WO2005018649A1 - Agent permettant d'inhiber la formation d'un produit final de saccharification - Google Patents

Agent permettant d'inhiber la formation d'un produit final de saccharification Download PDF

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WO2005018649A1
WO2005018649A1 PCT/JP2004/011991 JP2004011991W WO2005018649A1 WO 2005018649 A1 WO2005018649 A1 WO 2005018649A1 JP 2004011991 W JP2004011991 W JP 2004011991W WO 2005018649 A1 WO2005018649 A1 WO 2005018649A1
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peritoneal
phosphate
pyridoxal
age
dialysate
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PCT/JP2004/011991
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English (en)
Japanese (ja)
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Toshimitsu Niwa
Sakurako Nakamura
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Nagoya Industrial Science Research Institute
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Publication of WO2005018649A1 publication Critical patent/WO2005018649A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a final saccharification product production inhibitor.
  • a reaction in which an amino group of an amino acid, peptide, or protein reacts with a reducing sugar such as a ketone, an anoaldehyde, and particularly glucose to produce a brown pigment is referred to as a Maillard reaction.
  • Maillard reaction Akira A reaction in which an amino group of an amino acid, peptide, or protein reacts with a reducing sugar such as a ketone, an anoaldehyde, and particularly glucose to produce a brown pigment.
  • the Maillard reaction is an early reaction in which the amino group and gnorecose react non-enzymatically to form a Schiff base, followed by Amadori rearrangement, and an active intermediate having a dicarboxyl group such as 3-deoxyglucosone (3-DG). It consists of a metaphase reaction that forms the body, and a late reaction in which the active intermediate reacts non-enzymatically with the amino group and forms AGEs through repeated dehydration and condensation reactions.
  • 3-DG 3-deoxyglucosone
  • Non-patent document 1 The AGE imidazolone (non-patent document 1), N E - carboxymethyl lysine (CML) (Non-Patent Document 2), pentosidine, pyrraline, crossline, N carboxyanhydride Chez chill lysine, Mechiruda Rio key Searle lysine dimer, Dario key Searle lysine Dimers and the like have been identified.
  • Imidazolone is produced by the reaction of 3-DG with arginine (Non-Patent Document 1).
  • Non-patent Documents 15 There are Schheimer's disease, rheumatoid arthritis and the like.
  • Non-patent Document 6 Non-patent Document 6
  • Sclerosing peritonitis is one of the pathologies in which the involvement of AGE is known.
  • Patients with peritoneal dialysis may have diminished peritoneal function over a long period of five years, with peritoneal sclerosis (fibrosis) and encapsulating sclerosing peritonitis. For this reason, it is necessary to stop peritoneal dialysis early and shift to hemodialysis.
  • peritoneal dialysis Currently, in Japan, approximately There are 9,000 and the ratio is about 4%, which is extremely small compared to about 230,000 hemodialysis patients. If percutaneous sclerosing peritonitis, which is a fatal complication of peritoneal dialysis, can be prevented, peritoneal dialysis will become popular.
  • peritoneal sclerosis a neutral pH peritoneal dialysis solution that has low glucose degradation products (GDP) such as 3-deoxygnorecone (3-DG) has been developed.
  • GDP glucose degradation products
  • 3-DG 3-deoxygnorecone
  • GDP is produced by heat treatment for sterilization from gnorecose present in high concentrations in peritoneal dialysate (Non-Patent Documents 7 and 8).
  • Non-Patent Documents 9 and 10 the generation of GDP is suppressed by performing sterilization by filtration instead of heating.
  • Non-Patent Documents 11 and 12 In the peritoneum of patients with peritoneal sclerosis, 3-D-derived imidazolone, AGEs such as CML, transforming growth factor (TGF) _31, vascular endothelial growth factor (VEGF), and fibrosis, thickening, (Non-Patent Documents 11 and 12). No hepatocyte growth factor (HGF) deposition was observed in the peritoneal site where fibrosis was strong (Non-patent Document 12).
