WO2011052765A1 - Atténuateur de troubles rénaux provoqués par l'administration d'un médicament contenant du platine - Google Patents

Atténuateur de troubles rénaux provoqués par l'administration d'un médicament contenant du platine Download PDF

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Publication number
WO2011052765A1
WO2011052765A1 PCT/JP2010/069395 JP2010069395W WO2011052765A1 WO 2011052765 A1 WO2011052765 A1 WO 2011052765A1 JP 2010069395 W JP2010069395 W JP 2010069395W WO 2011052765 A1 WO2011052765 A1 WO 2011052765A1
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cisplatin
agent
infusion
administration
reducing
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PCT/JP2010/069395
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English (en)
Japanese (ja)
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純子 山下
幸史 國場
賢太 梶原
英樹 堂本
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味の素株式会社
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Priority to JP2011538515A priority Critical patent/JP6164719B2/ja
Publication of WO2011052765A1 publication Critical patent/WO2011052765A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a preventive or alleviating agent for renal damage, which is a side effect caused by administration of a drug containing platinum represented by cisplatin (cis-diamine dichloroplatinum (II), CDDP). More specifically, the present invention relates to the prevention or alleviation of the renal injury by an infusion solution containing bicarbonate ions. In addition, the present invention relates to a preventive or alleviating agent for renal injury, in which N-acetylcysteine is further combined with an infusion solution containing bicarbonate ions.
  • cisplatin Platinum-containing drugs represented by cisplatin are used as anticancer agents effective for testicular tumors, bladder cancer, renal pelvis / ureteral tumors and the like.
  • cisplatin is known to have serious side effects, particularly renal dysfunction, and this side effect greatly impairs its usefulness as a dose limiting factor for cancer treatment.
  • the mechanism of renal dysfunction caused by cisplatin administration is still unclear and has not been clarified in detail, histopathologically it is proximal tubule injury and takes the form of acute tubular necrosis .
  • serum urea nitrogen and creatinine are increased in response to renal dysfunction, which is a major problem.
  • Non-Patent Document 1 In order to reduce renal damage caused by cisplatin, forced diuresis by hydration using an appropriate infusion solution is generally used, and diuretics such as mannitol or furosemide may be used in combination.
  • diuretics such as mannitol or furosemide may be used in combination.
  • Non-Patent Document 1 These treatments are thought to cause a decrease in cisplatin concentration in renal tissue and a decrease in contact time between cisplatin and tubular epithelium.
  • the main infusion used for the water load for reducing this cisplatin-induced drug-induced renal injury is a physiological saline, and the use of an infusion containing bicarbonate ions is not known.
  • Non-patent Document 2 shows that urine pH and urinary excretion of platinum after cisplatin administration are high in rats that had previously been given free drinking of sodium bicarbonate-containing water, but no improvement in renal damage was observed. It has been reported.
  • Non-Patent Document 3 reports that the renal protection effect of diuretics against cisplatin administration, which is observed incompletely, is not the result of increased platinum urinary excretion. Has been. In general, the relationship between platinum urine excretion and kidney damage reduction is not clear.
  • Non-patent Document 4 Non-patent Document 4
  • urinastatin Patent Document 1
  • an extract of Kamizo Harukasan Patent Document 2
  • N-acetylcysteine is used in combination with the above-mentioned water load treatment, contained in a water load infusion solution, or used in combination with an infusion solution containing bicarbonate ions. None have been reported.
  • an object of the present invention is to provide a drug for reducing renal damage caused by a platinum-containing drug represented by cisplatin. It is.
  • the present invention provides the following (1) to (12).
  • An agent for reducing renal damage caused by administration of a platinum-containing drug which is an infusion solution containing bicarbonate ions.
  • the agent for reducing renal injury, wherein the platinum-containing drug is cisplatin.
  • the above-mentioned renal injury reducing agent which is an infusion solution for water load.
  • the agent for reducing renal damage which is an infusion solution further containing magnesium ions.
  • the said renal disorder reducing agent which is an infusion which further contains sodium ion, chloride ion, potassium ion, and calcium ion.
  • the above-mentioned renal injury reducing agent which is an infusion solution having a bicarbonate Ringer's solution composition.
  • the agent for reducing renal injury which is an infusion solution further containing glucose.
  • the above-mentioned renal injury reducing agent which is an infusion solution having a bicarbonate ion concentration of 15 to 35 mEq / L.
