋線維の萎縮を筋線維断面積を計測することにより評価した。免疫21日後に採取した上腕三頭筋の切片の速筋線維と筋線維境界部とを、anti-MHC IIB抗体およびanti-Laminin抗体(Sigma)を用いた免疫蛍光染色により標識し、MHC IIB陽性筋線維の断面積をImage Jソフトウェア(NIH)を用いて計測した。筋線維面積の分布をヒストグラムにして図4に示す。Ctrl群に比べてCIMマウスのVehicle投与群では筋線維の萎縮を示すヒストグラムの左側へのシフトが見られ、PSL投与群ではその傾向がさらに強かった。これらに対してBCAA投与群では、細い筋線維の割合の減少と太い筋線維の割合の増加が見られ、筋線維萎縮の改善について部分的な効果が得られた。
実施例1に記載の方法に従って、0.25g/kg BCAA+20mg/kg PSL、0.75g/kg BCAA+20mg/kg PSL、2.25g/kg BCAA+20mg/kg PSL(各BCAAは、イソロイシン、ロイシンおよびバリン(重量比としてイソロイシン:ロイシン:バリン=1:2:1.2)の配合物)、又は20mg/kg PSLを連日経口投与し、それぞれPSL単独投与群、PSL+BCAA併用投与群とした。また、BCAA等の代わりに0.5%メチルセルロース及び5%γシクロデキストリンを経口投与し、Vehicle投与群とした。
実施例1に記載の評価法によって得られた結果を図5に示す。BCAA+PSL併用投与群では、炎症スコアにおいてBCAAの投与量が異なるBCAA+PSL併用投与群のいずれでも、PSL単独投与群に比してより炎症を抑制する傾向が見られた。
実施例5における免疫21日後のCIMマウス及びコントロールマウス(Ctrl)から大腿四頭筋、大腿屈筋、および上腕三頭筋を採取し、筋重量を測定した。結果を図6に示す。PSL単独投与群では、筋重量の増加が認められなかったのに対し、BCAA+PSL併用投与群では、筋重量の増加が投与量に依存して認められた。
実施例5における免疫20日後に動物用握力計MK-380CM/R(室町機械)を用いて各マウスの前肢筋力を測定した。測定は各個体につき6回行い、その平均値を求めた。結果を図7に示す。PSL単独投与群では、前肢筋力の増加が認められなかったのに対し、BCAA+PSL併用投与群では、前肢筋力の増加が投与量に依存して認められた。
従って、本発明は特発性炎症性筋疾患及び治療中にステロイドミオパチーを合併する特発性炎症性筋疾患の予防又は治療のための医薬として有用である。
Claims (13)
- イソロイシン、ロイシンおよびバリンを有効成分として含有する、特発性炎症性筋疾患の予防又は治療剤。
- 特発性炎症性筋疾患が、多発性筋炎、皮膚筋炎、筋症状のない皮膚筋炎、小児皮膚筋炎、悪性腫瘍に合併する筋炎、他の膠原病に合併する筋炎、及び封入体筋炎からなる群より選択される、請求項1に記載の剤。
- 筋組織の炎症を抑制することを特徴とする、請求項1又は2に記載の剤。
- 筋萎縮および/または筋力低下を改善することを特徴とする、請求項1~3のいずれか1項に記載の剤。
- イソロイシン、ロイシンおよびバリンの重量比が、1:1~3:0.5~2.0である、請求項1~4のいずれか1項に記載の剤。
- ヒトに対する1日あたりの投与量が、イソロイシン、ロイシンおよびバリンの合計量として3~90gである、請求項1~5のいずれか1項に記載の剤。
- イソロイシン、ロイシンおよびバリンを有効成分として含有する組成物を、投与対象に投与することを含む、特発性炎症性筋疾患の予防又は改善方法。
- イソロイシン、ロイシンおよびバリンを有効成分として含有する組成物を、投与対象に投与することを含む、筋組織の炎症を抑制することを特徴とする、請求項7に記載の方法。
- イソロイシン、ロイシンおよびバリンを有効成分として含有する組成物を、投与対象に投与することを含む、筋萎縮および/または筋力低下を改善することを特徴とする、請求項7に記載の方法。
- イソロイシン、ロイシンおよびバリンの重量比が1:1~3:0.5~2.0である、請求項7~9のいずれか1項に記載の方法。
- ヒトに対する1日あたりの投与量が、イソロイシン、ロイシンおよびバリンの合計量として3~90gである、請求項7~10のいずれか1項に記載の方法。
- 特発性炎症性筋疾患が、治療中にステロイドミオパチーを合併する特発性炎症性筋疾患である、請求項1~6のいずれか1項に記載の剤。
- 特発性炎症性筋疾患が、治療中にステロイドミオパチーを合併する特発性炎症性筋疾患である、請求項7~11のいずれか1項に記載の方法。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA 2863809 CA2863809A1 (en) | 2012-02-06 | 2013-02-06 | Prophylactic or therapeutic agent for idiopathic inflammatory myopathies |
EP13747280.9A EP2813224A4 (en) | 2012-02-06 | 2013-02-06 | PROPHYLACTIC OR THERAPEUTIC AGENTS AGAINST IDIOPATHIC INFLAMMABLE MUSCLE DISEASES |
AU2013218690A AU2013218690A1 (en) | 2012-02-06 | 2013-02-06 | Prophylactic or therapeutic agent for idiopathic inflammatory myopathies |
JP2013557547A JP6145778B2 (ja) | 2012-02-06 | 2013-02-06 | 特発性炎症性筋疾患の予防又は治療剤 |
KR20147024903A KR20140121475A (ko) | 2012-02-06 | 2013-02-06 | 특발성 염증성 근질환의 예방 또는 치료제 |