  • TGF transforming growth factor
  • VEGF vascular endothelial growth factor
  • HGF hepatocyte growth factor
  • Non-Patent Document 1 Niwa T, Katsuzaki T, Miyazaki S, Miyazaki T, Ishizaki Y, Hayase F, Tatemichi N, Takei Y: Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients.J Clin Invest 99: 1272-1280, 1997
  • Non-Patent Document 2 Niwa T, Sato M, Katsuzaki T, et al: Amyloid ⁇ 2-microglobulin is modified with N ⁇ _ (carboxymethyl) lysine in dialysis-related amyloidosis.Kidney Int, 50: 1303-1309, 1996
  • Non-Patent Document 3 Vlassara H, Bucala R, Striker L .: Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging.Lab Invest. 70: 138-151, 1994
  • Non-Noon Literature 4 Franke S, Niwa T, Deuther-Conrad W, Sommer M, Hein G, Stein G: Immunochemical detection or imidazolone in uremia and rheumatoid arthritis.Clin Chim Acta. 300: 29—41, 2000
  • Non-Patent Document 5 Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA:
  • Non-Patent Document 6 Onorato JM, Jenkins AJ, Thorpe SR, Baynes JW: Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions.Mechanism of action of pyridoxamine. J Biol Chem. 275: 21177-21184, 2000
  • Non-Patent Document 8 Schalkwijk CG, Posthuma N, ten Brink HJ, ter Wee PM, Teerlink T: Induction of 1, 2-dicarbonyl compounds, intermediates in the formation of advanced glycation endproducts, during heat-sterilization of glucose? Based peritoneal dialysis fluids. Perit Dial Int 19: 325-333, 1999
  • Non-Patent Document 9 Tauer A, Zhang X, Schaub TP, Zimmeck T, Niwa T, Passlick-Deetjen J, Pischetsrieder M: Formation of advanced glycation end products during CAPD. Am J Kidney Dis 41 (S1): S57-S60, 2003
  • Non-special reference PM 10 Tauer A, Knerr T, Niwa T, et al: In vitro formation of N ⁇ -(carboxymethyl) lysine and imidazolones under conditions similar to continuous ambulatory peritoneal dialysis. Biochem. Biophys Res Commun 280: 1408-1414 , 2001
  • Patent text rat ⁇ 1 Nakamura S, Miyazaki S, Sasaki S, Morita T, Hirasawa Y, Niwa T: Localization of imidazolone in the peritoneum of CAPD patients: A factor for a loss of ultrafiltration.
  • Patent text rat ⁇ 2 Nakamura S, Tachikawa T, Tobita K, Miyazaki S, Sakai S, Morita T, Hirasawa Y, Weigle B, Pischetsrieder M, Niwa T: Role of advanced glycation end products and growth factors in peritoneal dysfunction in CAPD Patients.
  • Non-special reference literature 13 Honda K, Nitta K, Horita S, et al: Accumulation of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultra-filtration.Nephrol Dial Transplant 14: 1541-1549, 1999
  • Non-Patent Document 14 Margetts PJ, Kolb M, Gait T, Hoff CM, Shockley TR, Gauldie J: Gene transfer of transforming growth factor- ⁇ I to the rat peritoneum: Effect on membrane function.J Am Soc Nephrol 12: 2029- 2039, 2001
  • Patent Document 15 Inagi R, Miyata T, Yamamoto T, et al: Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: Role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis.FEBS Lett 463: 260-264, 1999
  • Non-Patent Document 16 Hippenstiel S, Krull M, Ikemann A, Risau W, Clauss M, Suttorp N: VEGr induces hyperpermeability by a direct action on endotneiial cells. Am J Physiol 274: L678-L684, 1998
  • Non-Noon Literature 17 Matsumoto K, Nakamura T: Hepatocyte growth factor: Renotropic role and potential therapeutics for renal disease.Kidney Int 59: 2023-2038, 2001
  • An object of the present invention is to provide a new final saccharification product production inhibitor (AGE production inhibitor) and a method of using the same.
  • Non-patent Documents 11 to 13 show the pathways in which peritoneal function declines due to AGE.
  • AGE deposited on the peritoneum binds to AGE receptors such as RAGE on the surface of fibroblasts and macrophage cells, and activates these cells to produce TGF_j31.
  • TGF_j31 enhances the production of collagen I, III, and TIMP-1 by fibroblasts (Non-Patent Document 14).
  • AGE also binds to AGE receptors such as RAGE on the surface of peritoneal mesothelial cells to produce VEGF.
  • VEGF enhances vascular hyperplasia and vascular permeability, leaks large molecules such as proteins, and consequently reduces the peritoneal filtration function (Non-Patent Documents 15, 16).
