WO2002047677A1 - Agents d'amelioration du stress du a un groupement carbonyle - Google Patents

Agents d'amelioration du stress du a un groupement carbonyle Download PDF

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Publication number
WO2002047677A1
WO2002047677A1 PCT/JP2001/010891 JP0110891W WO0247677A1 WO 2002047677 A1 WO2002047677 A1 WO 2002047677A1 JP 0110891 W JP0110891 W JP 0110891W WO 0247677 A1 WO0247677 A1 WO 0247677A1
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Prior art keywords
cysteamine
carbonyl
peritoneal dialysis
acceptable salt
compound
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PCT/JP2001/010891
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English (en)
Japanese (ja)
Inventor
Toshio Miyata
Original Assignee
Tokai University Educational System
Kurokawa, Kiyoshi
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Application filed by Tokai University Educational System, Kurokawa, Kiyoshi filed Critical Tokai University Educational System
Priority to JP2002549250A priority Critical patent/JPWO2002047677A1/ja
Priority to AU2002222613A priority patent/AU2002222613A1/en
Publication of WO2002047677A1 publication Critical patent/WO2002047677A1/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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention relates to an agent for improving carbonyl stress.
  • a state in which the production of carbonyl compounds due to non-enzymatic biochemical reactions is enhanced is called carbonyl stress.
  • Carboel compounds have been linked to adult diseases such as aging, diabetes, or arteriosclerosis via the Maillard reaction.
  • the Maillard reaction is a non-enzymatic sugar-containing reaction between a reducing sugar such as glucose and an amino acid or protein.
  • Maillard reported that the mixture of amino acids and reducing sugars turned brown when heated (Maillard, LC, Compt. Rend. So Biol., 72: 599, 1912).
  • the Maillard reaction has been studied in the field of food chemistry because it is involved in browning during food heat treatment and storage, generation of aroma components, taste, and protein denaturation.
  • Hb Ale glycosyl hemoglobin
  • AGE advanced glycation end products
  • peritoneal dialysis fluid acts on endothelial cells and mesothelial cells, and is thought to play an important role in reducing peritoneal function (VEGF: vascular endothelial growth factor). ) Production (Combet et al. J. Am. Soc.
  • An object of the present invention is to provide a carbonyl stress ameliorating agent which can be expected to be effective even in a systemic carbonyl stress state, and which is excellent in economy, stability, safety and operability.
  • the present inventors have attempted to search for a compound having an effect of reducing carbonyl compounds accumulated in blood or the like. As a result, the present inventors have clarified that the use of cysteamine or a pharmacologically acceptable salt thereof can reduce the concentration of a phenol compound in a medium, and completed the present invention. . That is, the present invention relates to the following carbonyl stress improvers and uses thereof.
  • a carbonyl stress improver comprising cysteamine or a pharmacologically acceptable salt thereof as an active ingredient.
  • a method for preparing a peritoneal dialysate having a reduced content of a porponium dialysate comprising the step of passing a peritoneal dialysate through the cartridge for trapping carbodiluic mixture according to [5].
  • a peritoneal dialysate containing cysteamine or a pharmacologically acceptable salt thereof is a peritoneal dialysate containing cysteamine or a pharmacologically acceptable salt thereof.
  • a fractionated container consisting of multiple compartments that can be stored separately for mixing at the time of use, or a plurality of combinable containers that can be stored separately for mixing at the time of use
  • Belly housed in a kit container consisting of containers
  • a membrane dialysate a peritoneal dialysate in which reducing sugar is contained in one chamber or container and cysteamine or a pharmaceutically acceptable salt thereof is contained in the other chamber or container.
  • the present invention relates to a method for improving carbonyl stress, comprising a step of administering cysteamine or a pharmacologically acceptable salt thereof.
  • the present invention relates to the use of cysteamine or a pharmaceutically acceptable salt thereof in the production of a carbonyl stress-ameliorating agent.
  • the present invention also relates to a peritoneal dialysis solution composition containing at least cysteamine, an osmotic pressure regulator, a buffer, and inorganic salts.
