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WO2014051398A1 - Composition pharmaceutique comprenant de l'acécaïnide ou un dérivé de celui-ci pour la prévention ou le traitement de maladies associées à une faiblesse musculaire - Google Patents

Composition pharmaceutique comprenant de l'acécaïnide ou un dérivé de celui-ci pour la prévention ou le traitement de maladies associées à une faiblesse musculaire Download PDF

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Publication number
WO2014051398A1
WO2014051398A1 PCT/KR2013/008722 KR2013008722W WO2014051398A1 WO 2014051398 A1 WO2014051398 A1 WO 2014051398A1 KR 2013008722 W KR2013008722 W KR 2013008722W WO 2014051398 A1 WO2014051398 A1 WO 2014051398A1
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Prior art keywords
acecainide
procainamide
hydrochloride
muscle
differentiation
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English (en)
Korean (ko)
Inventor
박성섭
권기선
성혜영
최정이
이광표
이승민
하종성
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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Publication of WO2014051398A1 publication Critical patent/WO2014051398A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/316—Foods, ingredients or supplements having a functional effect on health having an effect on regeneration or building of ligaments or muscles

Definitions

  • the present invention provides a composition for promoting differentiation of myoblasts comprising acecainide or a derivative thereof, or a pharmaceutically acceptable salt thereof, acecainide or a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • a method for promoting differentiation of myoblasts comprising treating an acceptable salt with an in vitro myoblast, or differentiating myoblasts by treating acecinide or a derivative thereof, procaineamide, or a pharmaceutically acceptable salt thereof, in vitro.
  • a pharmaceutical composition for preventing or treating muscle weakness-related diseases of muscle including a method of producing differentiated myoblasts, acecainide or a derivative thereof, procaineamide or a pharmaceutically acceptable salt thereof Composition and muscle strength for the prevention or improvement of diseases related to muscle weakness
  • a composition for treating muscle weakness associated with muscle weakness comprising administering a cosmetic composition, Acecainaid, or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. It relates to a method of treatment.
  • sarcopenia which progresses with aging, muscle atrophy caused by imbalances in protein metabolism or decreased muscle use, starvation, wasting diseases (such as cancer), and aging. Acardiotrophy and the like.
  • Sarcopenia refers to a decrease in muscle strength due to a decrease in muscle mass during aging. In addition to a decrease in muscle mass, the most hallmark of myopathy, a change in the type of muscle fibers is also observed. As age increases, Type 1 and Type 2 decrease in similar proportions, whereas with Myotropia there is no significant change in Type 2 muscle fiber thickness, but Type 1 muscle fiber thickness decreases significantly. It has been reported that this sarcoma causes old age and dysfunction among older people (Roubenoff R., Can. J. Appl. Physiol. 26, 78-89, 2001).
  • Muscular dystrophy is caused by a variety of factors, but little research is available on each. Decreases or decreases growth hormone, changes in neurological changes, changes in physiological activity, changes in metabolism, increases in the amount of sex hormones or fats or catabolic cytokines, and balances of protein synthesis and differentiation Induced by change (Roubenoff R. and Hughes VA, J. Gerontol. A. Biol. Sci. Med. Sci. 55, M716-M724, 2000). Reducing satellite cell activation is one of the major causes of muscle mass loss, which is the hallmark of muscular dystrophy. Satellite cells are small mononuclear cells located between the basement membrane and the sarcolemma of the muscle fibers.
  • Muscular atrophy is caused by malnutrition or long-term muscle inactivity, resulting in a breakdown in the balance of normal protein synthesis and degradation.
  • cardiac atrophy is caused by starvation, wasting diseases (cancer, etc.) and aging, myocardial fibers are thin and thin, and the nucleus is concentrated to become large and small.
  • muscle fascicles also lose volume, the entire heart becomes smaller, subcardiac adipose tissue decreases significantly, and coronary arteries are curved.
  • Consumable pigment appears as brown pigment at both ends of the nucleus of myocardial fibers, and the entire heart is brownish with reduction of adipose tissue.
  • stem cell therapy which separates satellite cells, differentiates them in vitro and introduces them into the body, and directly activates satellite cells in the body to promote muscle differentiation, thereby maintaining or strengthening muscles. It is emerging as a method to treat muscle weakness such as diminished syndrome (Shihuan Kuang, and Michael A. Rudnicki, Trends in Molecular Medicine 14, 82-31, 2008).
