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WO2001015723A1 - Medicaments pour la prevention ou le traitement de lesions ischemiques ou de lesions de reperfusion ischemique - Google Patents

Medicaments pour la prevention ou le traitement de lesions ischemiques ou de lesions de reperfusion ischemique Download PDF

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Publication number
WO2001015723A1
WO2001015723A1 PCT/JP2000/005974 JP0005974W WO0115723A1 WO 2001015723 A1 WO2001015723 A1 WO 2001015723A1 JP 0005974 W JP0005974 W JP 0005974W WO 0115723 A1 WO0115723 A1 WO 0115723A1
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WO
WIPO (PCT)
Prior art keywords
ischemia
injury
reperfusion
ischemic
reperfusion injury
Prior art date
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Ceased
Application number
PCT/JP2000/005974
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English (en)
Japanese (ja)
Inventor
Nobuo Sakurakawa
Takuro Mitsuzaki
Go Watanabe
Yasuhiro Uozaki
Minoru Tsukada
Yoshifumi Kubo
Hajime Ebisu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Mitsubishi Pharma Corp
Welfide Corp
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Application filed by Mitsubishi Pharma Corp, Welfide Corp filed Critical Mitsubishi Pharma Corp
Priority to AU68691/00A priority Critical patent/AU6869100A/en
Publication of WO2001015723A1 publication Critical patent/WO2001015723A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • 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 prophylactic or therapeutic agent for ischemic injury or ischemia-reperfusion injury, comprising heparin cofactor II (hereinafter referred to as “H C II”) as an active ingredient.
  • H C II heparin cofactor II
  • This ischemia-reperfusion injury occurs not only in the heart but also after reperfusion of organ tissues that have been subjected to ischemia in various organs, such as when blood flow is stopped during transplantation of organs including blood vessels and resumed. Is also a problem. Therefore, it is known to occur not only in the heart but also in many tissues such as the brain, kidney, liver, lung, knee, and digestive tract.
  • HC II like antithrombin III (hereinafter referred to as " ⁇ "), is an important anticoagulant protein existing in the body (Matsuo et al .: Biomedical Perspectives, 2, 269-274 (1993)). According to acrylamide gel electrophoresis (SDS-PAGE) analysis, it is a single-chain plasma glycoprotein with a molecular weight of 72 kDa (Dougls M. Tollfsen et al .: J. Biol. Chemistry, 257, 2167-2169 (1982)). . As the physiological function of HCII, it is known that it inhibits thrombin and other proteases.
  • HCII is also effective for the treatment of a disease caused by enhanced dysfunction of in vivo cells such as macrophages even when administered locally for the disease (Japanese Patent Application No. No. 191977).
  • HCII has a blood pressure lowering inhibitory action, and in particular, is useful as a preventive or therapeutic agent for blood pressure lowering because it suppresses blood pressure lowering caused by endotoxin shock.
  • Japanese Patent Application No. 11-93447 Japanese Patent Application No. 11-93447.
  • HCII when formulated as an active ingredient, its usefulness as a drug is considered.
  • An object of the present invention is to provide a novel prophylactic or therapeutic agent for ischemic injury or ischemia-reperfusion injury, and to provide a new pharmaceutical use of HCII.
  • the present inventors have conducted various studies in order to solve the above-mentioned problems, and as a result, have found that HCII has an effect of preventing or treating ischemia injury or ischemia-reperfusion injury, especially for ischemic heart disease.
  • the present inventors have found that the present invention is useful for prevention or treatment of ischemic injury or ischemia-reperfusion injury, and have completed the present invention. That is, the present invention is as follows.
  • a prophylactic or therapeutic agent for ischemic injury or ischemia-reperfusion injury comprising heparin cofactor II as an active ingredient.
  • the prophylactic or therapeutic agent according to the above (1) which is a preventive or therapeutic agent for ischemia-reperfusion injury.
  • a method for preventing or treating ischemic injury or ischemia reperfusion injury which comprises the step of administering heparin cofactor-1 II to a patient.
  • a method for preventing or treating ischemia-reperfusion injury which comprises a step of administering heparin cofactor-1 II to a patient.
  • ischemia-reperfusion injury is ischemia-reperfusion injury due to reperfusion after ischemia caused by ischemic heart disease.