  • the term "trapping of a carbonyl compound” means to reduce the concentration of a potent luponyl compound having a damaging effect on tissues or proteins.
  • a compound having a carbonyl compound trapping action may be particularly referred to as a carbazole compound trapping agent.
  • the carbonyl compound trap agent can reduce the effective concentration of a carbonyl compound having a protein-damaging effect by any mechanism such as chemical modification, adsorption, or decomposition of the carbonyl compound.
  • cysteamine or a pharmacologically acceptable salt thereof is used as a carbonyl compound trapping agent.
  • Cysteamine is a SH-containing low molecular weight amine having a structure in which the carboxyl group of cysteine is replaced by a hydrogen atom (HSCH 2 CH 2 NH 2 ). Cysteamine is also called 2-aminoethant hiol. Because it is easily synthesized from inexpensive raw materials, it can be obtained at low cost. Alone can be purified by sublimation, and the hydrochloride can be purified by recrystallization from an ethanol solution. It is stable at room temperature and easy to handle in many ways, including being easily soluble in water and aqueous alkaline solutions.
  • cysteamine easily generates disulfide by oxidation. This is a general property of thiol compounds. The degree of oxidation depends on the amount of oxygen and oxidant present. Since cysteamine disulfide has an amino group, it is still considered to be useful as a trapping agent for carbon compounds. Therefore, Regardless of whether disulfide is formed or not, the carbonyl compound trapping agent according to the present invention comprising cysteamine is useful. However, it is considered that cysteamine is excellent in the trapping effect of carbonyl compounds because the amino group and thiol group of cysteamine react with the carbonyl group of carbonyl compound to form a cyclic thiazolidine derivative.
  • disulfide which has lost the reactivity of the thiol group is inferior to cysteamine in terms of carbonyl compound trapping action. Therefore, in the carbonyl compound trapping agent according to the present invention, the smaller the amount of disulfide coexisting with cysteamine, the better.
  • Cysteamine has been known to be orally or intravenously administered to humans for the treatment of cystine storage disease and Huntington's disease (Shults, C. et al., Neurology, 36: 1099-1102 (1986), Gahl, WA et al., Pediatr. Res., 38: 579-584 (1995), Thoene, JG et al., J. Clin. Invest., 58: 180-189 (1976), Gahl, WA et al., N. Engl. J.
  • cysteamine is used in the present invention as a carbonyl stress improver excellent in economy, stability, safety, and operability.
  • the carbonyl compounds that cause carbonyl stress include, for example, the following compounds that accumulate in the blood of patients with renal failure due to oxidative stress.
  • the carbonyl stress improving agent according to the present invention contains cysteamine as an active ingredient.
  • the improvement of the carbon stress refers to the action of depriving the reactivity of the carbohydrate compound in the medium that comes into contact with the living body to reduce the protein modifying action. Specifically, for example, the adsorption, decomposition, or When an effect such as a decrease in reactivity can be expected, it can be said that it has an effect of improving carbonyl stress.
  • the medium that comes into contact with the living body specifically refers to peritoneal dialysis fluid, blood fluid, and other body fluids.
  • the cysteamine that can be used in the present invention may be a pharmacologically acceptable salt.
  • the carbonyl stress ameliorating agent according to the present invention can be combined with, for example, the following compounds or derivatives thereof that function as cysteamine or a pharmacologically acceptable salt thereof.
  • a derivative refers to a compound in which an atom or a molecule is substituted at any position of the compound.
  • Guanidine derivatives such as methyldanidine (JP-A-62-142114, JP-A-62-249908, JP-A-11-56614, JP-A-11-83059, JP-A-2-156, JP-A-2-156, 2-765, JP-A-2-42053, JP-A-6-9380, and JP-T5-505189).
  • thiazoline JP-A-10-167965
  • thiazole JP-A-4-19375, JP-A-9-159258
  • thiazolidine JP-A-5-201993, JP-A-3-261772, JP-A-3-261772
  • 5-membered heterocyclic compounds having one nitrogen atom and one sulfur atom such as 7-133264 and JP-A-8-157473
  • 5-membered heterocyclic compounds having one nitrogen atom and one oxygen atom such as oxazole (JP-A-9-59258).