  • acecainide hydrochloride or procaineamide hydro The present invention has been completed by confirming that the composition containing chloride can be used for preventing or treating muscle weakness-related diseases by promoting differentiation of myoblasts.
  • One object of the present invention is to provide a composition for promoting differentiation of myoblasts.
  • Another object of the present invention is to provide a method for promoting differentiation of myoblasts.
  • Another object of the present invention is to provide a method for producing differentiated myoblasts.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating muscle weakness-related diseases.
  • Still another object of the present invention is to provide a method for preventing or treating a muscle weakness-related disease.
  • Still another object of the present invention is to provide a food composition for preventing or improving a muscle weakness-related disease.
  • Another object of the present invention relates to a food composition for muscle strength.
  • Another object of the present invention is the muscle strength of muscle, comprising the step of administering Acecainaid or its derivative, Procainamide, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. It is to provide a method for treating a weakening-related disease.
  • the present invention provides a composition for promoting differentiation of myoblast (aceoinide) or derivatives thereof, or a pharmaceutically acceptable salt thereof.
  • Acecainide is a compound represented by the following Chemical Formula 1.
  • the term "derivative" used in the present invention means a compound in which the functional group of the acecainide compound is changed to the extent that the structure and properties of the parent are not significantly changed by introduction, substitution, oxidation, reduction, or the like.
  • the acetyl group and / or alkyl group at the N-terminus of the acecainide compound may be hydrogen, hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms.
  • Amine, nitro, alkyl carbonyl having 1 to 4 carbon atoms, carboxyl group and the like can be substituted.
  • the procainamide is a compound represented by the following formula (2).
  • the term "pharmaceutically acceptable salt” means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • the pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like, tartaric acid, formic acid, citric acid Sulfonic acids such as acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, organic carbonic acid such as fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric
  • carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N Organic salts such as -methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine and the like.
  • the salt may be acecainide hydrochloride (Acecainide HCl) or procainamide hydrochloride (Procainamide HCl), but is not limited thereto.
  • “Acecainide” in the present invention is the name of the International Union of Pure and Applied Chemistry (IUPAC) 4-acetamido-N- (2-diethylaminoethyl) benzamide (4-acetamido-N- (2-diethylaminoethyl) benzamide).
  • "Procainamide” is the name of the International Union of Pure and Applied Chemistry (IUPAC) 4-amino-N- (2-diethylacinoethyl) benzamide (4-amino-N- (2). -diethylaminoethyl) benzamide).
  • Acecainide and “Procainamide” are used for the purpose of inhibiting and treating cardiacarrhythmia, and pharmacologically, depolarization and repolarization of the heart, refractory and excitability, and impulse irritation of the myocardium. ) Is known to affect induction or membrane responsiveness. However, no association with myoblast differentiation is known. The present inventors have completed the present invention for the first time by identifying the use of myoblast differentiation in acecainide or its derivative, Procainamide, or a pharmaceutically acceptable salt thereof.
  • procainamide is a hydrochloride form that is approved by the Food and Drug Administration (FDA) and has been recognized for its safety and functionality. Cyanamide hydrochloride is advantageous in confirming efficacy through clinical experiments, etc., compared to any other compound, and thus is advantageous in actual human application.
  • FDA Food and Drug Administration
  • myoblast differentiation is a process in which myoblasts, which are mononuclear, form a multinuclear myotube through fusion.
  • Myoblasts corresponding to muscle precursor cells show Pax7 + markers when self-renewaling and Pax7 + / MyoD + when proliferating.
  • Cells of the differentiation stage forming the root canal can be distinguished using Pax7 - MyoD + MyoG + markers.
  • MyoD myosin D
  • MyoG myosin G
  • MyHC Myosin Heavy Chain
  • Promoting myoblast differentiation of the present invention is acekanide (Acecainide) or derivatives thereof in the medium for DMEM differentiation containing serum, or procainamide, or a pharmaceutically acceptable salt thereof, acecainide hydrochloride or procaine.
  • Medium treated with amide hydrochloride may be used, but is not limited thereto.
  • Acecainide (Acecainide) or a derivative thereof, Procainamide (Procainamide), or a pharmaceutically acceptable salt thereof, including a medium capable of promoting myocyte differentiation may be included without limitation.
  • 0.001 ⁇ M to 2.0 ⁇ M acecide hydrochloride or procaine amide hydrochloride may be used in the differentiation medium, and more preferably 0.001 ⁇ M to 1.0 ⁇ M acecide hydrochloride or procaineamide hydrochloride may be used. have.
