WO2022244551A1 - 治療材 - Google Patents
治療材 Download PDFInfo
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- WO2022244551A1 WO2022244551A1 PCT/JP2022/017596 JP2022017596W WO2022244551A1 WO 2022244551 A1 WO2022244551 A1 WO 2022244551A1 JP 2022017596 W JP2022017596 W JP 2022017596W WO 2022244551 A1 WO2022244551 A1 WO 2022244551A1
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- blood
- water
- insoluble carrier
- therapeutic material
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Definitions
- the present invention relates to a therapeutic material used for treating diseases whose symptoms are alleviated or cured by reducing blood phosphorus levels.
- Phosphorus is a mineral necessary for the human body, 85% of which is present in bones and teeth as calcium phosphate and magnesium phosphate, and the remaining 15% is bound to proteins and lipids and is present in the body as a constituent of cell membranes and nucleic acids. In addition to being present in cells, it is also a component of ATP that generates energy. It is also involved in various functions in the body, such as maintaining the pH balance and osmotic pressure of cells.
- the Klotho gene has been identified as a gene involved in progeria, which accelerates aging.
- Klotho gene-deficient mice have an imbalance between phosphorus intake and excretion, and phosphorus intake is associated with growth disorders and cardiac hypertrophy.
- a low-phosphorus diet is known to reduce progeria while prematurely dying.
- phosphate in the blood binds to calcium to form an insoluble salt, which is deposited in the cartilage tissue of joints and causes gout.
- Fetuin-A a serum protein
- CPP calciprotein particles
- Various theories have been proposed as to the cause of arteriosclerosis, and there is a theory that aggregated CPP promotes arteriosclerosis and causes vascular calcification.
- CPP cannot be removed by dialysis (Non-Patent Documents 1-3).
- Patent Document 1 An adsorbent for removing CPP from blood
- an object of the present invention is to provide a therapeutic material for use in the treatment of diseases whose symptoms are alleviated or cured by reducing blood phosphorus levels.
- the present inventors have made intensive studies to solve the above problems. As a result, the combination of dialysis treatment and blood treatment with specific calciprotein particle adsorbents can effectively reduce blood phosphorus levels, and the reduction in blood phosphorus levels alleviates or cures symptoms. The inventors have completed the present invention by discovering that it is possible to treat such diseases.
- TECHNICAL FIELD The present invention relates to a therapeutic material used for treatment of diseases whose symptoms are relieved or treated by reducing blood phosphorus levels. The present invention is shown below.
- the adsorptive group is bound to the water-insoluble carrier via a linker group,
- the above disease is cardiac hypertrophy, sarcopenia, emphysema, atrophy of the thymus, atrophy of adipose tissue, dementia, frailty, failure to thrive, pruritus, valvular heart disease, secondary hyperparathyroidism, bone metabolism
- the therapeutic agent according to the above [1] which is one or more diseases selected from abnormality and calciphylaxis.
- the linker group may have a substituent, a C 1-6 alkanediyl group, an ether group, a thioether group, an amino group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group,
- the therapeutic agent according to any one of [1] to [3] above, which is a thiourea group, a polyalkylene glycol group, a polyvinyl alcohol group, or a group in which 2 or more and 5 or less of these groups are linked.
- [5] The therapeutic agent according to any one of [1] to [4] above, wherein two or more phosphonic acid groups are covalently bonded to the linker group.
- the therapeutic material has a water-insoluble carrier and one or more adsorption groups selected from the group consisting of a phosphate group, a phosphonic acid group, a phosphinic acid group, an amino group, a carboxyl group, and a thiol group, and the adsorption group is attached to the water-insoluble carrier via a linker group,
- the therapeutic material is used so that the calciprotein particles in the blood are adsorbed to the adsorption group by permeating the blood that has undergone dialysis, or the permeated blood is dialyzed.
- the above disease is cardiac hypertrophy, sarcopenia, emphysema, atrophy of the thymus, atrophy of adipose tissue, dementia, frailty, failure to thrive, pruritus, valvular heart disease, secondary hyperparathyroidism, bone metabolism
- the linker group may have a substituent, a C 1-6 alkanediyl group, an ether group, a thioether group, an amino group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group,
- a method for treating a disease whose symptoms are alleviated or treated by reducing blood phosphorus levels comprising: treating the blood with a therapeutic agent and subjecting it to dialysis;
- the therapeutic material has a water-insoluble carrier and one or more adsorption groups selected from the group consisting of a phosphate group, a phosphonic acid group, a phosphinic acid group, an amino group, a carboxyl group, and a thiol group,
- a method, wherein the adsorptive group is bound to the water-insoluble carrier via a linker group.
- the above disease is cardiac hypertrophy, sarcopenia, emphysema, atrophy of the thymus, atrophy of adipose tissue, dementia, frailty, failure to thrive, pruritus, valvular heart disease, secondary hyperparathyroidism, bone metabolism
- the method of [15] above which is abnormal or calciphylaxis.
- the method of [16] above which further suppresses one or more diseases selected from heart failure, cerebrovascular disease, pneumonia, and gastrointestinal disease.
- the linker group optionally having a substituent, a C 1-6 alkanediyl group, an ether group, a thioether group, an amino group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group,
- the method according to [15] above which is a thiourea group, a polyalkylene glycol group, a polyvinyl alcohol group, or a group in which 2 or more and 5 or less of these groups are linked.
- two or more phosphonic acid groups are covalently bonded to the linker group.
- the water-insoluble carrier is porous.
- the water-insoluble carrier has an exclusion limit molecular weight of 1,000 or more and 10,000,000 or less.
