WO2003084545A1 - Medicament contenant un compose a base de riboflavine - Google Patents
Medicament contenant un compose a base de riboflavine Download PDFInfo
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- WO2003084545A1 WO2003084545A1 PCT/JP2003/004511 JP0304511W WO03084545A1 WO 2003084545 A1 WO2003084545 A1 WO 2003084545A1 JP 0304511 W JP0304511 W JP 0304511W WO 03084545 A1 WO03084545 A1 WO 03084545A1
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- riboflavin
- pharmaceutical composition
- derivative
- pharmacologically acceptable
- active ingredient
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- 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]
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
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Definitions
- the present invention relates to riboflavin, a riboflavin derivative, a pharmacologically acceptable salt thereof (hereinafter, sometimes referred to as a riboflavin compound), protein c, activated protein C, or a derivative thereof (hereinafter, protein C). And / or palin as an active ingredient.
- riboflavin a riboflavin derivative, a pharmacologically acceptable salt thereof (hereinafter, sometimes referred to as a riboflavin compound), protein c, activated protein C, or a derivative thereof (hereinafter, protein C). And / or palin as an active ingredient.
- the inflammatory response is involved in many diseases, and it has been found that the inflammatory response has an important effect not only on so-called inflammatory diseases but also on Alzheimer's dementia, heart disease and the like.
- the systemic inflammatory response syndrome which is a condition with signs of systemic inflammatory response, is an important sign to grasp the response of the invaded organism.
- ARDS adult respiratory distress syndrome
- DIC disseminated intravascular coagulation
- MOF multiple organ failure
- MO DS multiple organ dysfunction syndrome
- dysfunction of consciousness dyspnea, decreased blood pressure, etc.
- causes of this systemic inflammatory response syndrome include infections and various invasions such as trauma, burns, knee inflammation, and surgery.
- a riboflavin compound has an immune function stimulating action (Japanese Patent Application Laid-Open No. Hei 5-210864). It has been found that it is useful as a toxin shock prophylactic / therapeutic agent (Japanese Patent Application Laid-open No. 10-29441).
- an object of the present invention is to provide a pharmaceutical composition and the like which are more excellent as an immunostimulant or a therapeutic agent for infection prevention.
- the present inventors have conducted intensive studies and have found that administration of a riboflavin-based compound and a protein C-based compound in combination achieves extremely excellent immune function activating action and infection-preventive therapeutic action.
- the present invention relates to a medicament comprising riboflavin, a riboflavin derivative, or at least one of pharmacologically acceptable salts thereof, and protein c, activated protein c, or at least one of these derivatives as active ingredients. It provides a composition.
- At least one means that any one or more of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof may be used as an active ingredient, and protein C, This means that activated protein C or one or more of these derivatives may be used as an active ingredient.
- the “pharmaceutical composition” is not limited to a case where each active ingredient is physically mixed, but also includes a case where each active ingredient is dissolved in a solution.
- the “active ingredient” means a component that exhibits pharmacological activity in a living body or a component that does not exhibit pharmacological activity by itself, but enhances the pharmacological activity of another component when used in combination or coexistence with another component.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising riboflavin, a riboflavin derivative, or at least one of the pharmacologically acceptable salts thereof, and palin as active ingredients.
- V boflavin compound and valine are administered in combination or in a mixture.
- At least one means that any one or more of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof may be used as an active ingredient.
- composition and “active ingredient” are the same as described above.
- parin may be added as an additive.
- (1) riboflavin, a riboflavin derivative, or At least one pharmacologically acceptable salt and (2) palin are uniformly mixed in a powder or solution, or powders, granules, and powders containing (1) and powders, granules containing (2)
- the powder and the powder may be mixed and, if necessary, compressed into tablets or capsules to form tablets or capsules.
- the riboflavin compound and palin are preferably contained in a weight ratio (riboflavin compound: palin) of 1: 1 to 1: 10000, and preferably 1: 5 to 1: 10,000. More preferably, it is more preferably contained in a ratio of 1: 5 to 1:50.
- the present inventors have conducted intensive studies and have found that administration of a riboflavin-based compound, a protein c-based compound, and palin in combination provides an extremely excellent immune function stimulating action.