  • HGF has an effect of antagonizing the effect of TGF-J31 and suppressing fibrosis (Non-Patent Document 17).
  • TGF-iS1 reduces HGF expression.
  • AGE is a key molecule involved in peritoneal dysfunction, and if its production can be suppressed, peritoneal dysfunction can be prevented.
  • pyridoxal 5'-phosphate has a good AGE inhibitory action. Therefore, it was expected that the use of pyridoxal 5'-phosphate could effectively suppress the generation of AGE, and as a result, prevent the decline of peritoneal function.
  • pyridoxal 5′_phosphate effectively suppressed imidazolone production.
  • pyridoxal 5'_phosphate is effective in producing AGE, which is produced in the largest amount in peritoneal dialysis. It has been proved that it can be suppressed.
  • AGE which is produced in the largest amount in peritoneal dialysis. It has been proved that it can be suppressed.
  • the use of pyridoxal 5'-phosphate during peritoneal dialysis is a very effective means for preventing peritoneal dialysis-related decline in peritoneal function.
  • the present invention has been completed based on the above findings and provides the following configurations.
  • a final saccharified product formation inhibitor containing pyridoxal 5'_phosphate as an active ingredient [1] A final saccharified product formation inhibitor containing pyridoxal 5'_phosphate as an active ingredient.
  • a method for suppressing the production of terminal glycation products which comprises the step of administering pyridoxal 5′_phosphate to a patient.
  • a method for preventing or treating sclerosing peritonitis comprising: administering a therapeutically effective amount of pyridoxal 5′-phosphate to a patient.
  • a method of peritoneal dialysis which comprises the step of administering to a patient an effective amount of pyridoxal 5'-phosphate for preventing peritoneal sclerosis.
  • the present invention provides a novel AGE production inhibitor and an anti-peritoneal sclerosing agent.
  • the AGE production inhibitory effect of the agent of the present invention can be obtained with a higher and smaller dose than that of pyridoxamine known as an AGE production inhibitor.
  • the active ingredient of the drug of the present invention is vitamin Since it is a B6 phosphate ester conjugate, it is a drug with high safety and low risk of side effects.
  • Fig. 1 is a graph showing the results of incubating pyridoxal 5-phosphoric acid (hereinafter abbreviated as “PLP”) and 3-DG, and then measuring the 3-DG concentration by GC / MS. is there. PLP shows 3-DG force S trap.
  • PLP pyridoxal 5-phosphoric acid
  • FIG. 3 is a graph showing the results of EIA measurement of imidazolone produced by incubating 3-DG, BSA, and PLP. It can be seen that PLP suppresses imidazolone production in a concentration-dependent manner.
  • FIG. 4 is a graph showing the results of measuring the peritoneal thickness of each test group in a peritoneal dialysis test using rats. It can be seen that the addition of PLP to the peritoneal dialysate suppresses the increase in peritoneal thickening.
  • FIG. 5 is a graph comparing the imidazolone-positive area of each test group in a peritoneal dialysis test using rats. It can be seen that the addition of PLP to the peritoneal dialysate suppresses the increase in the imidazolone-positive area.
  • FIG. 7 is a graph comparing the type 1 collagen positive area of each test group in a peritoneal dialysis test using rats. It can be seen that the addition of PLP to the peritoneal dialysate suppresses the increase in type 1 collagen positive area.
  • FIG. 9 is a graph comparing the HGF-positive area of each test group in a peritoneal dialysis test using rats. Addition of PLP to peritoneal dialysate increases HGF volume area Power to do.
  • FIG. 10 is a graph comparing the VEGF-positive area of each test group in a peritoneal dialysis test using rats. It can be seen that the addition of PLP to the peritoneal dialysate suppresses the increase in VEGF-positive area.
  • FIG. 11 is a graph comparing the number of blood vessels in each test group in a peritoneal dialysis test using rats. Addition of PLP to the peritoneal dialysate suppresses the increase in the number of peritoneal blood vessels.
  • FIG. 12 is a diagram showing a route from AGE generation to peritoneal function decline.
  • the present invention relates to a drug containing pyridoxal 5′-phosphate (hereinafter abbreviated as “PLP”) as an active ingredient.
  • PRP pyridoxal 5′-phosphate
  • the agent of the present invention is used as an AGE formation inhibitor or as an anti-peritoneal sclerosing agent.