  • a method for preventing or treating ischemia-reperfusion injury which comprises a step of administering heparin cofactor-1 II after ischemia and before reperfusion.
  • a prophylactic or therapeutic agent for ischemic injury or ischemia-reperfusion injury according to any of (1) to (4) above, and the prophylactic or therapeutic agent for ischemic injury or ischemia-reperfusion injury A commercial package containing documentation stating that it can or should be used for prevention or treatment.
  • HCII used in the present invention is not particularly limited as long as it is purified to such an extent that it can be used as a medicament.
  • Naturally-derived HCII for example, human, monkey, pest, puma, Dogs, gray herons, mice, rats and other mammals.
  • those derived from a recombinant host genetically manipulated to produce HCII, those synthesized by chemical synthesis, etc. are those derived from a recombinant host genetically manipulated to produce HCII, those synthesized by chemical synthesis, etc.).
  • one or more amino acids in the amino acid sequence of HCII have mutations such as deletion, substitution, addition or induction, and those in which such mutations have been made by known means.
  • Naturally derived HCII can be obtained, for example, by purifying human whole blood, plasma, serum, or serum expressed from coagulated blood.
  • a method for purifying whole plasma fractionated plasma, corn by fractionation method I, supernatant ⁇ + III or fractionation IV or decryoplasm, anion exchange chromatography, cation exchange chromatography
  • An example is a method of performing a parin treatment on a lithography treatment or a solid-phase treatment (JP-A-9-286797).
  • hydrophobic chromatography fractionation with a water-soluble polymer, salting out, or use basic amino acid as a ligand.
  • Processing by affinity chromatography can be performed. These processes may be used alone or in combination.
  • the hydrophobic chromatographic treatment is carried out, for example, by bringing a solution containing HC II and a depolymerizing factor into contact with a carrier for hydrophobic chromatography under conditions of pH 6 to 9.
  • the term “molecular-weight-decreasing factor” as used herein refers to a substance that degrades HC II to a molecular weight.
  • Examples of the carrier for hydrophobic chromatography include an alkyl group type having 4 to 18 carbon atoms (for example, a butyl group type, an octyl group type, an octyl decyl group type), and a fuunyl group type.
  • Examples of the butyl group type include butyl monoagarose and butyl polyvinyl (trade name: butyl toyopearl, manufactured by Tosoh Corporation).
  • Examples of the octyl group type include octyl agarose, and examples of the octyl decyl group type include: Octyldecyl-garose and the like.
  • phenyl group type examples include phenyl monocellulose (trade name: Phenylseguchi Fine, manufactured by Seikagaku Corporation).
  • Phenylseguchi Fine manufactured by Seikagaku Corporation.
  • the fractionation treatment with the water-soluble polymer is preferably performed at 1 to 30 ° / o (w / v) of the water-soluble polymer. Is performed by adding to a solution containing HCII and a depolymerizing factor so as to have a concentration of 3 to 20% (w / v), more preferably 6 to 12% (w / v). By this treatment, HCII remains in the solution, and the low molecular weight factor precipitates. By centrifuging or filtering the treated solution and collecting the supernatant (filtrate), the low molecular weight factor can be separated from HCII.
  • the water-soluble polymer refers to polyethylene glycol (PEG), a nonionic surfactant or the like. PEG preferably has an average molecular weight of 4000 to 6000. Examples of the surfactant include polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene (20) sorbitan monooleate.
  • the salting-out treatment is performed by adding a salt such as sodium, potassium, barium, ammonium, etc., for example, chloride, sulfate, phosphate, etc. to a solution containing HCII and a molecular weight reducing agent at a concentration of 0.05 to 0.25 M. Is carried out. Preferably, a method in which barium chloride is added to a concentration of 0.05 to 0.2 M is exemplified. By this treatment, HCII remains in the solution, and the depolymerizing factor precipitates. By centrifuging or filtering the treatment solution and collecting the supernatant or solution, the low molecular weight factor can be separated from HCII.
  • a salt such as sodium, potassium, barium, ammonium, etc.
  • a solution containing HCII and a molecular weight-decreasing factor can be treated with a basic amino acid such as lysine or arginine (preferably lysine) as a ligand under a pH condition of 6 to 9.