  • Nitrogen-containing 6-membered heterocyclic compounds such as pyridine (JP-A-10-158244, JP-A-10-175954) and pyrimidine (JP-T-7-500811).
  • Nitrogen-containing condensed heterocyclic compounds such as indazole (JP-A-6-287180), benzoimidazole (JP-A-6-305964), and quinoline (JP-A-3-161144).
  • Oxygen-containing condensed heterocyclic compounds such as benzopyran (JP-A-3-204874, JP-A-4-1308586).
  • Nitrogen compounds such as rubazoyl (JP-A-2-156 and JP-A-2-753), carbazic acid (JP-A-2-167264), and hydrazine (JP-A-3-148220).
  • Flavonoids JP-A-3-240725, JP-A-7-206838, JP-A-9-1241165, WO 94/04520.
  • alkylamines JP-A-6-206818, JP-A-9-159233, JP-A-9-40626 and JP-A-9-112471.
  • Aromatic compounds such as ascochlorin (Japanese Patent Application Laid-Open No. 6-305959), benzoic acid (WO 91/11 997), and naphthyridinium pyrrole (Japanese Patent Application Laid-Open No. 10-158265).
  • Vitamins such as pyridoxamine (WO 97/09981).
  • SH group-containing compounds such as glutathione, cysteine, and N-acetyl cysteine.
  • SH group-containing proteins such as reduced albumin.
  • Inorganic compounds such as activated carbon, silica gel, alumina and calcium carbonate.
  • the carbonyl stress ameliorating agent of the present invention can be mixed with a physiologically acceptable carrier, excipient, diluent, or the like, and administered as a pharmaceutical composition orally or parenterally.
  • Oral preparations can be in the form of granules, powders, tablets, capsules, solvents, emulsions, or suspensions.
  • parenteral preparations dosage forms such as injections, infusions, external preparations, and suppositories can be selected.
  • Injectables include intravenous, subcutaneous, intramuscular, and intraperitoneal injections.
  • the topical drug can be a nasal drug, a patch, an ointment or the like.
  • cysteamine which is the main component
  • tablets for oral administration can be manufactured by adding an excipient, a disintegrant, a binder, a lubricant, and the like to cysteamine, mixing and compression-molding. Grant Lactose, starch, mannitol and the like are generally used as a vehicle.
  • the disintegrant calcium carbonate or calcium carboxymethylcellulose is generally used.
  • the binder gum arabic, carboxymethylcellulose, or polyvinylpyrrolidone is used.
  • lubricant talc, magnesium stearate and the like are known.
  • the tablet containing the carbonyl stress-ameliorating agent according to the present invention can be coated with a known coating for masking and enteric preparation.
  • a coating agent ethyl cellulose, polyoxyethylene glycol, or the like can be used.
  • An injection can be obtained by dissolving cysteamine as a main component together with a suitable dispersant, or dissolving or dispersing in a dispersion medium.
  • a suitable dispersant or dissolving or dispersing in a dispersion medium.
  • any of an aqueous solvent and an oily solvent can be used.
  • the aqueous solvent distilled water, physiological saline, Ringer's solution, or the like is used as the dispersion medium.
  • an oily solvent various vegetable oils or propylene glycol are used as a dispersion medium. At this time, a preservative such as paraben can be added as necessary.
  • a well-known isotonic agent such as sodium chloride or glucose and a pH adjuster such as hydrochloric acid or sodium hydroxide can be added to the injection.
  • a pH adjuster such as hydrochloric acid or sodium hydroxide
  • soothing agents such as benzalkonium chloride or procaine hydrochloride may be added.
  • the carbonyl stress-ameliorating agent according to the present invention can be used as an external preparation by converting cysteamine into a solid, liquid, or semi-solid composition.
  • an external preparation can be prepared by using the same composition as described above.
  • a semi-solid composition can be prepared by adding a thickening agent to an appropriate solvent, if necessary.
  • the solvent water, ethyl alcohol, polyethylene glycol, or the like can be used.