  • the agent for reducing renal damage which is further combined with N-acetylcysteine.
  • the present invention also provides a method for reducing renal damage caused by administration of a platinum-containing drug, comprising administering the above-mentioned agent for reducing renal damage to a subject in need of reduction or prevention of renal damage caused by administration of the platinum-containing drug.
  • the present invention also includes administration of an infusion solution containing bicarbonate ions to a subject in need of reduction or prevention of renal damage caused by administration of a platinum-containing drug, Provide mitigation methods.
  • the present invention also provides the use of an infusion solution containing bicarbonate ions for the manufacture of an agent for reducing renal damage caused by administration of a platinum-containing drug.
  • the agent for reducing renal damage caused by administration of a platinum-containing drug of the present invention which is an infusion solution containing bicarbonate ions, remarkably reduces renal dysfunction, which is a side effect of a platinum-containing drug (particularly cisplatin).
  • the infusion solution characterized by containing bicarbonate ions further reduces the kidney damage more significantly by combining with N-acetylcysteine.
  • FIG. 3 shows plasma urea nitrogen in the rat model of cisplatin-induced drug-induced renal injury of Example 1.
  • Day 0 indicates before water load
  • Day 4 and 5 indicate 4 and 5 days after cisplatin administration date, respectively. From the left, the results of 1 group (cisplatin, no water load), 2 groups (cisplatin + water load by physiological saline), and 3 groups (cisplatin + water load by bicarbon (registered trademark) infusion) are shown, respectively.
  • 1 group cisplatin, no water load
  • 2 groups cisplatin + water load by physiological saline
  • 3 groups cisplatin + water load by bicarbon (registered trademark) infusion
  • FIG. 3 is a diagram showing blood pH in a rat model of cisplatin-induced drug-induced renal injury of Example 1. Pre-hydration indicates before the start of moisture load, and Post-hydration indicates the end of moisture load. The results of group 1 (cisplatin, no water load), group 2 (cisplatin + water load with physiological saline), and group 3 (water load with cisplatin + bicarbon (registered trademark) infusion) are shown. * P ⁇ 0.05 Student's t-test It is a figure which shows the renal tissue disorder level scored in the histopathological examination of Example 2. FIG. The tissue score indicates the scored renal tissue damage level, and the larger the value, the greater the damage to the kidney tissue.
  • FIG. 4 shows plasma creatinine in the rat model of cisplatin-induced nephropathy of Example 3. Day 0 indicates before water load, and Day 4 and 5 indicate 4 and 5 days after cisplatin administration date, respectively.
  • the platinum-containing drug is a platinum complex chemotherapeutic agent typified by cisplatin, and includes, for example, cisplatin, carboplatin, nedaplatin, and oxaliplatin, with cisplatin and nedaplatin being preferred, and cisplatin being particularly preferred.
  • the agent for reducing renal damage caused by administration of a platinum-containing drug includes a preventive or therapeutic agent for renal dysfunction caused by administration of a platinum-containing drug.
  • the water load (hydration) is water replenishment and is to perform a larger amount of infusion for securing urine volume than in the case of maintenance infusion.
  • the infusion solution containing bicarbonate ions preferably contains an electrolyte that supplies bicarbonate ions (HCO 3 ⁇ , bicarbonate ions).
  • the electrolyte that supplies bicarbonate ions include sodium bicarbonate (sodium bicarbonate), calcium bicarbonate, potassium bicarbonate, and ammonium bicarbonate. Sodium bicarbonate is particularly preferable.
  • the infusion solution of the present invention can further contain one or more different electrolytes as required.
  • Examples of the electrolyte contained in the infusion solution of the present invention include sodium ion (Na + ), chloride ion (Cl ⁇ ), magnesium ion (Mg 2+ ), potassium ion (K + ), calcium ion (Ca 2+ ), Examples thereof include water-soluble salts that supply ions such as phosphate ions (more specifically, hydrogen phosphate ions (HPO 4 2 ⁇ ) or dihydrogen phosphate ions (H 2 PO 4 ⁇ )).
  • phosphate ions more specifically, hydrogen phosphate ions (HPO 4 2 ⁇ ) or dihydrogen phosphate ions (H 2 PO 4 ⁇ )
  • Examples of water-soluble salts that supply sodium ions include sodium chloride, sodium acetate, sodium citrate, sodium lactate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium glycerophosphate, sodium sulfate, and sodium bicarbonate.