  • a basic amino acid such as lysine or arginine (preferably lysine)
  • the carrier include insoluble supports such as polysaccharides, silica gel, and fibers. More specifically, it is agar, agarose, cross-linked agarose, cellulose, silica, nylon, hydrophilic vinyl polymer and the like.
  • HCII is recovered in the unadsorbed fraction, and the depolymerizing factor is adsorbed on the carrier.
  • the step of separating HCII from the low molecular weight factor should be performed at an early stage of purification. Is more preferred.
  • the solution containing HCII and the molecular weight-decreasing factor is contacted with immobilized heparin to bind HCII to heparin.
  • the immobilized heparin is, for example, monomeric heparin bound to a solid phase such as an insoluble support such as polysaccharide, silica gel, or fiber. Its support Examples of carriers include agar, agarose, cross-linked agarose, cellulose, silica, nylon, hydrophilic vinyl polymers, and others known in the art.
  • Such heparin immobilization on the solid phase may be performed not only before the above-described step of separating HCII and the molecular weight-decreasing factor but also after it.
  • the polymerized HCII means a polymer of HCII molecules, which has no physiological activity of HCII and low affinity for heparin. More specifically, it is a dimer or higher polymer.
  • HCII is washed with a buffer solution having a salt concentration of about 0.05 to 0.2 M or the like, preferably after stepwise increasing the salt concentration and repeating the washing operation, and then washed with a salt concentration of about 0.05 to 1.0 M, preferably 0.1 It is eluted from the immobilized heparin by a method such as contacting with a buffer solution of about 0.5 M, more preferably about 0.1 to 0.2 M.
  • the salt component for adjusting the ionic strength include sodium chloride, sodium chloride, ammonium sulfate, sodium thiocyanate, and sodium sulfate. Preferably it is sodium chloride.
  • the pH of the buffer is preferably set to 6 to 9.
  • the HCII-containing solution can be further subjected to anion exchange chromatography.
  • anion exchangers used include DEAE type [DEAE-Sephadex, DEAE-Cellulose, DEAE-Sepharose, DEAE-Polybininole (eg: DEAE-Toyopearl), etc.], QAE type [QAE-Sephadex, QAE-Cenorelose , QAE-Sepharose, QAE-Polyvinyl (eg ⁇ QAE—Toyopearl)].
  • Equilibration and washing of the anion exchanger in one treatment of anion exchange chromatography are performed using a 0.005 to 0.1 M citrate buffer (about pH 6 to 8) and a 0.005 to 0.1 M phosphate buffer (about ⁇ 6 to 8). ) Or by using 0.005 to 0.1 M Tris-HCl buffer (pH 7 to 9).
  • the elution of HCII from the anion exchanger is a buffer used for equilibration and washing, and contains 0 ⁇ 5-0.5 ⁇ , preferably 0.2-0.25 ⁇ sodium chloride. Is used.
  • the order of one treatment of ion exchange chromatography is not particularly limited, and can be arbitrarily selected.
  • All buffers used in each of the above steps should contain 0.001% to 1.0% (w / v) of a water-soluble polymer (eg, PEG4000) to prevent polymer formation. preferable.
  • the HC II active fraction obtained as a result of each of the above purification processes may be contaminated with low molecular weight HC II molecules.
  • HCII means a fragmented HCII molecule that gives a peak (shoulder) that can be distinguished from an effective HCII peak by high-performance liquid chromatography (hereinafter referred to as HPLC). Conditions will be described later). Therefore, in order to separate and remove the low molecular weight HCII, it is preferable that the HCII active fraction is further subjected to a separation step based on a difference in molecular weight such as ultrafiltration and Z or gel filtration chromatography.
  • the ultrafiltration membrane used for ultrafiltration is not particularly limited as long as it has a pore size that allows only low molecular weight HCII to pass without passing effective HCII.
  • Membrane of acrylonitrile copolymer, aromatic nylon, polysulfone, polyvinylidene polyfluoride, polyimide resin, etc. is usually used, and various forms such as tubular membrane, flat membrane, spiral module and hollow fiber module are selected and used it can. Since the pore size of the ultrafiltration membrane is not constant, if the difference in molecular weight between the low molecular weight HCII to be removed and the effective HCII is small, first concentrate the effective HCII by ultrafiltration, then It is preferable to carry out filtration chromatography.