- the therapeutic material for manufacturing a therapeutic means for treating a disease whose symptoms are relieved or treated by reducing blood phosphorus levels
- the therapeutic material has a water-insoluble carrier and one or more adsorption groups selected from the group consisting of a phosphate group, a phosphonic acid group, a phosphinic acid group, an amino group, a carboxyl group, and a thiol group,
- the adsorptive group is bound to the water-insoluble carrier via a linker group
- the therapeutic material is used so that the calciprotein particles in the blood are adsorbed to the adsorption group by permeating the blood that has undergone dialysis, or the permeated blood is dialyzed.
- the above disease is cardiac hypertrophy, sarcopenia, emphysema, atrophy of the thymus, atrophy of adipose tissue, dementia, frailty, failure to thrive, pruritus, valvular heart disease, secondary hyperparathyroidism, bone metabolism
- the linker group optionally having a substituent, a C 1-6 alkanediyl group, an ether group, a thioether group, an amino group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group,
- a substituent a C 1-6 alkanediyl group, an ether group, a thioether group, an amino group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group
- the blood phosphorus level can be effectively reduced, and the reduction of the blood phosphorus level can alleviate the symptoms or alleviate the symptoms of the disease to be treated. Therefore, the present invention is very useful as a therapeutic means for such diseases.
- FIG. 1 is a diagram schematically showing the balance of phosphorus in the case of dialysis alone and in the case of CPP adsorption and dialysis in combination.
- FIG. 2 is a schematic diagram showing an example of an adsorber using the therapeutic material according to the present invention.
- FIG. 3(1) is a graph showing plasma phosphorus concentrations before and after CPP adsorption treatment
- FIG. 3(2) is a graph showing plasma phosphorus concentrations before and after dialysis treatment and CPP adsorption treatment+dialysis treatment.
- FIG. 4 is a graph showing changes over time in plasma phosphorus concentration in the dialysis treatment group and the CPP adsorption treatment+dialysis treatment group.
- FIG. 5 is a gel photograph showing the results of analysis of proteins adsorbed by the adsorbent.
- the therapeutic material according to the present invention has a water-insoluble carrier and one or more adsorption groups selected from the group consisting of a phosphate group, a phosphonic acid group, a phosphinic acid group, an amino group, a carboxyl group, and a thiol group.
- the adsorbing group is bound to the water-insoluble carrier via a linker group, and is capable of adsorbing calciprotein particles (hereinafter abbreviated as "CPP").
- CPP is a complex of calcium phosphate and protein, more specifically a complex of calcium phosphate, particularly Posner cluster (component is Ca 9 (PO 4 ) 6 ), Fetuin-A, etc.
- Posner cluster component is Ca 9 (PO 4 ) 6
- Fetuin-A etc.
- the calcium phosphates include monetite ( CaHPO4 ), brushite ( CaHPO4.2H2O ), amorphous calcium phosphate ( Ca9PO4 ) 6 ), and hydroxyapatite ( Ca10 ( PO4)6 ( OH). 2 ), etc.
- CPPs may also take up proteins in bodily fluids other than Fetuin-A as complexes.
- CPPs examples include albumin, fibrinogen, RANKL (Receptor activator of nuclear factor kappa-B ligand), BMP-2 (Bone morphogenic protein 2), BMP-7 (Bone morphogenic protein 7). ), Osteoprotegerin and the like.
- CPPs also include abnormal forms produced by mutations in genes and the like.
- CPP binds with an electron-donating group.
- these adsorptive groups may be in the form of salts.
- counter cations that form such salts include alkali metal ions such as sodium ions and potassium ions; Group 2 metal ions such as calcium ions and magnesium ions.
- the amino group may be substituted as long as the nucleophilicity is not lost.
- substituents include C 1-6 alkyl groups, preferably C 1-4 alkyl groups, more preferably C 1-2 alkyl groups, and even more preferably methyl.
- the therapeutic material according to the present invention has a water-insoluble carrier and an adsorptive group for CPP, and the adsorptive group is bound to the water-insoluble carrier via a linker group.
- the linker group has the effect of increasing the positional freedom of the adsorptive group, facilitating the adsorption of the adsorptive group to the CPP, and facilitating the binding of the adsorptive group to the water-insoluble carrier.
- the linker group binds the water-insoluble carrier and the adsorptive group
- the valence of the linker group is n+1.
- the valence of the linker group is trivalent, which binds the water-insoluble carrier and the two adsorptive groups.
- the linker group may have a substituent.
- substituents include one or more substituents selected from a hydroxyl group, a C 1-6 alkoxy group, an amino group (--NH 2 ), and a halogeno group, with a hydroxyl group being preferred.
- the number of substituents per linker group is not particularly limited as long as it can be substituted. When the number of substituents per linker group is 2 or more, the multiple substituents may be the same or different.
- the C 1-6 hydrocarbon group includes, for example, a C 1-6 alkane-(n+1)yl group (n represents the number of adsorptive groups per linker group).
- the number of carbon atoms in the C 1-6 hydrocarbon group is preferably 2 or more, and preferably 5 or less or 4 or less.
- the C 1-6 hydrocarbon group may be linear or branched, preferably linear.
- a C 1-6 alkoxy group means a linear or branched saturated aliphatic hydrocarbonoxy group having 1 to 6 carbon atoms.
- methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, n-hexoxy and the like preferably C 1-4 alkoxy groups, more preferably C 1 -2 alkoxy group, more preferably methoxy.
- halogeno group can be exemplified by fluoro, chloro, bromo and iodo, preferably chloro or bromo, more preferably chloro.
- the number of adsorption groups per linker group is preferably 2 or more. Bringing two or more adsorptive groups close to each other allows CPPs to be more effectively adsorbed. On the other hand, if the number of adsorption groups per linker group is too large, the production of the adsorbent may become difficult.
- Examples of compounds that constitute a combination of an adsorptive group and a linker group to be bound to a water-insoluble carrier include pamidronic acid, alendronic acid, and neridronic acid.
