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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present invention relates to a composition for preventing and treating prion diseases. More specifically, the present invention relates to a pharmaceutical composition and a food composition for preventing and treating prion diseases, including melatonin as an active ingredient.
• Prion is a disease infector that is completely different from the existing pathogens such as bacteria, viruses, bears, and parasites. It is much smaller than ordinary viruses and causes infectious diseases that exclude genetic material, nucleic acid. Has When prions infect animals, including humans, sponge-like fears form in the brain, causing neuronal death, leading to degenerative neuropathy.
• ⁇ 3> Prion disease is not known to date, and many scientists estimate that the occurrence of prion disease may be related to normal prion protein ( ⁇ ).
• ⁇ 1 ⁇ is a glycoprotein present in the cell membrane, and most of it is expressed in the brain, and little is known about its in vivo function, but it is known to have cell growth and partial signaling functions.
• ⁇ ! ⁇ has an abnormal form, called modified prion protein (PrP). Unlike ⁇ , they tend to coagulate with each other, and it is estimated that these cohorts cause infectious sponiform encephalopathy (TSE).
• ⁇ consists of three helices (a helix) and two screens ( ⁇ sheets), which are converted to ⁇ ! ⁇ through a mechanism unknown to date.
• ⁇ ! ⁇ Has more folding structure than PrP C, and it is condensed with each other to become insoluble, protease
• Representative prion diseases include human CJD Creutzfeldt-Jakob disease,
• Bovine spongiform encephalopathy BSE
• scrapie of sheep CWD
• CWD chronic wasting disease
• TEE transmissible mink encephalopathy
• prion disease spreads homogeneously but causes greater problems when it has spread to heterogeneity.
• the most representative example of this is human vCJD, which has spread from bovine BSE.
• the inventors of the present application conducted research to develop a drug capable of effectively preventing and treating prion diseases, and as a result, confirmed that melatonin selectively inhibits prion-induced neurotoxin, and completed the present invention.
• an object of the present invention is to provide a pharmaceutical composition for preventing and treating prion diseases.
• the present invention provides a pharmaceutical composition for the prevention or treatment of pre-silver disease containing melatonin as an active ingredient.
• the prion disease is preferably human Creutzfeldt-Jakob disease
• the present invention provides a food composition for preventing or improving prion disease containing melatonin.
• melatonin does not affect cell viability, and selectively inhibits prion-induced neurotoxins
• the composition comprising the same may be used as an effective medicine and food for preventing or treating prion diseases. Can be.
• FIG. 1 shows the results of pretreatment with melatonin (12 hours) in proportion to concentration of SH-SY5Y neurons and exposure to 50 ⁇ PrP (106-126) for 24 hours.
• Cell viability was measured by annexin V assay.
• Ml represents the distribution of Annexin V positive cells.
• FIG. 2 is a bar graph showing the average of Annexin V positive cells. The significant difference between the control and the experimental group was * P ⁇ 0.05, ** P ⁇ 0.001, and the significant difference between PrP (106-126) and experimental groups was #p ⁇ 0.01.
• FIG. 3 shows 50 ⁇ of PrP (106-126), with and without melatonin (12 hours).
• the present invention provides a pharmaceutical composition for preventing or treating prion diseases containing melatonin as an active ingredient.
• the inventors of the present invention exposed a neuroblastoma showing PrP-induced apoptosis to melatonin, and performed an annexin V assay.
• Annexin V as a marker of early apoptosis is a widely used protein in flow cytometry because it has a strong binding affinity for PS.
• PS is an important phosphorus lipid in the cell membrane that is exposed to the outside of the cell membrane surface early in the apoptosis process. PS is a well known "eat me" signal during apoptosis. Regardless of the type of cell and apoptosis inducer, PS is expressed on the outer cell membrane very early after apoptosis begins.
• Annexin V has an anion when there is calcium ion It is a protein that binds to the phospholipid surface [14].
• Annex in V consists of 320 amino acids and has a molecular weight of 36 kDa.
• annexin V can be modified and stabilized to serve as an appropriate biological marker for assessing cell death.
• Various fluorescently labeled annexin Vs have been successfully used for the measurement of apoptosis. As a result, it was confirmed that melatonin exhibited the effect of selectively inhibiting the neurotoxin induced by prion in neuroblastoma.
• Melatonin in the present invention is a hormone secreted by the pineal gland of the brain, regulates sleep and daily rhythm, and devours free radicals derived from oxygen, It has antioxidant properties by stimulating antioxidant enzymes such as peroxidase, glutathione peroxide enzyme, glutathione reductase, and glucose ⁇ 6—phosphate dehydrogenase.
• Prion diseases in the present invention may include all neurological diseases related to prion-mediated apoptosis, and specifically, human Creutzfeldt-Jakob disease and Kuru disease. ), Gerstmann-Strsyndrome, fatal familial insomnia; bovine spongiform encephalopathy (bovine BSE); scrapie of sheep; chronic wasting of deer disease) or mink's TME (transmissible mink encephalopathy) and the like.
• composition of the present invention may contain one or more known active ingredients having a prophylactic or therapeutic effect in conjunction with melatonin.
• the melatonin is 0.001 to 50% by weight, preferably in the total pharmaceutical composition
• the melatonin may be adjusted in a content so that the appropriate amount per 1kg of the individual to which the pharmaceutical composition is administered in the entire pharmaceutical composition can be administered.
• the melatonin is included in the pharmaceutical composition to be administered in an amount of 50 mg / kg to 150 mg / kg, preferably 80 mg / kg to 120 mg / kg. Can be controlled.
• the melatonin is contained in the pharmaceutical composition to be administered in an amount of 0.0001 to 50 (g / kg, preferably 0.001 to 500 mg / kg, more preferably 0.001 to 300 mg / kg The amount included can be adjusted.
• the pharmaceutical composition of the present invention does not increase the efficacy, but It may further include ingredients that are commonly used to improve the smell, taste, vision and the like.