  • the thickener bentonite, polyvinyl alcohol, acrylic acid, methacrylic acid, or polybutylpyrrolidone is generally used.
  • a preservative such as Shii-Dani Benzalkonium is added. Can be added.
  • suppositories can be prepared by combining an oily base such as cocoa butter or an aqueous base such as a cellulose derivative as a carrier.
  • Cysteamine which is the main component of the carbonyl stress ameliorating agent of the present invention, is a compound that has already been reported for use as a pharmaceutical. Therefore, the necessary dose is administered to mammals including humans within the dose range generally accepted as safe.
  • the dose is appropriately selected according to the method of administration (dosage form) or the condition of the administration subject (physique, age, sex, symptoms).
  • oral administration of an adult daily dose of 0.1 to 200 mg / kg body weight / kg body weight, more preferably 1-2 mg / kg can provide an effect of improving carbonyl stress. .
  • the frequency of administration is a compound that has already been reported for use as a pharmaceutical. Therefore, the necessary dose is administered to mammals including humans within the dose range generally accepted as safe.
  • the dose is appropriately selected according to the method of administration (dosage form) or the condition of the administration subject (physique, age, sex, symptoms).
  • cysteinemin when administered for the purpose of improving carbonyl stress, no apparent toxicity is observed.
  • a method for administering the carbonyl stress ameliorating agent of the present invention to a living body addition to a peritoneal dialysate can also be mentioned. Since peritoneal dialysis is performed by injecting a dialysate into the peritoneal cavity, the carbonyl stress improving agent of the present invention may be added to the peritoneal dialysate in advance. The force-luponyl compound leaching into the peritoneal dialysate reacts with cysteamine to render it harmless, resulting in an improvement in carbonyl stress.
  • cysteamine added to the dialysate in advance can also be expected to have an effect of preventing the carbonyl compound generated during the production stage or storage during the treatment such as high-pressure steam sterilization of the dialysate, etc., in a preventive manner.
  • the composition of the peritoneal dialysate serving as a base to which cysteamine is added may be a known one.
  • Common peritoneal dialysis solutions are composed of osmotic agents, buffers, and inorganic salts.
  • Sugars such as glucose are used as the osmotic pressure regulator.
  • As the buffering agent a buffering system that gives an acidic (pH 5.0 to 5.4) pH mainly in consideration of the stability of glucose is often used.
  • buffering agents to give 7.0 before and after P H is a more physiological pH can be used.
  • a product form has been devised in which a buffer system for adjusting the pH during use is separately packaged so that the neutral pH can be used while using glucose.
  • a buffer system for adjusting the pH during use is separately packaged so that the neutral pH can be used while using glucose.
  • carbonyl compounds derived from the decomposition of glucose during heat sterilization or long-term storage are removed, it has been conventionally difficult to prepare pharmaceutically due to the decomposition of glucose. it can be used a buffer system or give P H suitably.
  • the peritoneal dialysate is usually supplemented with inorganic salts such as sodium chloride, calcium chloride, or magnesium chloride. These salts are added in order to bring peritoneal dialysis closer to physiological conditions and to improve biocompatibility.
  • the cysteamine in the present invention can be added to such a known formulation at the time of mixing the peritoneal dialysis solution, sealed as it is, and sterilized by heating. By doing so, it is possible to expect a preventive effect on the production of the carbonyl distillate from these main components during the heat sterilization treatment. Also, from fractionated containers consisting of multiple compartments that can be stored separately for mixing at the time of use, or from multiple connectable containers that can be separated and stored for mixing at the time of use Constructed kit In the peritoneal dialysis solution contained in a container, one room or container contains reducing sugar, and the other room or container contains cysteamine or a pharmacologically acceptable salt thereof. You may mix.
  • the sterile and storage-produced compounds rapidly bind to the mixed cysteamine.
  • excess cysteamine captures the carbohydrate compounds derived from the blood.
  • the cysteamine added to the peritoneal dialysis solution may be used alone, or may be used by mixing a known carbonyl compound trapping agent.