- water-insoluble means that when 1 g of the carrier is put in water and vigorously shaken for 30 seconds every 5 minutes at 20 ⁇ 5° C., the amount of water required to dissolve within 30 minutes is 1,000 mL or more. , preferably 10,000 mL or more.
- water-insoluble carriers include inorganic carriers, organic carriers, composite carriers obtained by combining these, such as organic carrier-organic carrier and organic carrier-inorganic carrier.
- Materials for the inorganic carrier include glass beads and silica gel.
- organic carrier materials include synthetic polymers and polysaccharides. Examples of synthetic polymers include crosslinked polyvinyl alcohol, crosslinked polyacrylate, crosslinked polyacrylamide, and crosslinked polystyrene.
- polysaccharides include crystalline cellulose and crosslinked polysaccharides.
- Commercially available products include porous cellulose gel GCL2000, Sephacryl (R) S-1000 in which allyl dextran and methylenebisacrylamide are covalently crosslinked, Toyopearl (R) acrylate carrier, and agarose crosslinked carrier.
- Examples include Sepharose (R) CL4B and Cellufine (R) , which is a cellulose-based crosslinked carrier.
- the water-insoluble carrier in the present invention is not limited to these exemplified carriers.
- the water-insoluble carrier desirably has a large surface area, and is preferably porous with a large number of pores of suitable size.
- the form of the carrier may be bead-like, monolithic, fibrous, or membrane-like (including hollow fibers), and any form can be selected.
- the therapeutic material according to the present invention can effectively adsorb CPP even when the porosity of the water-insoluble carrier is not very high.
- the exclusion limit molecular weight of the water-insoluble carrier is preferably 1,000 or more and 10,000,000 or less.
- the exclusion limit molecular weight is more preferably 8,000,000 or less, and even more preferably 6,000,000 or less.
- the present inventors have found that the therapeutic material according to the present invention can effectively adsorb CPP even when the porosity of the water-insoluble carrier is not so high. Specifically, since it is known that even 30,000 or less is effective, the exclusion limit molecular weight of the water-insoluble carrier is preferably 10,000 or more and 50,000 or less.
- the water-insoluble carrier is solid at normal temperature and normal pressure, and its size is not particularly limited and may be adjusted as appropriate. be able to.
- the average particle size is preferably 100 ⁇ m or more, more preferably 200 ⁇ m or more, and preferably 1 mm or less, more preferably 0.8 mm or less.
- the average particle size of the granular water-insoluble carrier can be obtained on a number basis by measuring the diameter of each carrier from an enlarged photograph of the carrier with a stereoscopic microscope or the like.
- a water-insoluble carrier generally has a large number of reactive groups such as hydroxyl groups on its surface. Therefore, a linker compound having, for example, an adsorptive group can be bound via the reactive group or via another reactive group introduced into the reactive group. For example, a hydroxyl group on the surface of a water-insoluble carrier is reacted with a linker compound having a carboxylic acid halide group or an active ester group to form an ester bond, or a linker compound having a halogeno group is reacted in the presence of a base to form an ether. A bond can be formed.
- linker compounds having nucleophilic groups such as hydroxyl groups and amino groups (--NH 2 ) can be reacted.
- a reductive amination reaction can be performed with a linker compound having an amino group to bind the linker compound via the amino group (--NH--).
- the adsorptive group bound to the linker compound may be protected with an appropriate protecting group and deprotected after the binding reaction.
- an adsorptive group may be introduced into the linker group.
- the adsorbing group is contained in a volume of 10 nmol or more and 100 ⁇ mol or less per unit volume (1 mL) of the water-insoluble carrier.
- the ratio is preferably 100 nmol or more, more preferably 1 ⁇ mol or more, still more preferably 3 ⁇ mol or more, and preferably 50 ⁇ mol or less.
- the volume of the water-insoluble carrier refers to the sedimentation volume.
- the sedimentation volume is the volume when the water-insoluble carrier is allowed to settle while vibrating in water, the sedimentation stops, and it is confirmed that the volume of the water-insoluble carrier does not change even when the vibration is applied. .
- the amount of adsorptive groups per unit volume of the water-insoluble carrier is determined, for example, by decomposing the water-insoluble carrier on which the adsorptive groups are immobilized under pressurized acid conditions. and then divided by the sedimentation volume of the water-insoluble carrier used for decomposition, or subtracting the amount of adsorbing groups remaining in the solution after the reaction from the amount of adsorbing groups used in the reaction, and further reacting It is obtained by dividing by the sedimentation volume of the water-insoluble carrier used in .
- blood is treated with a therapeutic material and subjected to dialysis.
- the order of the treatment with the therapeutic material and the dialysis treatment does not matter. That is, blood may be treated with a therapeutic agent to reduce the amount of CPP in the blood and then be subjected to dialysis treatment, or the blood may be treated with a therapeutic agent after being dialyzed to reduce the amount of CPP in the blood. You may
- a dialysis machine is used to draw blood from a patient.
- the rate at which blood is extracted that is, the blood flow rate Qb may be adjusted as appropriate.
- Examples of adsorbers include those illustrated in FIG.
- the adsorber of FIG. 2 has a column 6 filled with a granular therapeutic material 3 .
- Filters 4 and 5 are attached to both ends of the column 6 to prevent the outflow of the therapeutic material 3 while allowing blood to flow through the therapeutic material 3 .
- Lids 1b and 2b which can be liquid-tightly fixed to the column 6 by screws or the like, are attached to the mounting surfaces of the filters 4 and 5 of the column 6.
- the blood flow formed on the lids 1b and 2b is Blood can be supplied to the therapeutic material 3 in the column 6 through the inlet 1a, and blood in contact with the therapeutic material 3 in the column 6 can be discharged through the outflow port 2a.