  • anti-peritoneal sclerosing agent in the present invention refers to a drug used to prevent peritoneal sclerosis, or to prevent deterioration of symptoms of peritoneal sclerosis or to improve the symptoms (including partial or complete healing).
  • the anti-peritoneal sclerosing agents of the present invention include agents that can be used for prophylactic treatment of peritoneal sclerosis and agents that can be used for the treatment of peritoneal sclerosis (eg, capsular sclerosing peritonitis).
  • pyridoxal 5'-phosphate was found to have an inhibitory effect on AGE production.
  • AGE stimulates the production of TGF- / 31, as illustrated in FIG. 11, which causes an increase in collagen I and ⁇ ⁇ and an increase in TIMP-1 levels.
  • AGE causes elevated VEGF levels.
  • a drug containing pyridoxal 5'-phosphate as an active ingredient should be used to treat diseases caused by increased TGF-j31, increased collagen I or III, increased TIMP levels, and / or increased VEGF levels. It is expected that it can also be used for prevention or treatment.
  • pyridoxal 5'-phosphate is used to increase vascular hyperplasia or vascular permeability. Therefore, a drug containing pyridoxal 5'-phosphate as an active ingredient can also be used for prevention or treatment of diseases caused by vascular hyperplasia or increased vascular permeability. it is conceivable that.
  • pyridoxal 5'_phosphate used in the drug of the present invention is represented by the following chemical formula.
  • pyridoxal 5'-phosphate may exist in a state bound to another compound. It may also be present in the form of a pharmaceutically acceptable salt.
  • examples of other compounds here include peptides and proteins.
  • pharmaceutically acceptable salts here include, for example, salts (inorganic acid salts) with hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, boric acid and the like, formic acid, acetic acid, lactic acid, fumaric acid, maleic acid, It is a salt (organic acid salt) with tartaric acid, citric acid, etc.
  • a compound obtained by modifying a part of a certain compound may have the same properties and characteristics as the compound before modification. That is, the modification may not affect the specific properties of the compound. Considering this, even a modified product obtained by modifying pyridoxal 5'-phosphate can be used as an active ingredient in the present invention, as long as the activity of inhibiting AGE production is maintained.
  • a person skilled in the art can design a modified product such as a pyridoxal 5′-phosphate-based substituted product using a method for penetration of a compound that is not well known. It is also considered to be easy for a person skilled in the art to prepare a target decorative body using a known means for penetration based on a powerful design, and to examine its properties and actions.
  • Formulation of pyridoxal 5'-phosphate can be performed according to a conventional method. Place to formulate If so, other pharmaceutically acceptable ingredients (e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, saline) Etc.) can be contained.
  • other pharmaceutically acceptable ingredients e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, saline) Etc.
  • an excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used.
  • phosphate, citrate, acetate and the like can be used.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • a suspending agent glycerin monostearate, anolemminium monostearate, methinoresenololose, canoleboxy methinoresenololose, hydroxymethinoresenololose, sodium lauryl sulfate and the like can be used.
  • the soothing agent pendinoreal alcohol, chlorobutanol, sorbitol and the like can be used.
  • the stabilizer propylene glycol, diethylin sulfite, ascorbic acid and the like can be used.
  • preservative phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methyl paraben and the like can be used.
  • preservatives it is possible to use shiridani benzalkonium, paraoxybenzoic acid, chlorobutanol and the like.
  • the dosage form for formulation is not particularly limited, and may be prepared as tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, suppositories, and the like.
  • pyridoxal 5'-phosphate can be used as a component of a peritoneal dialysis solution.
  • the present invention provides, as another aspect, a peritoneal dialysis solution containing pyridoxal 5'-phosphate.
  • a peritoneal dialysis solution containing pyridoxal 5'_phosphate has an effect of preventing peritoneal sclerosis when applied (used for dialysis). Therefore, the use of such a peritoneal dialysis solution realizes a dialysis treatment with a low risk of occurrence of peritoneal sclerosis.
  • peritoneal dialysate of the present invention can be prepared by using pyridoxal 5′-phosphate in addition to such various components. Further, a predetermined amount of pyridoxal 5′-phosphate is added to a commercially available peritoneal dialysate to prepare the peritoneal dialysate of the present invention. In this case, the addition of pyridoxal 5′_phosphate may be performed immediately before use of the peritoneal dialysate.