  • sodium chloride, sodium bicarbonate, and sodium citrate are mentioned.
  • Examples of water-soluble salts that supply chloride ions include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.
  • Examples of the water-soluble salt for supplying magnesium ions include magnesium sulfate, magnesium chloride, magnesium acetate, and preferably magnesium chloride.
  • water-soluble salts that supply potassium ions include potassium chloride, potassium iodide, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium glycerophosphate, potassium sulfate, and potassium lactate.
  • potassium chloride is mentioned.
  • water-soluble salts that supply calcium ions include calcium chloride, calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate, and preferably calcium chloride.
  • water-soluble salts for supplying phosphate ions include sodium dihydrogen phosphate, disodium hydrogen phosphate, magnesium monohydrogen phosphate, magnesium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, Examples thereof include calcium monohydrogen phosphate and calcium dihydrogen phosphate.
  • a composition such as a hydrate can be used as an electrolyte contained in the infusion solution of the present invention.
  • the infusion solution containing bicarbonate ions preferably further contains one or more ions selected from the group consisting of sodium ions, potassium ions, calcium ions, magnesium ions, and chloride ions.
  • the infusion solution of the present invention contains all sodium ions, chloride ions, potassium ions, and calcium ions.
  • Ringer's solution refers to a physiological electrolyte solution having an ionic composition, osmotic pressure, and hydrogen ion concentration similar to that of an extracellular fluid that can be used for extracellular fluid replenishment.
  • the bicarbonate Ringer solution refers to a Ringer solution containing a bicarbonate as an alkalizing agent.
  • the infusion solution of the present invention preferably further contains glucose.
  • the infusion solution of the present invention may further contain a pH adjuster and the like.
  • the pH adjuster include acids such as hydrochloric acid, acetic acid, lactic acid, malic acid, succinic acid, and citric acid, and alkalis such as sodium hydroxide and potassium hydroxide. You may mix
  • the bicarbonate ion concentration is preferably 15 to 35 mEq / L, particularly preferably 20 to 30 mEq / L, and the pH is preferably 6 to 8, particularly 6.8 to 7.8. . In these cases, high chloroacidosis can be suitably prevented, which is preferable from the viewpoint of safety.
  • the infusion solution containing bicarbonate ions has the Ringer's solution composition
  • the following compositions and properties are preferred for the infusion of the present invention: Sodium ion: 128 to 143 mEq / L, preferably 130 to 140 mEq / L.
  • Potassium ion 3 to 5 mEq / L, preferably 3.5 to 4.5 mEq / L.
  • Calcium ion 2 to 4.5 mEq / L, preferably 2 to 4 mEq / L.
  • Magnesium ion 0.5 to 2 mEq / L, preferably 0.5 to 1.5 mEq / L.
  • Chlorine ion 100 to 125 mEq / L, preferably 103 to 123 mEq / L.
  • Bicarbonate ion 15 to 30 mEq / L, preferably 18 to 28 mEq / L.
  • Citrate ion (Citrate 3- ): 3 to 7 mEq / L, preferably 4 to 6 mEq / L. pH: 6 to 8, preferably 6.8 to 7.8. Osmotic pressure ratio (ratio to physiological saline): 0.9 to 2.0, preferably 0.9 to 1.0.
  • an infusion solution containing the above-described bicarbonate ion combined with N-acetylcysteine is preferred. In this case, the effect of reducing kidney damage is particularly enhanced.
  • N-acetylcysteine includes D-form, L-form, and mixtures thereof, and L-form is preferred.
  • the renal injury reducing agent may be, for example, a kit comprising a drug containing N-acetylcysteine and an infusion solution containing bicarbonate ion, but contains bicarbonate ion and N-acetylcysteine.
  • An infusion form is preferred.
  • the amount of bicarbonate ion is preferably 0.001 to 1.3, and more preferably 0.001 to 0.13, relative to the amount of N-acetylcysteine.
  • the N-acetylcysteine concentration is preferably 0.01 to 10 g / L in consideration of maintaining the anticancer effect of cisplatin, etc. 5 g / L is preferred.
  • the infusion solution containing bicarbonate ions further contains other electrolytes, etc., preparation at the time of use, a combination of two solutions of bicarbonate ion-containing solution and other electrolyte solutions, or a preparation filled with these in a two-chamber container
  • the one-component type is preferable from the viewpoint of convenience during use.