- the present invention provides an active ingredient comprising at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, protein c, activated protein c, or at least one of these derivatives, and parin.
- a pharmaceutical composition having the formula:
- the pharmaceutical composition of the present invention is useful as an immunostimulant or a protective agent for infection.
- Immunomulation means enhancing the immune function of a human or animal.
- composition of the present invention is particularly useful for preventing or treating hypercytokineemia.
- Hypersite force-in-blood is a disease associated with elevated levels of blood site force-in, such as Alzheimer's dementia, Castleman's disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Petit's disease, lupus erythematosus, arotame sclerosis, heart disease, atrial myxoma, Crohn's disease, ulcerative colitis, inflammatory bowel disease, gout, contact dermatitis, psoriasis, pulmonary fibrosis, acute glomerulonephritis , Mesangial proliferative nephritis, atherosclerosis, tuberous atherosclerosis, vasculitis, bronchial asthma, chronic gingivitis, periodontal disease, bleeding Hire 11
- Shock such as sexual shock, traumatic shock, brain tumor, malignant tumor, atopic dermatitis, allergic rhinitis, allergy such as allergic dermatitis, sepsis, septic shock, multiple organ failure, multiple organ failure after sepsis, whole body Inflammatory response syndrome, insulin-dependent diabetes mellitus, uveitis, chronic inflammation, blood disease, collagen disease, preoperative and postoperative infections, malaria disease, amyotrophic lateral sclerosis, idiopathic thrombocytopenic purpura Disease, severe myasthenia, autoimmune diseases such as hay fever, ischemia such as cerebral infarction and myocardial infarction, reperfusion injury, photosensitivity, pyometra, pyometra, otitis media, peritonitis, infective endocarditis, heart Endometritis, acute renal failure, acute liver injury, diarrhea.
- Shock such as sexual shock, traumatic shock, brain tumor, malignant tumor, atopic dermatitis,
- composition of the present invention is particularly useful for preventing or treating systemic inflammatory response syndrome.
- SIRS systemic inflammatory response syndrome
- CARS complex anti-inflammatory response syndrome
- the “prevention or treatment of systemic inflammatory response syndrome” of the present invention refers to adult respiratory distress syndrome (ARDS) caused by progression of the above-mentioned symptoms of SIRS and CARS, disseminated intravascular coagulation (DIC) ), Meaning that it also includes the prevention or treatment of dysfunction (MODS) such as multiple organ failure (MOF), and the pharmaceutical composition of the present invention is also extremely useful for the prevention or treatment of pathological conditions in which SIRS or CARS has progressed. It is.
- ARDS adult respiratory distress syndrome
- DIC disseminated intravascular coagulation
- MODS multiple organ failure
- MOF multiple organ failure
- composition of the present invention is particularly useful for preventing or treating sepsis or septic shock.
- Sepsis is a phenomenon in which a microorganism itself is excreted by infection with the microorganism. It refers to the state in which the endotoxin, which is excreted when the microorganism is broken down, spreads throughout the body.
- Septic shock is a condition in which one or more of the internal organs such as the heart, lungs, liver, kidney, spleen, brain, and spinal cord have malfunctioned as a result of the progression of sepsis, or an organ malfunction As a result, it means a state showing symptoms such as weakness, dizziness, difficulty standing up, decreased blood pressure, decreased body temperature, arrhythmia, ventricular fibrillation, dyspnea, decreased body temperature, convulsions, confusion, and unconsciousness. .
- the riboflavin derivative or a pharmacologically acceptable salt thereof includes flavin mononucleotide, flavin adenine dinucleotide, riboflavin traptide, sodium riboflavin phosphate, monodiethanolamine salt of riboflavin phosphate, leucoflavin, monohydroflavin, Preferably, leukoflavin phosphate esternole, leucoflavin mononucleotide, or leucoflavin adenine dinucleotide, or a pharmacologically acceptable salt thereof.
- the protein C is a vitamin K-dependent inactive glycoprotein produced in the liver and is one of the important blood coagulation regulators.