  • the MYH3 fold change value is negative in the negative control (DMSO) Compared to the positive control group (insulin 0.6 ⁇ g / mL), it was confirmed that acecide hydrochloride promotes myoblast differentiation (Fig. 1).
  • the acecainide or its pharmaceutically acceptable salt, acecainide hydrochloride is treated in differentiation medium of in vitro myoblasts at concentrations of 0.0001, 0.001, 0.01, 0.1, 0.2, 1.0 and 2.0 ⁇ M.
  • the differentiation promoting effect was higher than that of the positive control group at a concentration of 0.001 ⁇ M.
  • treatment of acecainide hydrochloride at a concentration of 0.1 ⁇ M showed higher differentiation promoting effect than insulin treatment of 0.6 ⁇ g / mL (about 1 ⁇ M) (FIG. 2).
  • the acecainide of the present invention (Acecainide) or derivatives thereof, Procainamide, or a pharmaceutically acceptable salt thereof, Acecainide hydrochloride or Procainamide hydrochloride are myoblasts. It can be usefully used to promote differentiation.
  • the composition may also include additional ingredients so long as they do not interfere with the promotion of myocyte differentiation.
  • the present invention is to promote the differentiation of myoblasts comprising the step of treating the acecainide (Procainamide), or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof to myoblasts Provide a method.
  • Acecainide or its derivative, Procainamide, or a pharmaceutically acceptable salt thereof, is as described above.
  • the method for promoting differentiation of myoblasts of the present invention is characterized by promoting differentiation by treating aceticinide or its derivative, procainamide, or a pharmaceutically acceptable salt thereof, in myoblasts in vitro or in vivo. It is done.
  • the present invention comprises the steps of differentiating progenitor cells by treating acetic acid or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof, to the progenitor cells. It provides a method for producing a source cell.
  • Acecainide or its derivative, Procainamide, or a pharmaceutically acceptable salt and salt concentration thereof, is as described above.
  • the production method of the present invention is characterized by producing a differentiated myoblast cell comprising the step of differentiating myoblast cells by treatment of acetic acid (Acecainide) or derivatives thereof procainamide (procainamide) in vitro or in vivo. It is done.
  • acetic acid Acecainide
  • procainamide procainamide
  • aceticinide hydrochloride (Acecainide hydrochloride) or procainamide hydrochloride (Procainamide hydrochloride) in the differentiation culture of the source cells to differentiate for 3 days and then subjected to phase contrast microscopy and immunocytochemical staining
  • the differentiation promoting composition was treated to induce differentiation of myoblasts, followed by Western blot to confirm the amount of MYH3 protein, which was found to be much higher than that of the negative control (FIGS. 6 and 13).
  • the present invention can produce differentiated, myoblasts that can form myotubes and express MYH3 protein in vitro or in vivo.
  • the present invention provides a pharmaceutical for the prevention or treatment of muscle weakness-related diseases of the muscle comprising the acecainide (Procainamide), or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof To provide a composition.
  • Acecainide or its derivative, Procainamide, or a pharmaceutically acceptable salt and salt concentration thereof, is as described above.
  • muscle weakening means a state in which the strength of one or more muscles is reduced.
  • the muscle weakness may be limited to any one muscle, one side of the body, upper limb or lower limb, or may appear throughout the whole body.
  • subjective muscle weakness symptoms including muscle fatigue or muscle pain can be quantified in an objective manner through physical examination.
  • Muscle weakness-related diseases in the present invention means all diseases that can occur due to muscle weakness, for example, but not limited to muscle reduction, muscular dystrophy or acardiotrophia (acardiotrophia).
  • composition of the present invention can be used for the prevention or treatment of myotropenia, muscular atrophy or heart atrophy through promoting differentiation of myoblasts.
  • the myopathy of the present invention refers to a gradual decrease in skeletal muscle mass due to aging, which directly leads to a decrease in muscle strength, and as a result, a condition in which various physical functions may be reduced and impaired.
  • muscular dystrophy is asymmetrical contraction of the muscles of the extremities, causing progressive degeneration of motor nerve fibers and cells in the spinal cord, resulting in Amyotrophic lateral sclerosis (ALS) and spinal progressive muscular dystrophy (Spinal). progressive muscular atrophy (SPMA).
  • ALS Amyotrophic lateral sclerosis
  • SPMA spinal progressive muscular dystrophy
  • the cardiac atrophy of the present invention is that the heart is contracted by external or internal factors, which can cause brown atrophy of the heart, which leads to a decrease in adipose tissue due to dryness and thinning of myocardial fibers when starvation, wasting disease, and aging. have.