  • Such an infusion preparation can be produced, for example, according to the methods described in JP-A-9-124491 and JP-A-10-279488. Commercial products can also be purchased and used.
  • N-acetylcysteine becomes a separate preparation from an infusion containing bicarbonate ions
  • the form is not particularly limited, and is mixed as it is or with a pharmaceutically acceptable carrier, for example, a solid preparation such as a tablet, It can be administered orally or parenterally as a liquid agent such as an internal solution or an injection solution. Of these, intravenous administration as an injection solution is preferred.
  • the preparations of these dosage forms can be produced according to known preparation methods in the field using conventional preparation materials.
  • the agent for reducing renal injury of the present invention is used by being administered to a subject in connection with administration of a platinum-containing drug. More specifically, it is used as an infusion before administration of the platinum-containing drug, as a medium at the time of administration of the platinum drug, or as an infusion after administration of the platinum-containing drug to prevent or reduce renal damage.
  • renal damage is prevented or reduced by administration as a fluid load infusion in connection with cisplatin administration.
  • the dose and method vary depending on the age, weight, symptom level, etc. of the administration subject. Specifically, when the subject is an adult, for example, it is used as follows. (1) Before administration of cisplatin, 1,000 to 2,000 mL of the renal injury reducing agent of the present invention is administered over 4 hours or more.
  • N-acetylcysteine may be included in the infusion solution of the present invention, or may be separately administered orally or parenterally in connection with the infusion solution or cisplatin administration of the present invention.
  • the dose varies depending on the age, weight, symptom level, etc. of the administration subject, and for example, in the case of oral administration, it is 0.0001 mg / kg to 5 g / kg.
  • the present invention will be more specifically disclosed with reference to examples, but the present invention is not limited thereto.
  • Bicarbon (registered trademark) infusion used in the following examples is an infusion containing bicarbonate ions (extracellular fluid replenisher, Ringer's solution), has the following composition, and has a pH of 6.8. 7.8 and osmotic pressure ratio of 0.9 to 1.0.
  • composition In 500 mL contain: Sodium chloride 3.07g Potassium chloride 0.15g Calcium chloride hydrate 0.11g Magnesium chloride 0.051g Sodium bicarbonate 1.05g Sodium citrate hydrate 0.245g
  • the electrolyte concentration (mEq / L) is as follows: Na + 135 K + 4 Ca2 + 3 Mg2 + 1 Cl-113 HCO3-25 Citrate 3- 5
  • Example 1 In this example, in a rat model of cisplatin-induced nephropathy, the effect of bicarbon (registered trademark) infusion, which is an infusion containing bicarbonate ions, on the progression of nephropathy was verified in comparison with physiological saline. did.
  • Water load 3 groups: Cisplatin (5 mg / kg, iv), n 8, water load by bicarbon (registered trademark) infusion
  • Test method 7 weeks old male SD rats were pentobarbital after quarantine habituation After anesthesia with sodium (Somnopentyl (registered trademark), Kyoritsu Pharmaceutical Co., Ltd.), remove the hair on the right side of the neck and the upper back and operate with an external disinfectant (Isodyne (registered trademark) solution, Meiji Seika Co., Ltd.) Steiger et al.
  • Example 2 Histopathological examination The kidney used in Example 1 above was removed on day 5 of the test, the kidney was excised, hematoxylin and eosin-stained sections of the kidney were prepared, pathological examination was performed, and the renal tissue injury level was scored as follows. Turned into. The results are shown in FIG. Score 4 (advanced): Almost all (100%) of the extramedullary zone damaged by cisplatin is impaired. Score 3 (moderate): About 70% of the extramedullary zone is impaired. Score 2 (mild): 30 of the extramedullary zone.
  • Steiger Insert the catheter from the right external jugular vein according to indwelling catheters in the upper right vena cava proximal portion.
  • the surgical site was sutured after a small amount of antibiotics (penicillin G potassium, 20 units, Meiji Pharmaceutical Co., Ltd.) was dropped.
  • the catheter placement date was set to the third day. Animals were housed in a post-operative metabolic cage (Natsume Seisakusho) and habituated.
  • N-acetylcysteine was blended at a concentration such that it was continuously infused at 30 mg / kg / 3 h in the water load solutions of the third group and the fourth group. Thereafter, body weight, food intake, and urine volume were measured daily until 5 days after cisplatin administration. Blood was collected from CVC before water load (hydration) on the first day of the test and 4 or 5 days after the day of cisplatin administration, which was considered to have peaked the worsening of renal dysfunction, and plasma urea nitrogen and plasma creatinine The quantity was measured. (3) Results 1) Plasma creatinine (plasma Cre) The results are shown in FIG.