- the activated protein C is a serine protease in which protein C is activated by a thrombin-thrompomodulin complex on vascular endothelial cells or the like. Activated protein C degrades both blood coagulation factor Va and factor Vla to specifically inactivate it, and has profipurin-lytic activity and anticoagulant activity.
- the protein C, the activated protein C, or a derivative thereof is not particularly limited.Natural human protein C, recombinant human protein C, natural human activated protein C (for example, dried concentrated human activated protein) C), recombinant human activated protein C (for example, Drotrecogina) and the like. Recombinant human protein C and its activated protein C include European Patent Application No.
- Patent application No. 913 0140.2 (LIN derivative and FLIN derivative), European patent application No. 9 13 0 144.6.0 (Q3 13 and Q 3 9 9), European Patent Application No. 8 8 3 1 2 2 0 1 .2 - ⁇ (F 1 6 7) Characterization and novel purification of recombinant human protein C from three mammalian cell lines, SC Betty Yan et al, BIOTECHNOLOGY Lol. 8 July 1990 The disclosed ones are exemplified. Valine does not necessarily need to be used in the form of a free amino acid, but may be in the form of an inorganic acid salt, an organic acid salt, an ester form, or an N-substituted form.
- the subject to which the pharmaceutical composition according to the present invention is administered is a human or an animal.
- the medicament of the present invention is particularly useful for prevention or treatment in humans.
- animals refer to industrial animals, companion animals and experimental animals.
- Industrial animals are livestock such as porcupines, pomas, pigs, goats, and sheep, poultry such as chicks, ducks, quails, turkeys, ostriches, etc., yellowtail, hamachi, red sea bream, maji, koi, rainbow trout, etc. It is an animal that needs to be bred industrially, such as fish.
- Companion animals refer to so-called companion animals such as dogs, cats, marmosets, small birds, hamsters, and goldfish, and companion animals.
- Laboratory animals include rats, guinea pigs, beagle dogs, miniptas, lizard monkeys, and cynomolgus monkeys. Shows animals used for research in fields such as medicine, biology, agriculture, and pharmacology.
- the dosage form of the pharmaceutical composition according to the present invention is not particularly limited, and varies depending on the disease state, its progress, and other conditions, but may be injections, tablets, granules, powders, fine granules, capsules, pills, Or, it is preferably contained in the form of an oral solution (including a syrup).
- intravenous administration When administered in the form of injections, it can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, intraarticularly, in the synovial sac, in the alveoli, in the periosteum, sublingually, in the oral cavity, etc.
- intravenous administration or intraperitoneal administration is particularly preferred.
- Intravenous administration may be either infusion or bolus.
- the dosage (the amount of the active ingredient) is not particularly limited, and the disease state, its progress, and other conditions (the kind, symptom, age, weight, sex, complications, administration time, administration method, dosage form, sensitivity, etc. of the administration target)
- a riboflavin compound in the case of an intravenous infusion of an injection, it is preferable to administer a riboflavin compound at a dose of 0.01 to 8 mg / kg / h for a few minutes to a week. It is more preferable to administer at 1 to 1 mg / kg / h for 6 hours to 4 days.
- the riboflavin compound When the bolus is administered intravenously, the riboflavin compound is 0.1 to 5 Omg / kg, preferably 0.3 to 2 Omg / kg, and the protein C compound is 0.01 to 1 Omg / kg. kg, preferably 0.1 to 1 mg / kg, and for valine it is 1 to 200 Omg / kg, preferably 10 to 50 Omg / kg.
- the riboflavin compound When administered intraperitoneally, the riboflavin compound is 0.1 to 50 mg / kg, preferably 0.3 to 2 Omg / kg, and the protein C compound is 0.01 to 10 mg / kg, preferably 0:: ⁇ lmg / kg, for valine 10-50 Omg / kg.
- the riboflavin compound When administered intramuscularly, the riboflavin compound is 0.1 to 5 Omg / kg, preferably 3 to 2 Omg / kg, and the protein C compound is 0.01 to 10 mg / kg, preferably 0 to 10 Omg / kg. 1 to: Lmg / kg and for valine 10 to 50 Otng / kg.