  • the amount of pyridoxal 5'-phosphate in the peritoneal dialysate is, for example, 40 nM (mol / 1) to 40 mM (mol / 1).
  • a method for inhibiting the production of terminal glycation products (a method for inhibiting AGE production) using pyridoxal 5′_phosphate is provided.
  • a step of administering pyridoxal 5′-phosphate to a patient is performed.
  • Pyridoxal 5'-phosphate is administered alone or with other substances. Typically, it is administered in the form of an agent of the invention described above.
  • the administration route is not particularly limited, and examples thereof include oral, intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, and transmucosal.
  • the dose of pyridoxal 5'-phosphate is set so as to obtain the expected effect (the effect of suppressing AGE production). It is preferable to set the dose of pyridoxal 5'-phosphate so that the expected effect is sufficiently obtained and there is no side effect due to the administration of pyridoxal 5'-phosphate, or the dose does not cause a therapeutic problem. .
  • the dose symptoms, age, sex, and weight of the patient are generally considered. Incidentally, those skilled in the art can determine an appropriate dose in consideration of these matters.
  • the amount of the active ingredient per day for an adult is about 10 ⁇ g to about 10 g, preferably about 10 g.
  • the administration schedule may be, for example, once a day, several times a day, once every two days, or once every three days. In preparing an administration schedule, the patient's condition, the duration of the effect of the drug, and the like can be considered.
  • Diseases or conditions to be prevented or treated by the method for suppressing AGE production of the present invention are not particularly limited as long as AGE is involved in the onset or progress of the disease.
  • aging diabetes, nephropathy, neuropathy, retinopathy, arteriosclerosis, renal failure, sclerosing peritonitis, dialysis Targets include myloidosis, arteriosclerosis, Alzheimer's disease, and rheumatoid arthritis.
  • the method of the present invention is effective for the prevention or treatment of sclerosing peritonitis
  • the present invention provides, as a specific embodiment thereof, the following methods, that is, a method comprising administering a therapeutically effective amount of pyridoxal 5'-phosphate to a patient.
  • the present invention provides a method for preventing or treating sclerosing peritonitis including the step of administering, and a method for peritoneal dialysis including the step of administering to a patient an effective amount of pyridoxal 5′-phosphate for preventing peritoneal sclerosis.
  • “therapeutically effective amount” and “effective amount for preventing peritoneal sclerosis” can be determined in consideration of the patient's medical condition, health condition, age, sex, weight, etc.
  • peritoneal dialysis is a blood purification treatment in which a dialysate is injected into the peritoneal cavity and the dialysate to which wastes, moisture, and the like have migrated through the peritoneum through the peritoneum by a certain period of storage is taken out of the body. is there.
  • a method of peritoneal dialysis continuous portable peritoneal dialysis (CAPD) and automatic peritoneal dialysis (APD) are known.
  • CAPD continuous portable peritoneal dialysis
  • API automatic peritoneal dialysis
  • the peritoneal dialysis method of the present invention can be applied to any of these methods.
  • the timing of administration of pyridoxal 5'-phosphate is not particularly limited.
  • administration is performed before dialysis treatment.
  • Dialysis treatment is generally performed multiple times.
  • administration of pyridoxal 5'-phosphate is performed before one or more dialysis treatments.
  • pyridoxal 5'-phosphate is administered prior to dialysis treatment, the dialysis treatment should be performed as soon as possible after administration in order to effectively exert the inhibitory effect of pyridoxal 5'-phosphate on AGE formation. Is preferred. From such a viewpoint, it is preferable to administer pyridoxal 5′-phosphate immediately before the dialysis treatment.
  • administration of pyridoxal 5'-phosphate may be performed during the dialysis treatment. That is, pyridoxal 5'-phosphate may be administered in parallel with the dialysis treatment.
  • pyridoxal 5'-phosphate is contained in the dialysate, such an administration method can be performed without complicating the dialysis operation at all, and the burden on patients and doctors is reduced.
  • the administration of pyridoxal 5'-phosphate may be carried out by a different route from the injection of the dialysate.
  • pyridoxal 5'-phosphate can also be performed after the dialysis treatment. However, in this case, in order to effectively exert the AGE generation inhibitory effect of pyridoxal 5'-phosphate, It is preferable to administer pyridoxal 5'-phosphate with as little time as possible after completion of the dialysis treatment. From a powerful viewpoint, it is preferable to administer pyridoxal 5'-phosphate immediately after the dialysis treatment.