  • the following formulation is generally used as the base dialysate composition. These prescriptions are only general and, in practice, more appropriate compositions are adopted according to the patient's condition. Glucose 1-5 ° / ow / v
  • cysteamine is added to the above basic formulation according to the present invention. That is, cysteamine is added so as to have a concentration of ImM or higher, preferably 10 mM or higher, more preferably 10 mM or higher and 100 mM or lower. If the amount of soybean curd is small, cysteamine is consumed by carbonyl compounds generated during production and storage, and carbonyl compounds that leach from the patient's blood or tissues into the dialysate during actual dialysis are treated. It is expected that you will not be able to do so.
  • the peritoneal dialysis solution of the present invention formulated according to the above-mentioned formulation is filled in a suitable closed container and sterilized.
  • Heat sterilization such as high pressure steam sterilization or hot water sterilization is effective for sterilization.
  • Specific examples include a flexible plastic bag made of polychloride rubber, polypropylene, polyethylene, polyester, or ethylene-vinyl acetate copolymer.
  • the container filled with the peritoneal dialysis solution may be wrapped with a packaging material having a higher gas barrier property.
  • filtration sterilization can be performed.
  • a pore size of about 0.2 ⁇ Sterilize by filtration using a microfilter equipped with a membrane filter.
  • generation of a carbonyl compound due to heating can be prevented.
  • the filter-sterilized peritoneal dialysis solution is filled into a container such as a flexible plastic bag and then sealed. Since a series of processes from sterilization to transportation are not different from the current production of dialysate, the peritoneal dialysate according to the present invention can be produced in the same steps.
  • cysteamine Under normal autoclaving conditions, cysteamine can maintain the necessary carbazole trapping action. Therefore, the heat sterilization operation can be performed after the cysteamine is added in advance when the peritoneal dialysate is blended. By doing so, it is possible to suppress the formation and accumulation of the carbonirubic mixture derived from the dialysate during heating. Of course, cysteamine also functions during storage or during peritoneal dialysis, and can suppress the generation and accumulation of carbonyl compounds.
  • cysteamine which has been sterilized by filtration later, may be added to the peritoneal dialysate that has been sterilized by heat in advance.
  • the timing of addition is not particularly limited. For example, it is preferable to add cysteamine after sterilizing the peritoneal dialysis solution, because it is possible to suppress the generation and / or accumulation of carbonyl compounds not only during peritoneal dialysis but also during storage of the peritoneal dialysis solution before dialysis.
  • cysteamine can be added immediately before or at the same time as dialysis.
  • the base solution and cysteamine are separately stored until just before use in the aforementioned soft plastic bag or the like, and the two are aseptically mixed immediately before the start of peritoneal dialysis.
  • a flexible plastic bag partitioned by a peelable adhesive portion as disclosed in JP-A-63-149149 is preferably used.
  • a connector for co-injection may be provided in the peritoneal dialysis circuit, and cysteamine may be injected from the connector.
  • a filter in which cysteamine is filled at any point in the circuit is used. Can also be arranged.
  • the peritoneal dialysis solution of the present invention is used for the same peritoneal dialysis treatment as the current peritoneal dialysis solution. That is, an appropriate amount of the peritoneal dialysis solution according to the present invention is injected into the peritoneal cavity of a dialysis patient, and low molecular weight components in the living body are transferred into the peritoneal dialysis solution through the peritoneum. Peritoneal dialysate is circulated intermittently and dialysis is continued according to the patient's condition. At this time, the carbonyl compound moves from the blood or from the peritoneum into the peritoneal dialysate together with dialysis components such as creatine, inorganic salts, and chloride ions. At the same time, the action of cysteamine reveals its damaging activity on the living body and renders it harmless.
  • the carbonyl stress-ameliorating agent of the present invention can be applied to a method for improving carbonyl stress through contact with blood or dialysate outside the body, in addition to administration to a living body.
  • the carrier for immobilizing cysteamine in the present invention is not particularly limited as long as it is harmless to the human body, or a material that is safe and stable as a material that comes into direct contact with blood or dialysate.
  • synthetic or natural organic high molecular compounds, inorganic materials such as glass beads, silica gel, alumina, or activated carbon, and those whose surfaces are coated with polysaccharides, synthetic polymers, etc., are used as carriers.