- CPP includes CPP, which is a complex of amorphous calcium phosphate and Fetuin-A, and CPP, in which at least part of amorphous calcium phosphate undergoes a phase transition from amorphous to crystalline. It is believed that CPPs containing mainly calcium phosphate crystals are adsorbed to the therapeutic material according to the present invention.
- the dialyzer used for dialysis treatment may be a hollow fiber type dialyzer or a laminated type (keel type) dialyzer.
- the material of the dialysis membrane that constitutes the dialyzer is not particularly limited.
- a sodium sulfonate copolymer can be used.
- a dialyzer using a dialysis membrane with large pores, called a high-performance membrane, can also be used.
- an adsorber containing the therapeutic agent of the present invention and a dialyzer are connected to a dialysis apparatus to treat blood.
- the dialyzer may be connected upstream or downstream of the adsorber.
- the present inventors found that although the blood phosphorus concentration can be reduced by a single dialysis, the blood phosphorus concentration after each dialysis may gradually increase over the long term even if dialysis is repeated continuously. I found something. The reason for this is that, as schematically shown in FIG. 1, phosphorus in blood is mainly the sum of phosphate that is not bound to protein and phosphate that is bound to protein. Phosphoric acid that can pass through the dialysis membrane can be removed by dialysis, whereas CPP, which is larger than the pores of the dialysis membrane, cannot be removed by dialysis and therefore remains in the blood even after dialysis.
- CPP may be formed from phosphoric acid, and the blood phosphorus concentration tends to gradually increase over the long term.
- the in vivo metabolism of phosphorus is improved by removing phosphoric acid and CPP at the same time, and the blood phosphorus concentration is stabilized and effectively. It is conceivable that it can be reduced.
- the blood phosphorus concentration can be measured by a conventional method.
- a plasma sample or serum sample is prepared from a blood sample by centrifugation or the like, and measured by the PNP-XDH method or molybdic acid direct method. That is, blood phosphorus concentration specifically refers to plasma phosphorus concentration or serum phosphorus concentration.
- PNP/XDH method hypoxanthine is produced from inorganic phosphorus in a sample by the action of purine nucleoside phosphorylase (PNP) in the presence of inosine, and xanthine is produced from this hypoxanthine and oxidized nicotinamide adenine dinucleotide (NAD).
- PNP purine nucleoside phosphorylase
- Xanthine and reduced nicotinamide adenine dinucleotide are produced by the action of dehydrogenase (XDH), and uric acid is produced from xanthine and oxidized nicotinamide adenine dinucleotide (NAD) by the action of xanthine dehydrogenase (XDH). and reduced nicotinamide adenine dinucleotide (NADH), and measuring the absorbance at 340 nm, which is the maximum absorption wavelength of NADH, to determine the concentration of inorganic phosphorus in the sample.
- inorganic phosphorus in a sample is combined with molybdate to form phosphomolybdic acid, and the absorbance in the ultraviolet region derived from phosphomolybdic acid is measured to measure the concentration of inorganic phosphorus.
- the frequency of blood treatment according to the present invention may be appropriately adjusted according to the patient's symptoms, severity, age, sex, etc. For example, once or more and 5 times or less per week, 1 hour per treatment 8 hours or less.
- CPPs in blood are adsorbed by permeating dialysis-treated blood through the therapeutic material according to the present invention, or CPPs in the blood are adsorbed by permeating blood through the therapeutic material according to the present invention.
- dialysis treatment of the blood later, the blood phosphorus concentration can be effectively reduced, and as a result, it becomes possible to treat diseases whose symptoms are relieved or cured by reducing the blood phosphorus concentration.
- Diseases whose symptoms are relieved or treated by reducing blood phosphorus levels include, for example, cardiac hypertrophy, sarcopenia, emphysema, thymic atrophy, adipose tissue atrophy, dementia, frailty, growth failure, cutaneous pruritus, and cardiac valves. disease, secondary hyperparathyroidism, disorders of bone metabolism such as osteoporosis, and calciphylaxis.
- heart failure is the leading cause of death for hemodialysis patients in Japan
- cerebrovascular disease such as cerebral hemorrhage or cerebral hemorrhage.
- Gastrointestinal diseases caused by hemodialysis include gastritis, gastric ulcer, and duodenal ulcer. Pneumonia is also suspected to be related to dialysis.
- blood treatment with the therapeutic agent according to the present invention can prevent heart failure, cerebrovascular disease, pneumonia, and gastrointestinal diseases caused by hemodialysis.
- inhibiting means preventing, treating and/or alleviating the symptoms of the above diseases caused by hemodialysis.
- the therapeutic material according to the present invention can be used for blood treatment by, for example, filling a column included in a therapeutic means such as a hemodialysis machine.
- Example 1 (1) Preparation of CPP adsorption column After adding an alkaline aqueous solution to 970 mL of porous cellulose beads (exclusion limit molecular weight: 5,000,000; particle size: 400 to 500 ⁇ m) to make the total volume 1,494 mL, 534 mL of epichlorohydrin was added. and reacted at 40° C. for 2 hours. After the reaction, the beads were thoroughly washed with water to obtain epoxidized cellulose beads. Alendronate sodium aqueous solution was added to the obtained epoxidized cellulose beads, and the mixture was shaken at 50° C. for 5 hours or more.
- adsorbent A alendronate-immobilized cellulose beads
- Sulfuric acid and nitric acid were added to the dried adsorbent A
- pressure acid decomposition was performed with a microwave decomposition apparatus, and the P element content of the solution obtained by the ICP-AES method was measured.
- the immobilized amount of alendronic acid was 6 ⁇ mol/mL from the results of elemental analysis.
- a citric acid buffer was added to 100 mL of the adsorbent A in a dry state, and a 100 mL column was filled with the adsorbent A in a suspended state to prepare a CPP adsorption column.