  • prevention refers to any action that inhibits or delays the onset of muscle weakness-related diseases by administration of the composition.
  • treatment refers to all actions that improve or beneficially change symptoms caused by muscle weakness-related diseases by administration of the composition.
  • composition of the present invention for administration, in addition to the acecainide (Acecainide) or derivatives thereof, Procainamide, or a pharmaceutically acceptable salt thereof acecainide hydrochloride or procaineamide hydrochloride And acceptable carriers, excipients or diluents.
  • the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions of the present invention are well known in the art to provide rapid, sustained or delayed release of Acecainide or its derivative, Procainamide, or a pharmaceutically acceptable salt thereof.
  • composition of the present invention may be applied in any formulation, but is preferably prepared for parenteral use.
  • Parenteral formulations may be in the form of sprays, such as injections, applications, aerosols, and the like.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • acecainide or its derivative, procainamide, or a pharmaceutically acceptable salt thereof is prepared in solution or suspension by mixing in water with a stabilizer or buffer, It may be formulated for unit administration of ampoules or vials.
  • composition comprising the acecainide of the present invention (Acecainide) or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof, can be used to strengthen the muscle strength of an individual who has a muscle weakness-related disease or an individual who may develop the disease. Can be injected directly into the area of need. Or a composition comprising acecainide or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof, is applied to in vitro or in vivo myoblasts to produce differentiated myoblasts, and then differentiated. Myoblasts may be injected into areas where muscle weakness-related disease develops or where muscle strength may be needed.
  • composition of the present invention as long as acecainide or its derivative, Procainamide, or a pharmaceutically acceptable salt thereof, does not interfere with the prevention or treatment of muscle weakness-related diseases, Additional ingredients can be included, for example, substances known to treat muscle weakness-related diseases.
  • Acecainide or a derivative thereof procainamide in the composition of the present invention may be included in the form of acecainide hydrochloride or procaineamide hydrochloride, and the concentration of 0.001 ⁇ M to 2.0 ⁇ M acecainide hydrochloride.
  • procaineamide hydrochloride may be used, more preferably 0.001 ⁇ M to 1.0 ⁇ M of acecide hydrochloride or procaineamide hydrochloride.
  • the pharmaceutical composition of the present invention is characterized by promoting differentiation of myoblasts.
  • the MYH3 fold change value is negative in the negative control (DMSO) Compared with the positive control group (insulin 0.6 ⁇ g / mL), it was confirmed that acecide hydrochloride promotes myoblast differentiation (Fig. 1).
  • the acecainide or its pharmaceutically acceptable salt, acecainide hydrochloride is treated in differentiation medium of in vitro myoblasts at concentrations of 0.0001, 0.001, 0.01, 0.1, 0.2, 1.0 and 2.0 ⁇ M.
  • the differentiation promoting effect was higher than that of the positive control group at a concentration of 0.001 ⁇ M.
  • treatment of acecainide hydrochloride at a concentration of 0.1 ⁇ M showed higher differentiation promoting effect than insulin treatment of 0.6 ⁇ g / mL (about 1 ⁇ M) (FIG. 2).
  • acecainide or derivative thereof procainamide, or a pharmaceutically acceptable salt thereof, acecainide hydrochloride or procainamide hydrochloride is a muscle cell differentiation promoting agent. It has been confirmed that the effect of promoting the differentiation of muscle cells different from or better than known insulin, therefore, the acekinide hydrochloride or procaineamide hydrochloride is effective in promoting the differentiation of myoblasts and prevention of muscle weakness-related diseases It was found to be useful for treatment.
  • the present invention provides a method of treating muscle weakness-related diseases by administering acecainide or a derivative thereof Procainamide, or a pharmaceutically acceptable salt thereof, to a subject. to provide.
  • the present invention is a food composition for preventing or improving muscle weakness-related diseases of muscles including the acecainide or derivatives thereof Procainamide, or a pharmaceutically acceptable salt thereof To provide. That is, the composition of the present invention may be used simultaneously or separately with a medicament for treating a disease before or after the onset of the muscle weakness-related disease in order to prevent or ameliorate the muscle weakness-related disease.
  • the concentration of Acecainide or its derivative Procainamide, or a pharmaceutically acceptable salt thereof, of Acecainide Hydrochloride or Procaineamide Hydrochloride is 0.001 ⁇ M to 2.0 ⁇ M. More preferably 0.001 ⁇ M to 1.0 ⁇ M.