US14/451,736 US20140343148A1 (en) | 2012-02-06 | 2014-08-05 | Prophylactic or therapeutic agent for idiopathic inflammatory myopathies |
US15/430,796 US20170151200A1 (en) | 2012-02-06 | 2017-02-13 | Prophylactic or therapeutic agent for idiopathic inflammatory myopathies |
AU2017279592A AU2017279592A1 (en) | 2012-02-06 | 2017-12-19 | Prophylactic or therapeutic agent for idiopathic inflammatory myopathies |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012023521 | 2012-02-06 | ||
JP2012-023521 | 2012-02-06 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/451,736 Continuation US20140343148A1 (en) | 2012-02-06 | 2014-08-05 | Prophylactic or therapeutic agent for idiopathic inflammatory myopathies |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013118773A1 true WO2013118773A1 (ja) | 2013-08-15 |
Family
ID=48947534
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2013/052730 WO2013118773A1 (ja) | 2012-02-06 | 2013-02-06 | 特発性炎症性筋疾患の予防又は治療剤 |
Country Status (7)
Country | Link |
---|---|
US (2) | US20140343148A1 (ja) |
EP (1) | EP2813224A4 (ja) |
JP (1) | JP6145778B2 (ja) |
KR (1) | KR20140121475A (ja) |
AU (2) | AU2013218690A1 (ja) |
CA (1) | CA2863809A1 (ja) |
WO (1) | WO2013118773A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015015149A1 (en) * | 2013-07-31 | 2015-02-05 | Leeds Metropolitan University | Dietary supplement |
JPWO2018105550A1 (ja) * | 2016-12-05 | 2019-10-24 | 大塚製薬株式会社 | 筋萎縮抑制組成物 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2831102A4 (en) | 2012-03-26 | 2015-12-02 | Pronutria Inc | NUTRIENT FRAGMENTS, NUTRIENT PROTEINS AND METHODS |
MX2014011459A (es) | 2012-03-26 | 2015-02-04 | Pronutria Inc | Proteinas nutritivas cargadas y metodos. |
EP2831100A4 (en) | 2012-03-26 | 2016-02-10 | Pronutria Inc | NUTRIENT PROTEINS AND METHODS |
EP2831099B1 (en) | 2012-03-26 | 2020-04-22 | Axcella Health Inc. | Nutritive fragments, proteins and methods |
AU2014324900A1 (en) | 2013-09-25 | 2016-05-19 | Axcella Health Inc. | Compositions and formulations for prevention and reduction of tumorigenesis, cancer cell proliferation and invasion, and methods of production and use thereof in cancer treatment |
US11369569B2 (en) * | 2015-06-15 | 2022-06-28 | University Of Virginia Patent Foundation | Target-specific delivery of therapeutic agents |
US20210260010A1 (en) * | 2018-06-20 | 2021-08-26 | Axcella Health Inc. | Compositions and methods for the reduction or treatment of inflammation |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07118150A (ja) * | 1993-08-31 | 1995-05-09 | Yoshiaki Akiyama | 分枝鎖アミノ酸を有効成分とする、呈味の調整された経口投与薬 |
JPH08198748A (ja) | 1995-01-27 | 1996-08-06 | Ajinomoto Co Inc | アミノ酸栄養組成物 |