- a ventilator PRO-Vmk II manufactured by Acoma Medical Industry Co., Ltd.
- a blood pressure measurement catheter (“Medicut LCV-UK kit” manufactured by Nippon Covidien, size: 16G, length: 70 cm) was filled with heparinized saline (about 10 units/mL), and the right aortic limb or left From the aortic side limb, the tip was inserted to reach the abdominal aorta. The other end was passed subcutaneously to reach the midline of the back and exposed to the outside of the body.
- a dialysis catheter (“Blood Access UK-Catheter Kit” manufactured by Nipro, cannula outer diameter: 12 Fr) was filled with heparinized saline (approximately 10 units/mL) and inserted into the neck.
- the abdomen was incised, the kidney was detached, the ureter, renal vein and renal artery were ligated, and the kidney was removed.
- a JMS hydrophilic Foley catheter (16 Fr, manufactured by JMS) was inserted into the body of the stomach and fixed to the stomach by a purse-string suture. The other end came out of the abdomen and was fixed to the skin. The skin was then sutured.
- the above CPP adsorption column was used, and blood was passed through the CPP adsorption column instead of the dialyzer under the same conditions as above.
- the CPP adsorption treatment + dialysis treatment group the CPP adsorption column immediately before use was washed with 1 L of physiological saline containing 2000 units/L of levaheparin injection, placed upstream of the dialyzer, and blood was collected under the same conditions as above. Passed through a CPP adsorption column and a dialyzer.
- the evaluation was completed only after the first treatment, two days after nephrectomy.
- heart failure and gastric ulcer were also observed.
- no pigs died suddenly in the CPP adsorption treatment + dialysis treatment group so treating blood with the therapeutic agent according to the present invention may suppress heart failure and gastrointestinal diseases due to dialysis treatment.
- Plasma phosphorus concentrations before and after CPP adsorption treatment are shown in FIG. 3(1), and plasma phosphorus concentrations before and after dialysis treatment and before and after CPP adsorption treatment+dialysis treatment are shown in FIG. 3(2).
- the results shown in FIG. 3 indicate that the dialysis treatment can reduce the plasma phosphorus concentration, while the CPP adsorption treatment can hardly reduce the plasma phosphorus concentration. From FIG. 1, it is expected that the removal of CPP will shift the equilibrium to the right and lower the plasma phosphorus concentration, but the removal of CPP alone does not lower the plasma phosphorus concentration.
- FIG. 4 shows changes over time in plasma phosphorus concentrations in the dialysis treatment group and the CPP adsorption treatment+dialysis treatment group.
- "*" indicates that a significant difference was recognized at p ⁇ 0.05 by the t-test.
- dialysis treatment alone continued to increase plasma phosphorus concentrations over time with intake of a high-phosphate diet.
- the initial plasma phosphorus concentration was the same as in the case of dialysis treatment alone, but there was a tendency to stabilize at a low level, and the plasma phosphorus concentration increased. Plasma phosphorus concentrations were significantly reduced compared to subsequent dialysis treatment alone.
- Example 2 (1) Preparation of CPP adsorption column Alendronate sodium aqueous solution was added to 530 mL of epoxidized porous cellulose beads (exclusion limit molecular weight: 30,000; particle size: 440 to 480 ⁇ m) and shaken at 70°C for 5 hours or more. Then, the beads were thoroughly washed with water to obtain alendronic acid-immobilized cellulose beads (adsorbent B). Sulfuric acid and nitric acid were added to the dried adsorbent B, pressure acid decomposition was performed with a microwave decomposition apparatus, and the P element content of the solution obtained by the ICP-AES method was measured.
- the immobilized amount of alendronic acid was 10 ⁇ mol/mL from the results of elemental analysis.
- Purified water was added to 100 mL of the above adsorbent B in a dry state, and the adsorbent B in a suspended state was filled in a 100 mL column to prepare a CPP adsorption column. For comparison, the same column was packed with epoxidized porous cellulose beads without immobilizing alendronic acid.
- the animals were fed after awakening, and on the day of dialysis, after treatment.
- the mice were fasted on the day of nephrectomy and the following day.
- tap water was freely taken as drinking water using an automatic water supply device.
- the adsorbent was removed from the column, and washed with heparin-containing Dulbecco-Voigt modified Eagle's minimum essential medium. 180 ⁇ L of EDTA solution was added to 0.10 g of adsorbent wet mass to elute the CPP adsorbed on the adsorbent.
- the eluate was subjected to polyacrylamide gel electrophoresis for protein size analysis.
- Example 1 shows that there is a correlation between the adsorption of CPP and the decrease in blood phosphorus concentration, and the water-insoluble carrier in Example 2 was able to adsorb CPP. It is believed that the water-insoluble carrier in Example 2 can lower blood phosphorus levels.