  • pyridoxal 5'-phosphate may be carried out at two or more of these times before, during, or after the dialysis treatment, but at any one time only.
  • PLP Not only Maillard reaction but also 3-DG generated by the polyol pathway is trapped by PLP, so PLP suppresses AGE formation more strongly.
  • the polyol pathway exists in erythrocytes, retina, lens nerve, renal glomerulus, heart, etc., and is enhanced in diabetes. PLP is expected to be effective in suppressing the progression of these complications by suppressing AGE production via the polyol pathway in diabetic complications such as retinopathy, neuropathy, and nephropathy. 1
  • GC / MS for the 3-DG measurement method was performed by the following method. 200 ng of 13 C-3-DG was added as an internal standard substance to 1 ml of the sample solution. Add 2 ml of ethanol, cap and shake gently. Centrifugation was performed at 3000 rpm for 10 minutes at 4 ° C. The supernatant was transferred to a spiral glass tube, and the solvent was blown off with a nitrogen stream so that ethanol did not remain. Ethanol splattered and 1 ml of solution The nitrogen was turned off when: 100 ⁇ g of 2,3-diaminonaphthalene was added as a reactant. Put the lid on and put it in the ice room.
  • 3-DG was detected at 21.8 minutes by selective ion detection (SIM) using the m / z 501.15 ion, and 3-DG was quantified from the peak area ratio.
  • 3-DG, BSA and pyridoxamine were incubated, and the amount of imidazolone produced was measured similarly.
  • EIA was measured according to the following method.
  • PLP has an AGE production inhibitory action because it traps 3-DG and suppresses imidazolone production.
  • PLP has a stronger inhibitory effect on AGE production than pyridoxamine at the same concentration.
  • the peritoneal thickness was measured under a microscope (100 times).
  • immunostaining was performed using antibodies against imidazolone, CML, TGF- / 31, HGF, VEGF, and type 1 collagen. Immunostaining was performed according to the following method.
  • Antibodies used (1) Egret anti-human HGF-a antibody (polyclonal);
  • Egret anti-TGF- ⁇ 1 antibody polyclonal
  • mouse anti-imidazolone antibody AG-1
  • Deparaffinization was performed using xylene and ethanol, followed by washing with distilled water for 5 minutes, phosphate buffered saline (PBS) for 5 minutes, acetone for 10 minutes, and further with distilled water and PBS.
  • PBS phosphate buffered saline
  • Proteinase K (0.01 mg / ml) was added and treated at 37 ° C for 10 minutes. After washing with PBS three times, washing with methanol containing 0.3% H 0 for 10 minutes and PBS twice, blocking with 10% serum was performed for 30 minutes. Each antibody was added and allowed to stand at 4 ° C. After washing three times with PBS, a secondary antibody with a biotin-labeled antibody was added. After 30 minutes, washing was performed three times with PBS. Peroxidase-conjugated streptavidin was added, reacted at 37 ° C for 30 minutes, washed three times with PBS, and developed with p-dimethylaminoazobenzene (DAB).
  • the immunostained tissue was observed with a microscope (X100, Nikon, Eclipse, ⁇ 600, ⁇ - ⁇ -35), captured with a digital net camera (Nikon, DN100), and ⁇ image (1.62) software And the positive area per 300 ⁇ of peritoneal length (m 2 ). Further, the number of blood vessels per peritoneal length 300 / m was measured by microscopic observation of the VEGF-stained tissue.
  • the CML positive area in the peritoneum was increased in the dialysate group.
  • the increase in the CML-positive area was suppressed in the solution + PLP group compared to the dialysate group.
  • the type 1 collagen positive area in the peritoneum increased.
  • the increase in type 1 collagen-positive area was suppressed compared to the dialysate group.
  • the TGF- / 31 positive area in the peritoneum was increased.
  • the increase in TGF- ⁇ 1 positive area was suppressed in the dialysate + PLP group compared to the dialysate group. It was.
  • the HGF-positive area in the peritoneum increased compared to the saline group and the dialysate group.
  • the dialysate group showed an increasing tendency of the VEGF positive area in the peritoneum.
  • the increase in VEGF-positive area was suppressed compared to the dialysate group.
  • the dialysate group showed an increase in the number of blood vessels in the peritoneum.