  • compositions of the present invention can be used for the prevention or amelioration of myotropia, muscular atrophy or atrophy.
  • the food composition is characterized in that to promote the differentiation of myoblasts (Myoblasst).
  • the term 'improvement' refers to any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
  • the composition of the present invention when used as a food additive, the composition may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the compositions of the present invention are added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the active ingredient may be used in an amount above the above range.
  • Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages and vitamin complexes, and includes all healthy foods in the conventional sense.
  • the health beverage composition of the present invention may contain various flavors or natural carbohydrates, etc. as additional components, as in the general beverage.
  • the natural carbohydrates described above may be used as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, and synthetic sweeteners such as saccharin and aspartame.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And a carbonation agent used for the carbonated beverage.
  • the composition of the present invention may contain a pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives may also be appropriately selected by those skilled in the art.
  • the present invention provides a composition for strengthening muscle strength, which includes acecainaid or a derivative thereof, Procainamide, or a pharmaceutically or pharmaceutically acceptable salt thereof.
  • Acecainaid or its derivative, Procainamide, or a pharmaceutically or pharmaceutically acceptable salt and salt concentration thereof, is as described above.
  • the term "strengthening muscle” refers to strengthening physical performance, increasing maximum endurance, increasing muscle mass, strengthening muscle recovery, reducing muscle fatigue, improving energy balance, or a combination thereof.
  • Muscle strength-enhancing compositions comprising acecainaid or derivatives thereof of the present invention, Procainamide, or pharmaceutically or pharmaceutically acceptable salts thereof, have the ability to differentiate myoblasts into muscle cells.
  • Increasing muscle mass can increase overall muscle mass, increasing maximum endurance, which in turn increases body performance and reduces muscle fatigue. Also, because muscle cells can be replaced quickly, they can be quickly healed against muscle damage.
  • composition for strengthening muscle of the present invention for administration, the acecainamide (Acecainaid) or a derivative thereof Procainamide, or a pharmaceutically or pharmaceutically acceptable salt thereof acecainide hydrochloride (Acecainide HCl) Or in addition to procainamide HCl, a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutically acceptable carrier, excipient or diluent is as described above.
  • composition for muscle strength of the present invention may be prepared in the form of a food composition or food additives, in particular in the form of a health food composition.
  • the food composition is as described above. Therefore, the composition for strengthening muscle strength of the present invention can be used in the form of supplements for muscle production, muscle strength of the general public as well as muscle reduction by aging.
  • acecainide (Acecainaid) acecainide hydrochloride
  • the muscle recovery test exercise performance test (grip test, balance test, endurance test )
  • exercise performance test gap test, balance test, endurance test
  • acecainide or a pharmaceutically acceptable salt thereof can be used for strength strengthening.
  • the equilibrium capacity test (Rotarod test) is carried out, the muscle strengthening ability By confirming, it was confirmed that procaineamide or a pharmaceutically acceptable salt thereof can be used for muscle strength use.
  • the invention provides a method comprising administering acecainaid or a derivative thereof, Procainamide, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. It provides a method of treating muscle weakness-related diseases.
  • Acecainide or derivatives thereof, Procainamide, or a pharmaceutically acceptable salt thereof, according to the present invention may promote muscle differentiation of myoblasts to form root canals, thereby preventing muscle weakness. , Can effectively improve muscle function. Therefore, the pharmaceutical composition including the same may be usefully used for the prevention or treatment of diseases related to muscle weakness.
  • Figure 1 shows the expression of myosin heavy chain 3 (myHin heavy chain 3, MYH3) protein in the late myocyte differentiation in order to confirm the myoblast differentiation effect of acecainide hydrochloride.
  • Figure shows the effect of promoting myocyte differentiation measured by In-Cell ELISA in cell line C2C12.
  • FIG. 2 is a diagram showing the differentiation-promoting effect of myoblast by treating acecainide hydrochloride to primary myoblasts (myoblast) by concentration.
  • FIG. 3 is a diagram showing the results of confirming the cytotoxicity when treated with acekinide hydrochloride in the primary source cell culture medium and differentiation medium.
  • FIG. 4 is a diagram showing the results of confirming the differentiation of the myoblast line C2C12 treated with acecide hydrochloride with a phase contrast microscope.
  • FIG. 5 is a diagram confirming the differentiation of myogenic cell line C2C12 treated with acecainide hydrochloride by immunocytochemistry.