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Abstract
Description
しかし本発明者らは、カルシプロテインパーティクルを吸着するための吸着材では血中リン濃度をほとんど低減することはできず、また、透析でも血中リン濃度を十分に低減できない場合があることを見出した。詳しくは、単回の透析により血中リン濃度は確かに低減できるが、透析を継続的に繰り返しても、透析後における血中リン濃度は上昇し続ける。
そこで本発明は、血中リン濃度の低減により症状が緩和または治療される疾患の治療に用いられる治療材を提供することを目的とする。
本発明は、血中リン濃度の低減により症状が緩和または治療される疾患の治療に用いられる治療材に関する。
以下、本発明を示す。
上記吸着基がリンカー基を介して上記水不溶性担体に結合されており、
血中リン濃度の低減により症状が緩和または治療される疾患の治療に用いられる治療材であり、
透析処理を受けた血液を透過させることにより当該血液中のカルシプロテインパーティクルが上記吸着基に吸着されるように用いられるか、または、透過させた血液が透析処理されるように用いられることを特徴とする、血中リン濃度の低減により症状が緩和または治療される疾患の治療に用いられる治療材。
[2] 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、およびカルシフィラキシスから選択される1または2以上の疾患である上記[1]に記載の治療材。
[3] 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される1または2以上の疾患の抑制に用いられる上記[1]または[2]に記載の治療材。
[4] 上記リンカー基が、置換基を有していてもよい、C1-6アルカンジイル基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である上記[1]~[3]のいずれかに記載の治療材。
[5] 上記リンカー基に2以上のホスホン酸基が共有結合している上記[1]~[4]のいずれかに記載の治療材。
[6] 上記水不溶性担体が多孔質である上記[1]~[5]のいずれかに記載の治療材。
[7] 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である上記[6]に記載の治療材。
上記治療材が、水不溶性担体、並びに、リン酸基、ホスホン酸基、ホスフィン酸基、アミノ基、カルボキシ基、およびチオール基からなる群より選択される1以上の吸着基を有し、 上記吸着基がリンカー基を介して上記水不溶性担体に結合されており、
上記治療材が、透析処理を受けた血液を透過させることにより当該血液中のカルシプロテインパーティクルが上記吸着基に吸着されるように用いられるか、または、透過させた血液が透析処理されるように用いられることを特徴とする使用。
[9] 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、およびカルシフィラキシスから選択される1または2以上の疾患である上記[8]に記載の使用。
[10] 上記リンカー基が、置換基を有していてもよい、C1-6アルカンジイル基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である上記[8]または[9]に記載の使用。
[11] 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される1または2以上の疾患を抑制するための上記[8]~[10]のいずれかに記載の使用。
[12] 上記リンカー基に2以上のホスホン酸基が共有結合している上記[8]~[11]のいずれかに記載の使用。
[13] 上記水不溶性担体が多孔質である上記[8]~[12]のいずれかに記載の使用。
[14] 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である上記[13]に記載の使用。
血液を治療材で処理し、且つ透析処理に付す工程を含み、
上記治療材が、水不溶性担体、並びに、リン酸基、ホスホン酸基、ホスフィン酸基、アミノ基、カルボキシ基、およびチオール基からなる群より選択される1以上の吸着基を有し、
上記吸着基がリンカー基を介して上記水不溶性担体に結合されていることを特徴とする方法。
[16] 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、またはカルシフィラキシスである上記[15]に記載の方法。
[17] 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される1または2以上の疾患を抑制する上記[16]に記載の方法。
[18] 上記リンカー基が、置換基を有していてもよい、C1-6アルカンジイル基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である上記[15]に記載の方法。
[19] 上記リンカー基に2以上のホスホン酸基が共有結合している上記[15]に記載の方法。
[20] 上記水不溶性担体が多孔質である上記[15]に記載の方法。
[21] 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である上記[20]に記載の方法。
上記治療材が、水不溶性担体、並びに、リン酸基、ホスホン酸基、ホスフィン酸基、アミノ基、カルボキシ基、およびチオール基からなる群より選択される1以上の吸着基を有し、
上記吸着基がリンカー基を介して上記水不溶性担体に結合されており、
上記治療材が、透析処理を受けた血液を透過させることにより当該血液中のカルシプロテインパーティクルが上記吸着基に吸着されるように用いられるか、または、透過させた血液が透析処理されるように用いられることを特徴とする使用。
[23] 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、およびカルシフィラキシスから選択される1または2以上の疾患である上記[22]に記載の使用。
[24] 上記リンカー基が、置換基を有していてもよい、C1-6アルカンジイル基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である上記[22]または[23]に記載の使用。
[25] 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される1または2以上の疾患を抑制するための上記[22]~[24]のいずれかに記載の使用。
[26] 上記リンカー基に2以上のホスホン酸基が共有結合している上記[22]~[25]のいずれかに記載の使用。
[27] 上記水不溶性担体が多孔質である上記[22]~[26]のいずれかに記載の使用。