- the riboflavin compound When administered orally, is 1 to 1000 rag / kg, preferably 10 to 50 Omg / kg, and the protein C compound is 0.1 to 100 mg / kg, preferably 1 to 50 mg / kg. mg / kg, 10 to 20 for valine 4511
- each dose can be reduced as compared with the case of single administration.
- the pharmaceutical composition according to the present invention may be administered as it is, or may be added to a commonly used excipient, and injected (for intravenous administration (for infusion or bolus administration), intraperitoneally) by a known method.
- intramuscular administration, subcutaneous administration, etc. oral preparations (tablets, granules, powders, fine granules, capsules, pills, oral liquid preparations, syrups, etc.), transdermal absorption preparations, eye drops , Nasal drops, suppositories, inhalants (aerosols, powder inhalers, liquid inhalers, etc.) and external preparations (ointments, creams, liquids, etc.). It can also be mixed with food, feed, drinking water, etc.
- a solubilizing agent if necessary; an H adjuster, a buffer, a suspending agent, an antioxidant, a preservative, an isotonic agent, and the like.
- the infusion may be constituted by using a solubilizing agent or the like as an infusion, or the infusion may be constituted by adding a pharmacologically acceptable modification thereof to the infusion.
- injections can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, and the like. Alternatively, it may be lyophilized to give a lyophilized preparation which can be dissolved before use.
- excipients When manufacturing oral solid preparations, excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, antioxidants, solubilizing agents, pills, etc., as necessary It can be added to make tablets, coated tablets, granules, powders, fine granules, capsules, pills and the like in the usual manner.
- solubilizing agent examples include, but are not particularly limited to, physiological saline, phosphate buffered physiological saline, lactated Ringer's solution, polyoxetylene hardened castor oil, polysorbate 80, nicotinamide, poly Oxyethylene sonolebitan monolaurate, macrogol, castor oil fatty acid ethyl ester and the like.
- the pH adjuster and buffer are not particularly limited, and include, for example, organic acids or inorganic acids and Z or salts thereof, sodium hydroxide, meglumine, and the like.
- suspending agent examples include, but are not particularly limited to, methylcellulose, polysorbate 80, hydroxyxethyl cellulose, gum arabic, canoleboximetinole cellulose cellulose, polyoxyethylene sorbitan monolaurate. And the end of the traga- nent.
- antioxidant examples include, but are not limited to, ascorbic acid, sodium ferroferonole, ethoxyquin, diptinoledroxytonolene, butynolehydroxydisole, and the like.
- preservative examples include, but are not particularly limited to, methyl paraoxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and tarezole.
- the tonicity agent is not particularly restricted but includes, for example, sodium chloride.
- excipient examples include, but are not limited to, starch, corn starch, dextrin, glucose, lactose, sucrose, sugar alcohol, hydrogenated oil, mannitol, erythritol, xylitol, crystalline cellulose, anhydrous silicic acid, calcium silicate, And calcium hydrogen diphosphate.
- binder examples include, but are not particularly limited to, polyvinylpyrrolidone, ethylcellulose, methylcellulose, ⁇ -starch starch, gum arabic, hydroxypine pinoresenorelose, hydroxypropinolemethinoresenorelose, Noreboximetinolenose norreose, sodium ureboxymethinoresenolerose, propylene glycol cornole, sodium polyacrylate, polyvinyl alcohol and the like. ⁇
- disintegrant examples include, but are not limited to, crospovidone, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, , Calcium carbonate, carboxymethylcellulose power, and the like.
- lubricant examples include, but are not particularly limited to, magnesium stearate, talc, calcium stearate, stearyl sodium fumarate, polyethylene glycol 600, and the like.
- a film coating such as hydroxypropylmethylcellulose may be applied as necessary.
- an oral liquid preparation In the case of producing an oral liquid preparation, a coloring agent, a flavoring agent, an antioxidant, a solubilizing agent, and the like can be added as necessary, and the oral liquid preparation can be produced by a conventional method.
- a riboflavin compound and a protein c compound are administered simultaneously or separately, a riboflavin compound and valine are simultaneously or separately administered, or It has been found that administration of the system compound, the protein c system compound, and valine at the same time or at different times can also achieve an extremely excellent immune function stimulating action.