WO2002060431A1 (fr) * | 2001-01-30 | 2002-08-08 | Ajinomoto Co., Inc. | Medicaments therapeutiques/prophylactiques contre des maladies inflammatoires |
WO2005055997A1 (ja) | 2003-12-15 | 2005-06-23 | Ajinomoto Co., Inc. | 炎症性疾患の治療及び予防用医薬組成物 |
WO2008072663A1 (ja) | 2006-12-12 | 2008-06-19 | Ajinomoto Co., Inc. | ステロイド療法における副作用の改善・抑制用組成物 |
JP2009517473A (ja) * | 2005-11-30 | 2009-04-30 | ネステク ソシエテ アノニム | 筋肉損失の治療のための方法 |
JP2012023521A (ja) | 2010-07-14 | 2012-02-02 | Funai Electric Co Ltd | テレビジョン受像機及び録画システム |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050101605A1 (en) * | 2003-11-07 | 2005-05-12 | Ahmed Salah U. | Oral liquid formulations of methotrexate |
-
2013
- 2013-02-06 KR KR20147024903A patent/KR20140121475A/ko not_active Application Discontinuation
- 2013-02-06 EP EP13747280.9A patent/EP2813224A4/en not_active Withdrawn
- 2013-02-06 JP JP2013557547A patent/JP6145778B2/ja not_active Expired - Fee Related
- 2013-02-06 CA CA 2863809 patent/CA2863809A1/en not_active Abandoned
- 2013-02-06 AU AU2013218690A patent/AU2013218690A1/en not_active Abandoned
- 2013-02-06 WO PCT/JP2013/052730 patent/WO2013118773A1/ja active Application Filing
-
2014
- 2014-08-05 US US14/451,736 patent/US20140343148A1/en not_active Abandoned
-
2017
- 2017-02-13 US US15/430,796 patent/US20170151200A1/en not_active Abandoned
- 2017-12-19 AU AU2017279592A patent/AU2017279592A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07118150A (ja) * | 1993-08-31 | 1995-05-09 | Yoshiaki Akiyama | 分枝鎖アミノ酸を有効成分とする、呈味の調整された経口投与薬 |
JPH08198748A (ja) | 1995-01-27 | 1996-08-06 | Ajinomoto Co Inc | アミノ酸栄養組成物 |
WO2002060431A1 (fr) * | 2001-01-30 | 2002-08-08 | Ajinomoto Co., Inc. | Medicaments therapeutiques/prophylactiques contre des maladies inflammatoires |
WO2005055997A1 (ja) | 2003-12-15 | 2005-06-23 | Ajinomoto Co., Inc. | 炎症性疾患の治療及び予防用医薬組成物 |
JP2009517473A (ja) * | 2005-11-30 | 2009-04-30 | ネステク ソシエテ アノニム | 筋肉損失の治療のための方法 |
WO2008072663A1 (ja) | 2006-12-12 | 2008-06-19 | Ajinomoto Co., Inc. | ステロイド療法における副作用の改善・抑制用組成物 |
JP2012023521A (ja) | 2010-07-14 | 2012-02-02 | Funai Electric Co Ltd | テレビジョン受像機及び録画システム |
Non-Patent Citations (8)
Title |
---|
ANN RHEUM DIS., vol. 67, no. 12, December 2008 (2008-12-01), pages 1670 - 7 |
ANN RHEUM DIS., vol. 70, 2011, pages A80 - A81 |
CELL METABOLISM, vol. 13, 2010, pages 170 - 182 |
CURR. OPIN. PHARMACOL., vol. 10, 2010, pages 346 - 352 |
See also references of EP2813224A4 |
SHIMIZU, N. ET AL.: "Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle", CELL METABOLISM, vol. 13, 2011, pages 170 - 182, XP028144015 * |
SUGIHARA, T. ET AL.: "A New Murine Model to Define the Critical Pathologic and Therapeutic Mediators of Polymyositis", ARTHRITIS & RHEUMATISM, vol. 56, no. 4, 2007, pages 1304 - 1314, XP055160849 * |