  • the dialysate + PLP group suppressed the increase in the number of peritoneal vessels compared to the dialysate group.
  • PLP suppressed peritoneal fibrosis such as type 1 collagen.
  • PLP suppressed the expression of TGF-iS1, which promotes fibrosis, and promoted the expression of HGF, which suppresses fibrosis.
  • PLP suppressed the expression of VEGF, which promotes vascular growth, and suppressed the increase in the number of peritoneal vessels.
  • the agent of the present invention can be used for the prevention or treatment of various diseases or conditions in which AGE is involved in the onset and progress of AGE.
  • the agent of the present invention is particularly problematic in that it develops with peritoneal dialysis, and can be used for the prevention or treatment of sclerosing peritonitis.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un nouvel agent permettant d'inhiber la formation d'un produit final de saccharification et son procédé d'utilisation. L'invention concerne principalement un médicament contenant un pyridoxal 5'-phosphate comme ingrédient actif, et un procédé permettant d'inhiber la formation d'un produit final de saccharification par utilisation du pyridoxal 5'-phosphate. L'invention concerne enfin une méthode permettant de traiter la péritonite sclérosante, une méthode permettant d'effectuer une dialyse péritonéale, etc.
PCT/JP2004/011991 2003-08-25 2004-08-20 Agent permettant d'inhiber la formation d'un produit final de saccharification WO2005018649A1 (fr)

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JP2005513305A JPWO2005018649A1 (ja) 2003-08-25 2004-08-20 最終糖化産物生成抑制剤

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JP2003-300417 2003-08-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006126523A1 (fr) * 2005-05-24 2006-11-30 Tokai University Educational System Agent de protection du peritoine
JP2011241174A (ja) * 2010-05-18 2011-12-01 Jms Co Ltd アミロイド形成抑制物質を含有する溶液組成物
JP5128003B2 (ja) * 2010-07-23 2013-01-23 学校法人東海大学 腹膜透析患者用の経口医薬組成物及びその用法

Citations (4)

* Cited by examiner, † Cited by third party
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JPH10324629A (ja) * 1997-03-28 1998-12-08 Otsuka Pharmaceut Co Ltd Ａｇｅ生成阻害組成物
JPH11512432A (ja) * 1995-09-12 1999-10-26 ユニヴァースティ オブ カンザス メディカル センター 前進性グリケーション最終産物の中間体とアマドリ転位後の阻害
JP2001523663A (ja) * 1997-11-17 2001-11-27 ユニヴァースティ オブ カンザス メディカル センター 進歩した糖化最終生成物中間体及び後−アマドリ阻害
WO2002083127A1 (fr) * 2001-04-09 2002-10-24 Tokai University Educational System Compositions inhibant la modification proteique

Patent Citations (4)

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JPH11512432A (ja) * 1995-09-12 1999-10-26 ユニヴァースティ オブ カンザス メディカル センター 前進性グリケーション最終産物の中間体とアマドリ転位後の阻害
JPH10324629A (ja) * 1997-03-28 1998-12-08 Otsuka Pharmaceut Co Ltd Ａｇｅ生成阻害組成物
JP2001523663A (ja) * 1997-11-17 2001-11-27 ユニヴァースティ オブ カンザス メディカル センター 進歩した糖化最終生成物中間体及び後−アマドリ阻害
WO2002083127A1 (fr) * 2001-04-09 2002-10-24 Tokai University Educational System Compositions inhibant la modification proteique

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Title
BOOTH A ET AL: "In vitro kinetic studies of formation of antigenic advanced glycation end-products(AGEs). Novel inhibition of post-Amadori glycation pathways", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 9, 30 October 1997 (1997-10-30), pages 5430 - 5437, XP000960757 *
BOOTH A ET AL: "Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 220, no. 1, 29 January 1996 (1996-01-29), pages 113 - 119, XP002024845 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006126523A1 (fr) * 2005-05-24 2006-11-30 Tokai University Educational System Agent de protection du peritoine
JPWO2006126523A1 (ja) * 2005-05-24 2008-12-25 学校法人東海大学 腹膜保護剤
JP2011241174A (ja) * 2010-05-18 2011-12-01 Jms Co Ltd アミロイド形成抑制物質を含有する溶液組成物
JP5128003B2 (ja) * 2010-07-23 2013-01-23 学校法人東海大学 腹膜透析患者用の経口医薬組成物及びその用法

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