  • Fig. 6 shows the results of Western blot expression of myosin heavy chain 3 (MYH3) in primary myocytes and myoblast cell lines C2C12 treated with acekanide hydrochloride.
  • FIG. 7 is a graph showing the grip force improvement effect of mice by treatment with acecainide hydrochloride in comparison with before and after muscle immobilization period.
  • FIG. 8 is a graph showing the effect of improving the equilibrium capacity of mice by treatment with acecainide hydrochloride, before and after muscle immobilization period.
  • FIG. 9 is a graph showing the endurance improvement effect of mice treated with acecainide hydrochloride in comparison with before and after muscle immobilization period.
  • FIG. 10 is a diagram showing the TA muscle weight after muscle immobilization of muscle recovery of mice by treatment with acecainide hydrochloride.
  • Figure 11 is a diagram showing the results of confirming the differentiation of the myoblast line C2C12 treated with procaine amide hydrochloride by a phase contrast microscope.
  • FIG. 12 is a diagram confirming the differentiation of myoblast line C2C12 treated with procaine amide hydrochloride by immunocytochemistry.
  • FIG. 13 shows Western blot expression of myosin heavy chain 3 (MYH3) in primary myoblasts and myoblasts treated with procaine amide hydrochloride and C2C12.
  • FIG. 14 is a diagram showing the effect of improving the equilibrium capacity of the mouse by treatment with procaine amide hydrochloride, before and after the muscle immobilization period.
  • Example 1-1 Primary Myoblast Isolation and Culture
  • the cells (primary stem cells) obtained above were re-dissolved in 2 ml F10 medium (Invitrogen) and transferred to a 100 mm general culture vessel as P1. Then, by using the difference in adhesion between the primary source cells and other cells such as fibroblast in order to concentrate only the primary source cells, the culture medium transferred to the culture vessel and the floating primary source cells contained therein for 1 hour intervals. Transfer to the culture vessel coated with 0.1% gelatin was repeated to P5.
  • the cells were cultured in an incubator containing 5% CO 2 at 37 ° C. and replaced with fresh F10 medium every two days. Cells were separated from the culture vessel using 0.005% trypsin for passage, and DMEM (Dulbecco's Modified Eagle Medium, Invitrogen) with 5% horse serum was used to induce differentiation into muscle cells. .
  • F10 medium Invitrogen
  • Example 1-2 Myogenic cell line C2Cl2 culture
  • C2Cl2 is a myogenic cell line obtained from live mice of C3H species and is widely used for myocyte differentiation studies.
  • the C2C12 cells were cultured in normal cell culture medium and differentiation medium, respectively.
  • DMEM with 10% young bovine serum (fetal bovine serum) was used as a normal cell culture medium (GM), and DMEM containing 2% horse serum was used as a differentiation medium (DM). It was.
  • Example 2-1 Exploration of Differentiation Promotion Using In-Cell ELISA
  • In-Cell ELISA was performed to compare the protein levels of myosin heavy 3 (myH3) expressed in primary myoblasts themselves.
  • the cells were washed again with 1 ⁇ PBS and treated with 100 ⁇ l blocking buffer containing 0.1% bovine serum albumin at room temperature for 1 hour.
  • the cells were washed three times with 1X PBS, and then 100 ⁇ l of the primary antibody (SC-20641, Santa Cruz Biotechnology) diluted 1: 500 was added and reacted at 37 ° C. for 2 hours.
  • the reacted cells were washed three times with 1 ⁇ PBS again, and then 100 ⁇ l of a secondary antibody (Goat anti-Rabbit IgG-HRP) diluted 1: 10,000 was added and reacted at 37 ° C. for 1 hour.
  • a secondary antibody Goat anti-Rabbit IgG-HRP
  • the In-Cell ELISA used in this experiment was able to quantify the expression level of the target protein by fixing the cells on the container and drilling a hole in the cell membrane, unlike using a sandwich ELISA.
  • the primary antibody used to compare the degree of differentiation of primary myoblasts is an antibody that recognizes myosin heavy chain 3 (MYH 3), a protein that begins expression when myoblast differentiation progresses. It was an antibody (sc-20641, Rabbit, Santa Cruz Biotechnilogy) prepared using the carboxyl terminal (1641-1940) as an antigen.