- the present invention relates to a pharmaceutical composition containing riboflavin, a riboflavin derivative, or at least one of their pharmacologically acceptable salts, comprising a protein, activated protein C, or a derivative thereof. It provides a pharmaceutical composition for simultaneous or separate administration with at least one, or for simultaneous or separate administration with palin.
- Administered simultaneously or separately '' refers to the case where both pharmaceutical compositions are separately prepared and administered simultaneously, or the case where the other pharmaceutical composition is administered after a certain period of time has elapsed after administration of one pharmaceutical composition It is a meaning including.
- the administration forms of both pharmaceutical compositions may be the same or different 'forms, and the administration sites may be the same or different.
- the present invention relates to riboflavin, a riboflavin derivative, Containing a pharmaceutical composition containing as an active ingredient at least one of the following salts, and a pharmaceutical composition containing at least one of protein C, activated protein C, or a derivative thereof as an active ingredient:
- a device comprising: a container;
- the present invention provides a container containing a pharmaceutical composition containing riboflavin, a riboflavin derivative, or at least one of pharmacologically acceptable salts thereof as an active ingredient, and a pharmaceutical composition containing norin as an active ingredient.
- a container containing a pharmaceutical composition containing riboflavin, a riboflavin derivative, or at least one of pharmacologically acceptable salts thereof as an active ingredient, and a pharmaceutical composition containing norin as an active ingredient.
- the “device” may be, for example, a treatment kit including the container, an infusion device including the container, or the like.
- the present invention provides a pharmaceutical composition comprising, as an active ingredient, at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and at least one of protein C, activated protein C, and a derivative thereof.
- a pharmaceutical composition comprising: a pharmaceutical composition comprising one as an active ingredient; and a pharmaceutical composition comprising the pharmaceutical composition, wherein the pharmaceutical composition is maintained in a state where the pharmaceutical compositions are not in contact with each other.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: a pharmaceutical composition containing riboflavin, a riboflavin derivative, or at least one of their pharmacologically acceptable salts as an active ingredient; and a pharmaceutical composition containing palin as an active ingredient. It is intended to provide a medicine in which the pharmaceutical compositions are held in a state where they do not come into contact with each other.
- “Pharmaceuticals in which the pharmaceutical compositions are held in a state where they do not come into contact with each other” means, for example, in the case of an injection, each pharmaceutical composition is placed in a syringe and / or in a bag for injection via a V, a septum or the like. This is the case where each of the pharmaceutical compositions is partitioned and filled with each other via a partition or the like in the force capsule tablet.
- the present invention provides at least riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof for producing an immunostimulating agent or an agent for preventing or treating infection.
- PC leak 11
- the present invention relates to the use of at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and a protein c, an activated protein c, or at least one of these derivatives. It is intended to provide a method for producing an immunopotentiator or an agent for preventing and treating infection.
- the present invention provides the use of at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and palin for producing an immunopotentiator or an agent for preventing or treating infection. is there.
- the present invention provides a method for producing an immunopotentiator or a remedy for protection against infection by using riboflavin, a riboflavin derivative, or at least one of pharmacologically acceptable salts thereof, and valine. It is.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and a protein C, an activated protein c, or at least one of these derivatives.
- An immunostimulatory agent or a therapeutic agent for infection prevention comprising a combination of a pharmaceutical composition containing one as an active ingredient and a pharmaceutical composition.
- the present invention also provides a pharmaceutical composition comprising, as an active ingredient, at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising palin as an active ingredient.
- the present invention provides an immunostimulant or a protective and therapeutic agent for infection.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and at least one of protein C, activated protein C, and a derivative thereof. It is intended to provide a use of the pharmaceutical composition for immunization or protection against infection by administering a pharmaceutical composition containing one as an active ingredient simultaneously or separately.
- the present invention PC defibrillation 11
- a pharmaceutical composition comprising, as an active ingredient, at least one of rabin, a riboflavin derivative, or a pharmacologically acceptable salt thereof; and at least one of protein C, activated protein C, or a derivative thereof.