  • inorganic materials such as glass beads, silica gel, alumina, or activated carbon, and those whose surfaces are coated with polysaccharides, synthetic polymers, etc., are used as carriers.
  • Examples of the carrier composed of a high molecular compound include, for example, polymethyl methacrylate polymer, polyacrylonitrile polymer, polysulfone polymer, vinyl polymer, polyolefin polymer, fluorine polymer polymer, Polyester-based polymer, polyamide-based polymer, polyimide-based polymer, polyurethane-based polymer, polyacryl-based polymer, polystyrene-based polymer, polyketone-based polymer, silicon-based polymer, cellulose-based polymer, chitosan-based Polymers.
  • Polysaccharides such as galose, cellulose, chitin, chitosan, sepharose, dextran and their derivatives, polyester, polyvinyl chloride, polystyrene, polysolephone, polyether sulfone, polypropylene, polybutyl alcohol, polyallyl ether sulfone, poly Acrylic acid esters, polymethacrylic acid esters, polycarbonate, acetylated cellulose, polyatarylonitrile, polyethylene terephthalate, polyamide, silicone resin, fluororesin, polyurethane, polyether urethane, polyacrylamide, derivatives thereof, etc.
  • These polymer materials can be used alone or in combination of two or more. When two or more are combined, cysteamine is immobilized on at least one of them.
  • the shape of the carrier is not limited, and examples thereof include a film shape, a fibrous shape, a granular shape, a hollow fiber shape, a nonwoven fabric shape, a porous shape, and a honeycomb shape.
  • a film shape By varying the thickness, surface area, thickness, length, shape, and / or size of these carriers, the area of contact with blood or dialysate can be controlled.
  • a known method for example, a physical adsorption method, a biochemical specific bonding method, an ionic bonding method, a covalent bonding method, or a graphing method may be used.
  • a spacer may be introduced between the carrier and cysteamine.
  • the carbon to which the amino group of the cysteamine molecule is bonded can be covalently bonded to the functional group on the solid phase side via the functional group.
  • cysteamine refers to a structure represented by the following formula (1).
  • X represents a solid phase bound via an arbitrary functional group.
  • Cystine can be used as a compound having a structure in which a functional group is added to cysteamine.
  • Cysteine can be said to be a cysteamine derivative having a structure in which a carboxyl group is bonded to the carbon to which the amino group of cysteamine is bonded.
  • cysteamine can be immobilized.
  • the cysteamine thus bound still has an amino group and an SH group necessary for the trapping action of the carbonyl compound after the binding. Therefore, the strong carbinole compound trapping action of cysteamine can be maintained even after immobilization.
  • Such a compound in which H, which directly binds to C of cysteamine, in particular, is substituted with an appropriate functional group is useful for immobilizing cysteamine.
  • Compounds in which H directly bonded to C is substituted with a functional group and the functional group is used to bind to the solid phase are included in the cysteamine of the present invention.
  • Cysteamine having an amino group and an SH group forms a cyclic thiazolidine derivative by reacting with a carbonyl compound, thereby rendering the carbonyl compound harmless. It is preferable to bind cysteamine to the solid phase by covalent bond, since the amount of cysteamine eluted from the solid phase can be minimized.
  • a functional group present on the carrier may be used. Examples of the functional group include a hydroxyl group, an amino group, an aldehyde group, a carboxyl group, a thiol group, a hydroxyl group, a silanol group, an amide group, an epoxy group, and a succinylimide group.
  • the covalent bond include an ester bond, an ether bond, an amino bond, an amide bond, a sulfide bond, an imino bond, and a disulfide bond.
  • the carrier on which the cysteamine of the present invention is immobilized can be sterilized by a known method. Specific examples include high-pressure steam sterilization, gamma irradiation sterilization, and gas sterilization. Various forms are conceivable for contacting blood with a carrier on which cysteamine is immobilized. For example, both can be brought into contact in the following manner.
  • the blood is not necessarily whole blood, and the plasma may be processed after separating the plasma.
  • the processed blood can be returned to the patient. ⁇ If necessary, it can be stored in a blood bag.