  • HRP conjugated goat anti-rabbit antibody ADI-SAB-300, Enzo Life Sciences
  • Cytotox 96 Non-Radioactive Cytotoxicity Assay (Promega), which measures lactate dehydrogenase (LDH), an enzyme secreted during cell death to measure cytotoxicity against insulin and acecainide or procainamide hydrochloride Kit was used.
  • LDH lactate dehydrogenase
  • GM Cell culture medium
  • DM cell culture medium and differentiation medium
  • 50 ⁇ l of each sample was transferred to a 96-well flat bottom plate, and then 50 ⁇ l of a substrate solution (reconstituted substrate mix) was added thereto for 30 minutes at room temperature.
  • 50 ⁇ M H 2 O 2 was treated as a control for complete cell death.
  • 50 ⁇ l stop solution was added to the cells, and the absorbance was measured at 490 nm and expressed as a ratio with respect to LDH value at the time of cell death by lysis buffer.
  • the cytotoxicity of the acecainide hydrochloride measured in the differentiation medium (DM) of primary root cells did not differ significantly depending on the concentration, and was not high compared to insulin.
  • DM differentiation medium
  • Example 4-1 Phase contrast microscopy
  • C2Cl2 cells were treated with 0.1% gelatin-coated cover glass with DMSO and acekinide hydrochloride, respectively. Differentiation was carried out for 3 days and observed under a phase contrast microscope.
  • C2Cl2 cells were differentiated for 3 days in 0.1% gelatin coated cover glass. After washing the cells with 1 X PBS, fixed with 3.7% paraformaldehyde (paraformaldehyde) at room temperature for 15 minutes, washed three times with 1 X PBS, then added permeabilization buffer for 15 minutes at room temperature Reacted. After washing three times with 1 X PBS again and reacted with PBST (blocking uffer, PBS containing 0.5% Tween 20) containing 1% BSA for 30 minutes to inhibit the unspecific antibody binding. Primary antibody to MYH3 (SC-20641, Santa Cruz Biotechnology) was added 1: 500 diluted in blocking buffer, and then reacted at room temperature for 1 hour.
  • PBST blocking uffer, PBS containing 0.5% Tween 20
  • a secondary antibody Goat anti-Rabbit IgG-HRP diluted 1: 5000 was added to the blocking buffer and reacted at room temperature for 1 hour, followed by 1 X PBS. Washed three times. The cover glass was placed on the slide glass and photographed with a fluorescence microscope to analyze the results.
  • the protein expression was confirmed by staining with an antibody against MYH3 to compare the degree of myoblast differentiation on the third day after inducing differentiation of C2Cl2 cell line while treating DMSO (negative control) and acecainide hydrochloride, respectively. .
  • DMSO negative control
  • acecainide hydrochloride acecainide hydrochloride
  • Example 4-3 Western blot
  • Cells were cultured in culture medium for 24 hours, followed by differentiation of primary myoblasts with DMSO (control), insulin (0.6 ⁇ g / ml) and acecainide hydrochloride (0.2 ⁇ M), respectively, in the differentiation medium. Induced. On day 3 of differentiation induction, cells were obtained and centrifuged for 3 minutes at 1200 rpm. 100 ⁇ l Lysis buffer was added to the cells, followed by sonication and centrifugation at 3000 rpm for 10 minutes to obtain a water-soluble protein. 4 X sample buffer was added to boil water. The reaction was carried out for 5 minutes. 10 ⁇ g of protein was loaded onto a 12% SDS-PAGE gel to develop and then transferred to the Watman membrane.
  • DMSO control
  • insulin 0.6 ⁇ g / ml
  • acecainide hydrochloride 0.2 ⁇ M
  • the membrane was blocked at room temperature for 1 hour with 5% skim milk powder, and washed five times with TTBS (0.03% Tween 20, Tris 2.42 g, NaCl 9 g, pH 7.4 1 L) for 5 minutes.
  • the primary antibody was diluted 1: 500 in TTBS containing 5% skim milk powder, and then reacted at room temperature for 2 hours, and then washed 5 times with TTBS for 5 minutes.
  • the secondary antibody was diluted 1: 5000 in TTBS containing 5% skim milk, and then reacted at room temperature for 2 hours, washed 5 times with TTBS for 5 minutes, followed by ECL (Enhanced Chemiluminescent solution, Pierce) Was added.
  • ECL Enhanced Chemiluminescent solution, Pierce
  • C2C12 cell line has a very high effect of promoting myoblast differentiation by acecainide hydrochloride. Able to know.