- Diseases requiring immunostimulation or infection prevention characterized by administering a pharmaceutical composition as an active ingredient and a subject to a subject (eg, animal) simultaneously or separately (eg, inflammatory disease, high cytokine) Blood bleeding and systemic inflammation reaction syndrome).
- the present invention also provides a pharmaceutical composition containing riboflavin, a riboflavin derivative, or at least one of their pharmacologically acceptable salts as an active ingredient, and a pharmaceutical composition containing palin as an active ingredient simultaneously or simultaneously. It is intended to provide use of the pharmaceutical composition for administration at another time to effect immunostimulation or protection against infection.
- the present invention provides a pharmaceutical composition comprising, as an active ingredient, at least one of riboflavin, a riboflavin derivative, or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising parin as an active ingredient.
- Diseases requiring immunostimulation or protection against infection characterized by being administered to a subject (eg, animal) at the same time or at another time (eg, inflammatory disease, hypercytosis, systemic inflammatory response syndrome) ) Is provided.
- 5'-riboflavin sodium phosphate (riboflavin sodium phosphate) was prepared by synthesizing riboflavin sodium phosphate (5, -FMN-Na) from the Japanese Pharmacopoeia.
- APC Activated Protein C: Activated Protein C
- Anact C trade name, Teijin Limited, Lot No: SC002
- LPS Lipopolysaccharide: lipopolysaccharide
- Escherichia coli Escherichi. Coli serotype Ol 11 B4 lipopolysaccharide from Sigma (Sigma Chemical Co., St. Louis, MO, USA).
- Palin was purchased from Wako Pure Chemical.
- the 5′-FMN-Na, APC, LPS and valine were used after being dissolved in physiological saline (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan).
- Aminolevane (trade name) was purchased from Otsuka Pharmaceutical Co., Ltd. for use as an amino acid injection for improving hepatic encephalopathy (hereinafter referred to as amino acid injection).
- This aminolevan (trade name) contains 8.4 g of L-valine in 100 OmL, and has a Fischer ratio (valine + mouth isine + isoloicin) / (tyrosine + phenylalanine) [molar ratio] of 37.05. Which is an injection solution containing a plurality of amino acids.
- mice Male ICR mice (approximately 30 g per animal) were purchased from Japan SLC Inc. (Shizuo ka, Japan) at 5 weeks of age, at 23 ° C (acceptable range: 20-26 ° C), relative humidity 55% (allowable range: 40-70%) conditions were used in a 12-hour light / dark cycle (light on at 7 am and light off at 7 pm). At this time, the mice were given sterilized tap water and pellet food (MF, Oriental Yeast Co., Tokyo, Japan). After acclimating to this environment for one week, they were subjected to experiments.
- Japan SLC Inc. Shizuo ka, Japan
- relative humidity 55% allowable range: 40-70%
- S EB Staphylococcus aureus toxin
- mice Male BALBZc mice (approximately 25 g per mouse) were purchased from Nippon Charles River at 5 weeks of age and adapted for one week under the same conditions as the male ICR mice described above, and subjected to experiments. .
- Example 1 Effect on endotoxin-induced shock mouse model
- 10 mg of LPS was administered to 10 male ICR mice (6 weeks old) in each group.
- Endotoxin (LPS) -induced shock mice were prepared by intravenous administration.
- 5'-FMN-Na dose: 10 mg '/ kg dissolved in physiological saline and sterilized by filtration
- APC dissolved in physiological saline and sterilized by filtration
- Example 2 Effect on Exotoxin-Induced Shock Mouse Model First, 0.75 mg Zkg of SEB was intraperitoneally administered to 10 male B ALB / c mice (6 weeks old) in each group, and D-galactosamine 1. 8 g / kg ip Upon administration, exotoxin (SEB) -induced shock mice were created.
- SEB exotoxin
- 5'-FMN-Na dose: 20 mgZkg dissolved in physiological saline and sterilized by filtration
- APC dissolved in physiological saline and sterilized by filtration
- Example 3 Effect on Endotoxin-Induced Shock Mouse Model
- 5'-FMN-Na dose: l Omg / kg
- parin dissolved in physiological saline and sterilized by filtration
- Dose 200 mg Zkg
- 5'-FMN-Na dose: 10 mg / kg
- parin dose: 20 Omg / kg
- the control group received 3.5 ml of physiological saline intravenously for 6 hours instead of the drug.