  • Gels used for gel filtration chromatography include cross-linked dextran beads (eg, Sephadex), Futachika polyacrylamide beads (eg, Biogel), agarose gel (eg, Sepharose), and dextran monoacrylamide (eg, Sephacryl). ) And the like.
  • a 0.01 to 0.05% citrate buffer or a phosphate buffer (about 6 to 9) containing O to 0.5M, preferably 0.1 to 0.2M sodium chloride is used.
  • the purity was 98% or more, preferably 99.9 ° /.
  • the above HC II-containing composition can be obtained (PCT / JP98 / 04939).
  • those derived from the recombinant host include, for example, native HCII (see, for example, Blinder et al., Biochemistry, 27, 752-759 (1988)), or antithrombin activity is retained or improved.
  • a culture solution or cell extract obtained by culturing a host cell transformed with a gene encoding the mutated HC II (see, for example, JP-A-3-139280), or encoding HC II It can also be obtained from bodily fluids or milk of transgenic animals incorporating the gene.
  • the preventive or therapeutic agent for ischemic injury or ischemia-reperfusion injury of the present invention includes an agent for suppressing ischemia injury occurring in a living tissue during ischemia and reperfusion injury occurring during reperfusion after ischemia.
  • ischemic injury or ischemia-reperfusion injury include heart disorders (eg, ischemic heart disease, myocardial infarction, etc.), cerebrovascular disorders (eg, cerebral thrombosis, cerebral infarction, etc.), kidney disorders (eg, nephritis, UX insufficiency) Etc.), liver disorders (eg, fulminant hepatitis, etc.), lung disorders (eg, acute lung injury, adult respiratory distress syndrome (ARDS), etc.), and knee disorders (eg, knee inflammation, etc.).
  • heart disorders eg, ischemic heart disease, myocardial infarction, etc.
  • cerebrovascular disorders eg, cerebral thrombosis, cerebral infarction, etc.
  • kidney disorders e
  • ischemic injury or ischemia reperfusion injury examples include ischemia injury due to vascular occlusion during organ transplantation including blood vessels or surgery involving ischemia, and ischemia reperfusion due to reperfusion after ischemia due to vascular occlusion. Obstacles are a specific example.
  • the disorders also include new myocardial * a tissue disorders that occur after reperfusion in ischemic heart disease.
  • the agent for preventing or treating ischemic injury or ischemia-reperfusion injury of the present invention can be formulated by a method known per se. At this time, if necessary, treatments such as heating, sterilization, sterilization filtration, freeze-drying, etc. are performed, and pharmaceutically acceptable additives (eg, carriers, excipients, buffers, isotonicity) in each treatment step. Agents, stabilizers, diluents, solubilizers, etc.) Freeze-dried; ⁇ form of liquid, liquid, etc. is obtained.
  • pharmaceutically acceptable additives eg, carriers, excipients, buffers, isotonicity
  • a freeze-dried preparation in which HC II is prepared as a freeze-dried product together with a pharmaceutically acceptable excipient and then dissolved in a suitable vehicle (eg, distilled water, sterile purified water, physiological saline, etc.) at the time of use.
  • a suitable vehicle eg, distilled water, sterile purified water, physiological saline, etc.
  • the lyophilized preparation is preferably diluted with, for example, distilled water for injection so that the HCII concentration becomes about 0.1 to 100 mg / ml.
  • compositions that can be incorporated into the prophylactic or therapeutic agent for ischemic injury or ischemia-reperfusion injury of the present invention include, for example, buffers (those that maintain a physiologically preferable pH value of the preparation) , Isotonic agent (the salt is not particularly limited as long as it maintains the physiologically isotonic salt concentration of the preparation), stabilizing agent (eg, sugars such as mannitol, sorbitol, etc.) ) And the like, but not particularly limited thereto.
  • buffers such as a physiologically preferable pH value of the preparation
  • Isotonic agent the salt is not particularly limited as long as it maintains the physiologically isotonic salt concentration of the preparation
  • stabilizing agent eg, sugars such as mannitol, sorbitol, etc.
  • the route of administration of the agent for preventing or treating ischemic injury or ischemia-reperfusion injury according to the present invention includes parenteral administration.
  • the administration form include injections, infusions, or mucous membranes or skin Absorbents and the like.