  • mice used 20 C57BL / 6 male mice weighing 20 g ( ⁇ 2 g) at 8 weeks of age, and the laboratory maintained constant conditions (temperature 22 ⁇ 2 ° C., humidity 55 ⁇ 5%). A 12-hour photoperiod and a 12-hour dark cycle were applied per day, and water and food were freely ingested during the experiment. Experimental animals were divided into control groups which were assigned to each of the same body weights and were administered with acecainide hydrochloride or procaine amide hydrochloride.
  • Acecainide hydrochloride or procaineamide hydrochloride (Sigma Chemical C., St. Louis, MO, USA) was dissolved in distilled water in the experimental group to prepare 20 mg / kg orally administered. Administration was continued even during the period of muscle immobilization described below.
  • mice we used a tibialis anterior muscle immobilization (TA) protocol to induce muscle regeneration in mice, which uses a medical staple to thigh and shin on one leg of the mouse. Fix it so that it does not move and leave it for 3 days and then release the fixed leg. If you can't use your leg muscles by casting your legs, the muscles will be lost. This is a way to induce muscle regeneration by freezing the muscles so that they can be lost and moved again.
  • the muscle weights of the animals were compared on the 7th and 14th day, respectively.
  • Example 5-2 Exercise test and test result
  • An exercise test was conducted to confirm the improvement of exercise ability by acecide hydrochloride or procaine amide hydrochloride.
  • the assessment of motor performance includes the gripstrength test to confirm the increase in physical force, the rota-rod test to confirm the improvement of equilibrium, and the treadmill test to confirm the endurance improvement. Three behavioral tests were performed. The exercise performance was assessed before and after TA muscle immobilization.
  • the grip force was measured using a gripper tester for the mouse of BIOSEB.
  • the mouse was placed on the wire mesh attached to the instrument panel to monitor the strength of the force, and the force of the mouse to hold the wire mesh was measured while pulling the tail downward. The average value shown five times in succession was used.
  • the motion was applied using a rotarod device consisting of six partitions with a diameter of 7 cm and 15 cm, and a cylindrical rod with a height of 60 cm. Starting at a rotational speed of 10 rpm and accelerating until reaching a speed of up to 40 rpm for 5 minutes, the time remaining in the rotarod without the mouse falling was measured. The average value of three times of 15 minutes rest and exercise was measured again.
  • both the experimental group administered with acecainide hydrochloride and the experimental group administered with procaine amide hydrochloride showed improved exercise ability to maintain equilibrium sensation after muscle immobilization compared to the control group. (FIG. 8, FIG. 14).
  • mice were run in isolated lanes each time, and the time until the mouse was exhausted, i.e. determined to be unwilling to run, was measured. The determination that there was no willingness to run was recorded after the mouse was exhausted after 10 seconds of not remaining outside the lane. This experiment could not be repeated for the same mouse.
  • the mouse was placed on the device and started at a speed of 8 rpm, accelerated by 2 rpm every 10 minutes, and run at a maximum of 18 rpm. Starting with no inclination, the tilt was increased by 5 degrees every 30 minutes.
  • Example 6-1 Phase contrast microscopy
  • Procainamide hydrochloride H 2 NC 6 H 4 CONHCH 2 CH 2 N (C 2 H 5 ) 2 .HCl, molecular weight 271.79 except that the same method as described in Example 4-1 The experiment was carried out as. When differentiating C2C12 cells with 0.5 ⁇ M of procaineamide hydrochloride, the myotubes were formed more than DMSO, so the differentiation promoting effect was confirmed (X100) (FIG. 11).
  • Example 6-3 Western blot
  • procainamide hydrochloride Except for using procainamide hydrochloride, the cells were cultured in culture medium in the same manner as described in Example 4-3, and cultured for 24 hours, followed by DMSO (control) in differentiation medium, and Procaine amide hydrochloride (0.5 ⁇ M) was treated daily to induce differentiation of primary myoblasts. As a result, it was confirmed that the amount of myocin heavy chain (MyHC) protein and the amount of myogenin protein contained in the same amount of protein was significantly increased in the procaine amide hydrochloride treatment group (FIG. 13).
  • MyHC myocin heavy chain

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JP2007528705A (ja) * 2003-06-27 2007-10-18 エチコン、インコーポレイテッド 心臓及び循環器系疾患の治療において使用するための分娩後由来細胞
JP2007529548A (ja) * 2004-03-18 2007-10-25 サマリタン，ファーマスーティカルス，インク． 抗ｈｉｖベンズアミド化合物およびベンゾアート化合物

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