- Example 4 Effect on Endotoxin-Induced Shock Mouse Model
- 5'-FMN-Na dose: 1 Omg / kg
- physiological saline a physiological saline
- an amino acid injection solution dose: 3.5 ml / mouse
- 5'-FM NNa dose: 10 mg / kg
- amino acid injection dose: 3.5 ml / mouse
- the pharmaceutical composition of the present invention is useful as an immunostimulating agent or an agent for preventing or treating infection, an agent for preventing or treating hypercytokinemia, systemic inflammatory response syndrome, sepsis or septic shock.
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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JP2003581785A JP4355578B2 (ja) | 2002-04-09 | 2003-04-09 | リボフラビン系化合物を含む医薬 |
AU2003227475A AU2003227475A1 (en) | 2002-04-09 | 2003-04-09 | Drug containing riboflavin compound |
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JP2002106685 | 2002-04-09 | ||
JP2002-106685 | 2002-04-09 |
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WO2003084545A1 true WO2003084545A1 (fr) | 2003-10-16 |
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PCT/JP2003/004511 WO2003084545A1 (fr) | 2002-04-09 | 2003-04-09 | Medicament contenant un compose a base de riboflavine |
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JP (1) | JP4355578B2 (ja) |
AU (1) | AU2003227475A1 (ja) |
WO (1) | WO2003084545A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005220108A (ja) * | 2004-02-09 | 2005-08-18 | Meiji Univ | メイラード反応抑制剤及びメイラード反応の抑制方法 |
WO2006070874A1 (ja) * | 2004-12-28 | 2006-07-06 | Toudai Tlo, Ltd. | 低酸素応答促進剤 |
JP2015017082A (ja) * | 2013-06-14 | 2015-01-29 | 独立行政法人科学技術振興機構 | Aβペプチド酸化体 |
JP2018070581A (ja) * | 2017-04-19 | 2018-05-10 | 誠一 荒木 | 還元型ビタミンb2製剤 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0679398A1 (en) * | 1991-09-13 | 1995-11-02 | Eisai Co., Ltd. | Immunopotentiating and infection protective agent and production thereof |
EP0747395A1 (en) * | 1995-06-06 | 1996-12-11 | Clintec Nutrition Company, An Illinois Partnership | Composition for treating renal failure |
-
2003
- 2003-04-09 JP JP2003581785A patent/JP4355578B2/ja not_active Expired - Fee Related
- 2003-04-09 WO PCT/JP2003/004511 patent/WO2003084545A1/ja active Application Filing
- 2003-04-09 AU AU2003227475A patent/AU2003227475A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0679398A1 (en) * | 1991-09-13 | 1995-11-02 | Eisai Co., Ltd. | Immunopotentiating and infection protective agent and production thereof |
EP0747395A1 (en) * | 1995-06-06 | 1996-12-11 | Clintec Nutrition Company, An Illinois Partnership | Composition for treating renal failure |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005220108A (ja) * | 2004-02-09 | 2005-08-18 | Meiji Univ | メイラード反応抑制剤及びメイラード反応の抑制方法 |
WO2006070874A1 (ja) * | 2004-12-28 | 2006-07-06 | Toudai Tlo, Ltd. | 低酸素応答促進剤 |
JP2015017082A (ja) * | 2013-06-14 | 2015-01-29 | 独立行政法人科学技術振興機構 | Aβペプチド酸化体 |
US10035831B2 (en) | 2013-06-14 | 2018-07-31 | Japan Science And Technology Agency | Oxidized Aβ peptide |
US11643448B2 (en) | 2013-06-14 | 2023-05-09 | Japan Science And Technology Agency | Oxidized Aβ peptide |
JP2018070581A (ja) * | 2017-04-19 | 2018-05-10 | 誠一 荒木 | 還元型ビタミンb2製剤 |
Also Published As
Publication number | Publication date |
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JP4355578B2 (ja) | 2009-11-04 |
AU2003227475A1 (en) | 2003-10-20 |
JPWO2003084545A1 (ja) | 2005-08-11 |
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