[28] 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である上記[27]に記載の使用。
(1)CPP吸着カラムの作製
多孔質セルロースビーズ(排除限界分子量:5,000,000;粒径:400~500μm)970mLにアルカリ性水溶液を加えて全容量を1,494mLにした後、エピクロルヒドリン534mLを加え、40℃で2時間反応させた。反応後、ビーズを水で十分洗浄してエポキシ化セルロースビーズを得た。得られたエポキシ化セルロースビーズにアレンドロン酸ナトリウム水溶液を加え50℃で5時間以上振盪した。その後、水で十分洗浄して、アレンドロン酸固定セルロースビーズ(吸着材A)を得た。乾燥させた吸着材Aに硫酸と硝酸を加えてマイクロウェーブ分解装置で加圧酸分解を行い、ICP-AES法により得られた溶液のP元素の含有量測定を行った。アレンドロン酸の固定化量は元素分析の結果から6μmol/mLであった。
乾燥状態の上記吸着材A100mLにクエン酸バッファーを加え、吸着剤Aを懸濁状態で100mL容のカラムに充填してCPP吸着カラムを作製した。
8~12週齢、体重23.2~31.9kgのミニブタ15匹を、透析処理群7匹、CPP吸着処理群4匹、およびCPP吸着処理+透析処理群4匹に任意に分けた。
アトロピン硫酸塩0.05mg/kg、塩酸メデトミジン0.05mg/kg、およびミタゾラム0.5mg/kgをミニブタの頸背部筋肉内に投与することにより沈静化させた後、人工呼吸器(「PRO-Vmk II」アコマ医科工業社製)を使って10~15mL/kg、18~22回分の条件で呼吸させつつ、吸入麻酔器(「Vigor21 II DX」アコマ医科工業社製)を使ってN2O:O2=1:1の混合ガス-0.5~1.5%イソフルランの条件下でミニブタを麻酔し、頭部と腹部を毛刈した。血圧測定用カテーテル(「メディカットLCV-UKキット」日本コヴィディエン社製,サイズ:16G,長さ:70cm)の内部をヘパリン加生理食塩水(約10unit/mL)で満たし、右大動脈側肢または左大動脈側肢より、先端部を腹部大動脈へ到達させるだけの長さを挿入した。他端は、皮下を通して背部正中部に到達させ、体外へ露出させた。
次いで、透析カテーテル(「ブラッドアクセス UK-カテーテルキット」ニプロ社製,カニューレ外径:12Fr)内をヘパリン加生理食塩水(約10unit/mL)で満たし、頸部へ挿入した。腹部を切開し、腎臓を剥離して、尿管、腎静脈、腎動脈を結索し、腎臓を摘出した。胃体部にJMS親水性フォーリーカテーテル(16Fr,ジェイ・エム・エス社製)を挿入して、巾着縫合して胃に固定した。他端は腹部から出し、皮膚に固定した。その後、皮膚を縫合した。
腎不全モデル動物を測定ゲージに入れ、ブラッドアクセスカテーテルを個人用透析装置(「NCU-12」と「NCV-10」ニプロ社製)に接続した。
覚醒後、透析処理群では、ダイアライザー(「中空糸透析器FB-90P β ECO」ニプロ社製,膜面積:0.9m2)を用い、腎臓摘出手術より2日後から2日に1回、150mL/minの血液流量で抜き出した血液をそのまま体内へ5時間循環させ、透析を行った。
CPP吸着処理群では、上記CPP吸着カラムを用い、上記と同様の条件で血液をダイアライザーの代わりにCPP吸着カラムに通した。
CPP吸着処理+透析処理群では、使用直前のCPP吸着カラムを、レバヘパリン注射液2000unit/Lを添加した生理食塩水1Lで洗浄し、ダイアライザーの上流側に設置し、上記と同様の条件で血液をCPP吸着カラムとダイアライザーに通した。
実験期間中、高リン食(MP1.2倍P特注飼料,オリエンタル酵母社製)200gと普通固型飼料(NS,日生研社製)200gを混合し、16:00~18:00に給餌した。但し、カテーテル植え込み手術日は覚醒後に、透析日には処理後に給餌した。また、腎臓摘出日とその翌日は絶食させた。また、自動給水装置を用い、飲料水として水道水を自由に摂取させた。
腎摘出から2日後に、実験動物から抜き出した血液と、処理後の血液における血漿リン濃度を測定した。具体的には、ヘパリンNa処理真空採血管に血液を採取し、遠心分離して血漿を得、生化学自動分析装置(「AU480」ベックマン・コールター社製)を用い、PNP・XDH法により血漿中のリン濃度を測定した。透析処理群とCPP吸着処理+透析処理群では、腎摘出から6日後、14日後、22日後、および28日後にも、実験動物から抜き出した血液と、処理後の血液における血漿リン濃度を測定した。
腎摘出手術から30日後までに、透析処理群では7匹中4匹が、CPP吸着処理+透析処理群では4匹中4匹が生存した。なお、CPP吸着処理群については、腎摘出後2日後にあたる1回目の処理のみで評価を終了した。また、透析処理群における突然死の原因を調べたところ心不全であり、胃潰瘍も認められた。一方、CPP吸着処理+透析処理群では突然死したブタはいなかったことから、本発明に係る治療剤で血液を処理することにより、透析処理による心不全や消化器疾患を抑制できる可能性がある。
CPP吸着処理前後における血漿リン濃度を図3(1)に、透析処理前後およびCPP吸着処理+透析処理前後における血漿リン濃度を図3(2)に示す。
図3に示される結果の通り、透析処理により血漿リン濃度を低減することができる一方で、CPP吸着処理では血漿リン濃度をほとんど低減できないことが示された。なお、図1からは、CPPを除去することで平衡が右へ進み、血漿リン濃度が低下することが予想されるが、CPPを除去するだけでは血漿リン濃度は低下していない。
図4に示される結果の通り、透析処理のみでは、高リン酸食の摂取により血漿リン濃度は経時的に上昇し続けた。
それに対してCPP吸着処理に加えて透析処理を行った場合には、当初の血漿リン濃度は透析処理のみの場合と同様であったが、低く安定化する傾向があり、血漿リン濃度が上昇し続ける透析処理のみの場合に比べて、血漿リン濃度が有意に低減された。
上記結果の理由としては、血液を透析処理とCPP吸着処理の両方に付すことにより、タンパク質に結合していないリン酸とタンパク質に結合しているリン酸を同時に除去することで、リンの生体内代謝が改善され、血中リン濃度を安定的かつ有効に低減できたことが考えられる。
以上より、透析処理とCPP吸着材による血液処理とを組み合わせることで、血中のリン酸を効果的に低減することができることが示された。
(1)CPP吸着カラムの作製
エポキシ化多孔質セルロースビーズ(排除限界分子量:30,000;粒径:440~480μm)530mLにアレンドロン酸ナトリウム水溶液を加え、70℃で5時間以上振盪した。その後、水で十分洗浄してアレンドロン酸固定セルロースビーズ(吸着材B)を得た。乾燥させた吸着材Bに硫酸と硝酸を加えてマイクロウェーブ分解装置で加圧酸分解を行い、ICP-AES法により得られた溶液のP元素の含有量測定を行った。アレンドロン酸の固定化量は、元素分析の結果から10μmol/mLであった。