  • Example 4 Oxidative stress measurement In a rat model of cisplatin-induced drug-induced nephropathy, what effect bibicarbonate (registered trademark) infusion containing bicarbonate ions has on the oxidative stress associated with the progression of nephropathy, The d-ROMs (Diacron-Reactive Oxygen Metabolites) test value was used as an index indicating the degree of oxidative stress, and was evaluated in comparison with physiological saline. The d-ROMs test value can be used as an index for comprehensive evaluation of the oxidative stress state. For example, biological sample analysis Vol. 32, no. 4, p. 301_306, 2009.
  • the present invention is useful for reducing renal damage caused by cisplatin administration, and can make cancer treatment with a platinum-containing drug typified by cisplatin more effective.

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Abstract

Selon la présente invention, les troubles rénaux provoqués par l'administration d'un médicament contenant du platine tel que le cisplatine peuvent être atténués. En association avec l'administration d'un médicament contenant du platine, de l'humidité est chargée au moyen d'une solution de perfusion contenant de l'ion bicarbonate telle qu'une solution de Ringer au bicarbonate.
PCT/JP2010/069395 2009-10-27 2010-10-26 Atténuateur de troubles rénaux provoqués par l'administration d'un médicament contenant du platine WO2011052765A1 (fr)

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JP2011538515A JP6164719B2 (ja) 2009-10-27 2010-10-26 白金含有薬剤投与による腎障害の軽減剤

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014121323A (ja) * 2012-12-21 2014-07-03 Stembios Technologies Inc 幹細胞による行為効果を評価する方法
WO2018193648A1 (fr) * 2017-04-18 2018-10-25 国立大学法人東北大学 Procédé de purification du sang à l'aide d'un agent d'alcalinisation
US10143710B2 (en) 2010-08-04 2018-12-04 StemBios Technologies, Inc. Somatic stem cells
JPWO2018193648A1 (ja) * 2017-04-18 2020-02-27 国立大学法人東北大学 アルカリ性化剤による血液浄化
WO2020196381A1 (fr) * 2019-03-28 2020-10-01 株式会社大塚製薬工場 Perfusion pour administration sous-cutanée

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Chudoku Kanja no Yueki to Kyosei Ri'nyoho", MEDICAL PRACTICE, vol. 23, 2006, pages 373 - 378 *
"Prevention of contrast-induced nephropathy by hydration with sodium bicarbonate solution", SOGO RINSHO, vol. 58, 10 April 2009 (2009-04-10), pages 186 - 191 *
EUROPEAN JOURNAL OF CANCER, vol. 44, 2008, pages 2608 - 2614 *
J CARDIOL, vol. 50, no. 2, 2007, pages 119 - 126 *
ONCOLOGY REPORTS, vol. 10, 2003, pages 851 - 857 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10143710B2 (en) 2010-08-04 2018-12-04 StemBios Technologies, Inc. Somatic stem cells
JP2014121323A (ja) * 2012-12-21 2014-07-03 Stembios Technologies Inc 幹細胞による行為効果を評価する方法
WO2018193648A1 (fr) * 2017-04-18 2018-10-25 国立大学法人東北大学 Procédé de purification du sang à l'aide d'un agent d'alcalinisation
JPWO2018193648A1 (ja) * 2017-04-18 2020-02-27 国立大学法人東北大学 アルカリ性化剤による血液浄化
JP7219898B2 (ja) 2017-04-18 2023-02-09 国立大学法人東北大学 アルカリ性化剤による血液浄化
JP2023022079A (ja) * 2017-04-18 2023-02-14 国立大学法人東北大学 アルカリ性化剤による血液浄化
JP7525868B2 (ja) 2017-04-18 2024-07-31 国立大学法人東北大学 アルカリ性化剤による血液浄化
WO2020196381A1 (fr) * 2019-03-28 2020-10-01 株式会社大塚製薬工場 Perfusion pour administration sous-cutanée
CN113646043A (zh) * 2019-03-28 2021-11-12 株式会社大塚制药工场 皮下给药用输液
JP7442206B2 (ja) 2019-03-28 2024-03-04 株式会社大塚製薬工場 皮下投与用輸液

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