• the composition may be inorganic or organic, such as vitamins B1, B2, B6, C, E, niacin, carnitine, betaine, folate pantothenic acid, biotin, zinc, iron, calcium, cream, magnesium, and combinations thereof. Additives may further be included.
• the composition may include a substance that is used alone or has a prophylactic or therapeutic activity against a previously used prion disease.
• the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and may be formulated for human or veterinary use for oral or parenteral use.
• diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants can be used.
• Solid form preparations for oral administration include sperm, pills, powders, granules and capsules. Such solid form preparations may comprise at least one excipient such as starch, calcium carbonate in a composition comprising a compound of the present invention. ), Sucrose or lactose, and 3 ⁇ 4 Latin.
• lubricants such as magnesium, styrate and talc may be used.
• Oral liquid preparations include suspensions, solvents, emulsions and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple limes.
• Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations and suppositories.
• non-aqueous and suspending solvent vegetable oils such as propylene glycol, polyethylene glycol and olive oil, injectable esters such as ethyl oleate and the like can be used.
• the pharmaceutical composition of the present invention may be administered to a subject to prevent or treat free silver disease.
• the term "individual” has a disease caused by prion disease or its direct or indirect cause, including humans having a disease that can be improved by administering the pharmaceutical composition of the present invention. Mammals such as cattle, sheep deer, and mink.
• the term "administration" means introducing the pharmaceutical composition of the present invention to a subject in any suitable manner.
• the route of administration may be oral or parenteral via any general route so long as it can reach the desired tissue.
• the pharmaceutical composition of the present invention may be administered by any device that allows migration to target cells.
• composition of the present invention is administered in a pharmaceutically effective amount.
• “Pharmaceutically effective amount” for a given dose means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the sex, age, severity, drug activity or drug of the patient. Sensitivity to, time of administration, route of administration and rate of administration, duration of treatment, factors including concomitant drug use, and other factors well known in the medical arts.
• the compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. It may be single or multiple doses.
• the administration method of the composition containing the compound prepared according to the preparation method of the present invention is preferably oral administration or intravenous administration. Dosage levels for a particular patient may vary depending on gender, age, health diet, time of administration, method of administration, drug combination and severity of disease.
• the present invention provides a food composition for preventing and improving prion diseases, including melatonin.
• the food composition of the present invention may be added to a health food for the purpose of suppressing prion disease.
• the composition of the present invention When the composition of the present invention is 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 amount of active ingredient can be determined appropriately depending on the purpose of use (prevention, health or therapeutic treatment).
• the compositions of the 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 because there is no problem in terms of safety.
• Examples of foods to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, 3 ⁇ 4, ice cream, various soups, drinks, tea, Drink preparations, alcoholic beverages and vitamin complexes, including all health foods in the conventional sense.
• the natural carbohydrates mentioned above are the parent Disaccharides such as nosaccharide, maltose and sucrose, and natural sweeteners such as dextrin and cyclotex trine, and synthetic sweeteners such as saccharin and aspartame.
• the ratio of the natural carbohydrate is generally about 0.001 to 0.4g, preferably about 0.002 to 0.03g per 100 food compositions of the present invention.
• the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, Glycerin, alcohol, carbonation agent used in carbonated drinks, and the like.
• the food composition of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage. These components can be used independently or in combination. The proportion of such additives is not critical but is generally selected in the range of 0.001 to 0.1 parts by weight per 100 parts by weight of the food composition of the present invention.
• Cells Obtained from Culture collection (ATCC, Rockville, MD, USA). Cells are minimal essential medium (Hyclone Laboratories, Logan) containing 10% fetal bovine serum (FBS; Invitrogen-Gibco, Grand Island, NY, USA) and gentamycin (0.1 mg / ml) , UT, USA) and were maintained in a humidified incubator at 37 ° C and 5% CO 2 conditions.
• FBS fetal bovine serum
• gentamycin 0.1 mg / ml
• Peptron (Seoul, Korea). Peptides were dissolved in sterile dimethylsulfoxide at a concentration of 12.5 mM and stored at -80 ° C.
• Apoptosis was determined by performing Annexin V assay on detached cells (Santa Cruz Biotechnology, Santa Cruz, CA, USA) according to the protocol provided by the producer.
• the measurement of Annexin V is by fluorescence measurements at an excitation wavelength of 488 nm and an emission wavelength of 525-530 nm, which is equivalent to the Guava EasyCyte HT apparatus (Millipore, Billerica, Mass., USA). Use.
• TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling
• TUNEL analysis was performed using an in situ ApoBrdU DNA fragmentation assay kit (BioVision, San Francisco, CA, USA) according to the protocol provided by the producer, which was performed to measure the degree of apoptosis.
• Cells were washed with phosphate buffer saline (PBS) and fixed for 15 minutes with paraformaldehyde.
• PBS phosphate buffer saline
• the average of the annexin V-positive cells is represented by a bar graph as shown in FIG. 2.
• the present invention relates to a composition for the prevention and treatment of prionone disease, and is applicable to the industry for the treatment and prevention of prion disease.

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Citations (2)

• 2012
  • 2012-01-16 KR KR1020120004749A patent/KR20130084047A/ko not_active Ceased
• 2013
  • 2013-01-09 WO PCT/KR2013/000171 patent/WO2013109016A1/fr not_active Ceased

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