乾燥状態の上記吸着材B100mLに精製水を加え、吸着剤Bを懸濁状態で100mL容のカラムに充填してCPP吸着カラムを作製した。比較のために、アレンドロン酸を固定化しないエポキシ化多孔質セルロースビーズ自体を同カラムに充填した。
実施例1と同様にして腎不全モデル動物2匹を作製し、ブラッドアクセスカテーテルを個人用透析装置(「NCU-12」と「NCV-10」ニプロ社製)に接続した。使用直前の前記CPP吸着カラムまたは担体のみを充填したカラムを、レバヘパリン注射液2000unit/Lを添加した生理食塩水1Lで洗浄して透析装置に設置し、腎臓摘出手術から2日後に、150mL/minの血液流量で抜き出した血液をそのまま5時間循環させた。
実験期間中、高リン食(MP1.2倍P特注飼料,オリエンタル酵母社製)200gと普通固型飼料(NS,日生研社製)200gを混合し、16:00~18:00に給餌した。但し、カテーテル植え込み手術日は覚醒後に、透析日には処理後に給餌した。また、腎臓摘出日とその翌日は絶食させた。また、自動給水装置を用い、飲料水として水道水を自由に摂取させた。
生理食塩水で返血を終了したカラムから吸着材を取り出し、ヘパリン含ダルベッコ・フォークト変法イーグル最小必須培地で吸着材を洗浄した。吸着材湿潤質量0.10gにEDTA溶液180μLを加えて、吸着材に吸着されたCPPを溶出した。溶出液をポルアクリルアミドゲル電気泳動に供して、タンパク質サイズの分析を行った。結果を図5に示す。
図5に示される結果の通り、水不溶性担体の排除限界分子量が30,000であり、CPPよりも小さい多孔度の不溶性担体ではCPPを吸着できなかったのに対して、同じ不溶性担体を含むCPP吸着材であっても、CPPを吸着できることが確認できた。
また、実施例1により、CPPの吸着と血中リン濃度の低下には相関関係にあることが示されており、且つ実施例2における水不溶性担体がCPPを吸着することができたことから、実施例2における水不溶性担体は血中リン濃度を低下することができると考えられる。
Claims (21)
- 水不溶性担体、並びに、リン酸基、ホスホン酸基、ホスフィン酸基、アミノ基、カルボキシ基、およびチオール基からなる群より選択される1以上の吸着基を有し、
上記吸着基がリンカー基を介して上記水不溶性担体に結合されており、
血中リン濃度の低減により症状が緩和または治療される疾患の治療に用いられる治療材であり、
透析処理を受けた血液を透過させることにより当該血液中のカルシプロテインパーティクルが上記吸着基に吸着されるように用いられるか、または、透過させた血液が透析処理されるように用いられることを特徴とする、血中リン濃度の低減により症状が緩和または治療される疾患の治療に用いられる治療材。 - 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、およびカルシフィラキシスから選択される1または2以上の疾患である請求項1に記載の治療材。
- 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される2以上の疾患の抑制に用いられる請求項2に記載の治療材。
- 上記リンカー基が、置換基を有していてもよい、C1-6炭化水素基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である請求項1に記載の治療材。
- 上記リンカー基に2以上のホスホン酸基が共有結合している請求項1に記載の治療材。
- 上記水不溶性担体が多孔質である請求項1に記載の治療材。
- 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である請求項6に記載の治療材。
- 血中リン濃度の低減により症状が緩和または治療される疾患を治療するための治療材の使用であって、
上記治療材が、水不溶性担体、並びに、リン酸基、ホスホン酸基、ホスフィン酸基、アミノ基、カルボキシ基、およびチオール基からなる群より選択される1以上の吸着基を有し、
上記吸着基がリンカー基を介して上記水不溶性担体に結合されており、
上記治療材が、透析処理を受けた血液を透過させることにより当該血液中のカルシプロテインパーティクルが上記吸着基に吸着されるように用いられるか、または、透過させた血液が透析処理されるように用いられることを特徴とする使用。 - 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、およびカルシフィラキシスから選択される1または2以上の疾患である請求項8に記載の使用。
- 上記リンカー基が、置換基を有していてもよい、C1-6アルカンジイル基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である請求項8または9に記載の使用。
- 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される1または2以上の疾患を抑制するための請求項8~10のいずれかに記載の使用。
- 上記リンカー基に2以上のホスホン酸基が共有結合している請求項8~11のいずれかに記載の使用。
- 上記水不溶性担体が多孔質である請求項8~12のいずれかに記載の使用。
- 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である請求項13に記載の使用。
- 血中リン濃度の低減により症状が緩和または治療される疾患を治療するための方法であって、
血液を治療材で処理し、且つ透析処理に付す工程を含み、
上記治療材が、水不溶性担体、並びに、リン酸基、ホスホン酸基、ホスフィン酸基、アミノ基、カルボキシ基、およびチオール基からなる群より選択される1以上の吸着基を有し、
上記吸着基がリンカー基を介して上記水不溶性担体に結合されていることを特徴とする方法。 - 上記疾患が、心肥大、サルコペニア、肺気腫、胸腺の萎縮、脂肪組織の萎縮、認知症、フレイル、成長障害、皮膚掻痒症、心臓弁膜症、二次性副甲状腺機能亢進症、骨代謝異常、またはカルシフィラキシスである請求項15に記載の方法。
- 更に、心不全、脳血管障害、肺炎、および消化器疾患から選択される1または2以上の疾患を抑制する請求項16に記載の方法。
- 上記リンカー基が、置換基を有していてもよい、C1-6アルカンジイル基、エーテル基、チオエーテル基、アミノ基、カルボニル基、チオニル基、エステル基、アミド基、ウレア基、チオウレア基、ポリアルキレングリコール基、ポリビニルアルコール基、または、2以上、5以下のこれら基が連結された基である請求項15に記載の方法。
- 上記リンカー基に2以上のホスホン酸基が共有結合している請求項15に記載の方法。
- 上記水不溶性担体が多孔質である請求項15に記載の方法。
- 上記水不溶性担体の排除限界分子量が1,000以上、10,000,000以下である請求項20に記載の方法。
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