  • a cysteamine-immobilized carrier in the blood bag, it is possible to trap the * Carboniril conjugate that accumulates and accumulates during storage.
  • the contact between the carrier on which the cysteamine of the present invention is immobilized and blood can be performed in the course of blood purification including hemodialysis, blood filtration, hemofiltration dialysis, blood adsorption, or plasma separation.
  • hemodialysis and trapping of a troponyl compound can be performed simultaneously by disposing a carrier on which cysteamine is immobilized in a hemodialysis circuit.
  • a carrier on which cysteamine is immobilized in a hemodialysis circuit.
  • cysteamine it is preferable to fix cysteamine to the hemodialysis membrane.
  • Known dialysis membranes can be used as the carrier. Examples thereof include cellulose derivatives such as regenerated cellulose and cellulose triacetate, polymethinolemethacrylate, polyolefin, polysulfone, polyacrylonitrile (PAN), polyamide, polyimide, polyether nylon, silicone, and polyester copolymer. It is not particularly limited.
  • a column filled with a cysteamine-immobilized carrier may be arranged in the hemodialysis circuit as described above without using the dialysis membrane as a carrier.
  • Anticoagulants may be used together to prevent blood clotting during extracorporeal circulation it can.
  • the anticoagulant include heparin, low-molecular-weight heparin, and fusan (nafamostat mesilate). These may be immobilized on a carrier.
  • a method of contacting peritoneal dialysate with fixed cysteamine is also effective in improving carbonyl stress.
  • a peritoneal dialysis solution is stored in a container in which cysteamine is immobilized, or in a container containing cysteamine which is immobilized on a carrier such as particles or fibers, and carbodiyl is produced and accumulated during storage. Compounds can be trapped. In the latter case, the insoluble carrier can be separated from the peritoneal dialysate by filtration or the like.
  • the column may be filled with beads or fibrous carrier in which cysteamine is immobilized to form a cartridge for trapping a carbonyl compound, and the peritoneal dialysate may be brought into contact with the cartridge and then introduced into the peritoneal cavity.
  • the carbonyl compound in the dialysate can be removed.
  • the peritoneal dialysis solution is used for trapping the carbamine-irrigated compound trap in which cysteamine is immobilized in the circulation circuit.
  • cysteamine can be adjusted by changing the amount of cysteamine immobilized on the carrier or the amount of the carrier on which cysteamine is immobilized.
  • the effects of the carbazole stress improver of the present invention can be confirmed by monitoring the concentration of a carbonyl compound or AGE in a peritoneal dialysate or blood.
  • the blood AGE concentration is compared between a group to which the carbohydrate stress ameliorating agent of the present invention is administered and a control.
  • the control should be a non-treated group, or a control drug or a saline-administered group in which only the main agent, cysteamine, has been removed from the improver.
  • the carbonyl compound include dalioxal (G0), methyldalioxal (MG0), and 3-deoxydalcosone (3DG).
  • pentosidine or the like can be used as an index.
  • a method for quantifying pentosidine by reversed-phase HPLC is known (Miyata T, et al. J Am Soc Nephrol 7: 1198-1206, 1996).
  • FIG. 1 is a graph showing the trapping effect of cysteamine on carbonyl compounds.
  • the vertical axis represents the residual ratio (%) of the carbonyl compound measured using high performance liquid chromatography, and the horizontal axis represents the incubation time (hour).
  • FIG. 2 is a graph showing the trap effect of cysteamine on the dicarboyl conjugate in peritoneal dialysis (CAPD) solution.
  • the vertical axis represents the residual ratio (%) of the carbonyl compound measured by high performance liquid chromatography, and the horizontal axis represents the incubation time (hour).
  • FIG. 3 is a graph showing the effect of cysteamine on inhibiting the production of pentosidine.
  • the vertical axis represents the concentration of pentosidine (nmol / ml), and the horizontal axis represents the concentration of added aminoguanidine and cysteamine (lmM, 5raM, 10 mM).