YOKO TABUSHI ET AL.: "Kin'en no Kinshojo to sono Hyokaho", RHEUMATOLOGY, vol. 26, no. 5, 2001, pages 420 - 427, XP008174813 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015015149A1 (en) * | 2013-07-31 | 2015-02-05 | Leeds Metropolitan University | Dietary supplement |
JPWO2018105550A1 (ja) * | 2016-12-05 | 2019-10-24 | 大塚製薬株式会社 | 筋萎縮抑制組成物 |
JP7077235B2 (ja) | 2016-12-05 | 2022-05-30 | 大塚製薬株式会社 | 筋萎縮抑制組成物 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2013118773A1 (ja) | 2015-05-11 |
KR20140121475A (ko) | 2014-10-15 |
US20170151200A1 (en) | 2017-06-01 |
CA2863809A1 (en) | 2013-08-15 |
US20140343148A1 (en) | 2014-11-20 |
AU2017279592A1 (en) | 2018-01-18 |
AU2013218690A1 (en) | 2014-09-25 |
EP2813224A4 (en) | 2015-06-24 |
JP6145778B2 (ja) | 2017-06-14 |
EP2813224A1 (en) | 2014-12-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6145778B2 (ja) | 特発性炎症性筋疾患の予防又は治療剤 | |
US10583125B2 (en) | Method for treating neurodegenerative diseases | |
RU2012117563A (ru) | Режим дозирования модулятора рецептора s1p | |
JP3906716B2 (ja) | 耐糖能異常用薬剤 | |
EA028060B1 (ru) | Комбинированная терапия бокового амиотрофического склероза | |
CA2124912A1 (en) | Therapeutic composition | |
JP6044667B2 (ja) | 耐糖能異常用医薬組成物及び飲食品 | |
WO2022253034A1 (zh) | 吡咯并嘧啶类化合物的用途 | |
JP3415643B2 (ja) | 筋ジストロフィー症治療薬 | |
EA034394B1 (ru) | Биотин для лечения амиотрофического латерального склероза | |
US20150094380A1 (en) | Agent for improving vesicourethral dyssynergia | |
WO2009098533A1 (en) | Non -immunosuppressive cyclosporin for the treatment of muscular dystrophy | |
CN110325214A (zh) | 用于预防和治疗神经元损伤的低剂量药物组合 | |
WO2022135462A1 (zh) | Magl抑制剂的医药用途 | |
JP2006028194A (ja) | 耐糖能異常用医薬組成物及び飲食品 | |
WO2005055997A1 (ja) | 炎症性疾患の治療及び予防用医薬組成物 | |
CN112641765B (zh) | 丙泊酚的抗疲劳制药用途 | |
JP2015227288A (ja) | けいれん重積発作の治療用医薬組成物 | |
US20140121164A1 (en) | Prevention of kidney injury or disease | |
JP6935930B2 (ja) | 生薬成分を含む肺高血圧症の予防又は治療剤 | |
JPH11171763A (ja) | 肝疾患治療剤 | |
JP6401028B2 (ja) | 鯨筋肉抽出物からなる中長期記憶障害予防改善剤 | |
CN113645978A (zh) | 用于预防或治疗肺纤维化的药剂 | |
WO2016208045A1 (ja) | 脊髄小脳変性症における運動失調の治療剤の投与レジメン |
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: 13747280 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013557547 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2863809 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013747280 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20147024903 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2013218690 Country of ref document: AU Date of ref document: 20130206 Kind code of ref document: A |