  • Peritoneal dialysis (CAPD) solution (Baxter PD-4, 1.5) 9001, add 100 ⁇ of aminoguanidine or cysteamine in 0.1 M phosphate buffer ( ⁇ 7.4) The mixture was kneaded and adjusted to a concentration of 0, 1, 5, 1 OmM after mixing, and incubated at 37 ° C for 2 hours. After completion of the incubation, dalipoxal, methyldioxal, and 3-deoxydalcosone were measured using high performance liquid chromatography.
  • CPD-4 Peritoneal dialysis
  • the present invention provides a carbonyl stress ameliorating agent which is excellent in the action of removing carbonyl stress. Further, according to the present invention, it is possible to provide a carbonyl stress ameliorating agent which can be expected to have a carbonyl compound removing effect not only in vitro but also in vivo.
  • the cysteamine constituting the ameliorating agent of the present invention is a drug excellent in economy, stability, safety, and operability.
  • the carbonyl stress ameliorating agent of the present invention can be used as an agent that directly acts on carbonyl stress in blood dialysis or peritoneal dialysis by bringing it into contact with blood or dialysate. Alternatively, the carbonyl stress-ameliorating agent of the present invention can be administered in the form of oral administration or the like, and can also be used as an agent that directly acts on carbonyl stress in a living body.

Abstract

L'invention concerne des agents d'amélioration du stress dû à un groupement carbonyle, lesquels comprennent la cystéamine. On peut utiliser ces agents en tant que médicaments agissant directement sur le stress dû à un groupement carbonyle, en mettant les mettant en contact avec le sang ou un dialysat, lors d'une hémodialyse ou d'une dialyse péritonéale. On peut également utiliser ces agents, que l'on peut administrer par voie orale, etc., en tant que médicaments agissant directement sur le stress dû à un groupement carbonyle, in vivo.
PCT/JP2001/010891 2000-12-12 2001-12-12 Agents d'amelioration du stress du a un groupement carbonyle WO2002047677A1 (fr)

Priority Applications (2)

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JP2002549250A JPWO2002047677A1 (ja) 2000-12-12 2001-12-12 カルボニルストレスの改善剤
AU2002222613A AU2002222613A1 (en) 2000-12-12 2001-12-12 Agents for ameliorating carbonyl stress

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JP2000378112 2000-12-12
JP2000-378112 2000-12-12

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WO2002047677A1 true WO2002047677A1 (fr) 2002-06-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7384558B2 (en) 2004-07-26 2008-06-10 Baxter International Inc. Compositions capable of inhibiting reactive oxygen and carbonyl species
JP4820286B2 (ja) * 2003-02-28 2011-11-24 バクスター・インターナショナル・インコーポレイテッド 高分子ケトアルデヒド

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010606A1 (fr) * 1998-08-24 2000-03-02 Kurokawa, Kiyoshi Medicaments de sedation de l'agression du carbonyle et des dialysats peritoneaux
WO2000069466A1 (fr) * 1999-05-12 2000-11-23 Kurokawa, Kiyoshi Agent de piegeage de composes carbonyles sanguins
WO2001024790A1 (fr) * 1999-10-06 2001-04-12 Kurokawa, Kiyoshi Agents permettant de soulager le stress induit par le carbonyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010606A1 (fr) * 1998-08-24 2000-03-02 Kurokawa, Kiyoshi Medicaments de sedation de l'agression du carbonyle et des dialysats peritoneaux
WO2000069466A1 (fr) * 1999-05-12 2000-11-23 Kurokawa, Kiyoshi Agent de piegeage de composes carbonyles sanguins
WO2001024790A1 (fr) * 1999-10-06 2001-04-12 Kurokawa, Kiyoshi Agents permettant de soulager le stress induit par le carbonyle

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4820286B2 (ja) * 2003-02-28 2011-11-24 バクスター・インターナショナル・インコーポレイテッド 高分子ケトアルデヒド
US7384558B2 (en) 2004-07-26 2008-06-10 Baxter International Inc. Compositions capable of inhibiting reactive oxygen and carbonyl species

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JPWO2002047677A1 (ja) 2004-04-15
AU2002222613A1 (en) 2002-06-24

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