  • the prophylactic or therapeutic agent of the present invention may be administered locally.
  • the preventive or therapeutic agent for ischemic injury or ischemia-reperfusion injury of the present invention can be administered at any time before, during, or after ischemia, and ischemic injury or ischemia-reperfusion injury is predicted.
  • This dose can be appropriately increased or decreased according to the patient's symptoms, weight, sex, etc., but is usually 0.1 to 300 mg / kg, preferably; Administer 100 mg / kg once to several times per B.
  • the administration is preferably performed, for example, after ischemia and before reperfusion.
  • the amount of HC II is calculated from the numerical value (A280) obtained by measuring the absorbance at a wavelength of 280 nm for 1 mL of an HC II-containing solution having a purity of 98% or more in HPLC analysis under the following conditions.
  • the extinction coefficient was calculated as 5.93.
  • the 11 + II II which was obtained according to the method of Kohn et al. (J. Am. Chem. So, 72, 465 (1950)), was used for the heparin affinity chromatography-carrier (trade name: he (Parintoyopearl: manufactured by Tosoh I) was passed through a lOOmL column which was washed with 10 mM sodium citrate buffer (pH 6.8) containing 21% ethanol, and then 400 mM at 2-10 ° C. of Kuen acid Natoriumu aqueous lOraM containing chloride Natoriumu (P H7. 0) to afford the eluate fractions were eluted (hereinafter referred to as "Paris emission eluent to”) used.
  • the heparin eluate was diluted with 20 mM phosphate buffer (pH 8) and washed with the same buffer. After passing through a column packed with an anion exchanger (trade name: QAE Toyopearl 550C: manufactured by Tosoh Corporation), the eluted fraction was eluted using 20 mM phosphate buffer containing 250 ⁇ sodium chloride. Obtained. The eluate was dialyzed against a 0.02 M buffer of Tris-monohydrochloride (pH 8.5).
  • heparin affinity chromatography carrier (trade name: Heparinto Yopearl: manufactured by Tosoh Corporation) washed with the same buffer, lOOmM sodium chloride was added.
  • the eluted fraction was eluted using a 20 mM Tris-monohydrochloride buffer (pH 8.5) to obtain an eluted fraction.
  • the composition (5 mL) was added to a hydrophobic chromatography support ( Trade name: Phenylsephalose: Amersham Pharmacia) and equilibrated with 20 mM Tris-hydrochloric acid buffer (developing solution) containing 1 M ammonium sulfate ( ⁇ 6 x 5 cm, column volume lOraL) ). After applying the composition to the column, the column volume 15723
  • Occlusion was performed for 15 minutes, followed by reperfusion. Before and after drug administration, the left ventricular pressure volume map was recorded with the left ventricular volume measuring device Sigma 5 (manufactured by eycom, The Netherlands) 15 minutes after LAD occlusion (immediately after reperfusion) and 15, 60, and 120 minutes after reperfusion.
  • the ventricular end-systolic elastance (Ees, an index of left ventricular contractility) and the arterial effective elastance (Ea, afterload) were calculated, and the ventricular artery coupling (Ees / Ea) was calculated.
  • left ventricular function (Ees / Ea) decreased in the control group immediately after reperfusion.
  • Ees / Ea did not decrease in the group to which HC II was administered, suggesting that HC II has an inhibitory effect on left ventricular dysfunction (Table 1).
  • NO 2 one / N0 shortly after reperfusion 3 - is, endothelin after 15 minutes reperfusion - 1 is increased, but it was suggested that vascular endothelial disorder occurs, either in the HC II group There was no increase in the parameters (Tables 2 and 3).
  • Example 2 Cardioprotective effect of HC II in rat myocardial ischemia-reperfusion model
  • HC II (42mg / 7.24raL / kg AT Administer a solvent (10 mM phosphate buffer, 0.15 NaC1, pH 7.0) from the left femoral artery as a control, and 5 minutes later, ligate the coronary artery for 20 minutes to perform myocardial ischemia. Blood was taken.
  • Left ventricular function was measured before administration of the drug and at 30, 60, and 120 minutes after reperfusion, using left ventricular pressure analysis software (Vmax TC Analize ver. 1.1.0, Fujitech).
  • LV dP / dt max was calculated as an index of systolic function
  • LV dP / dt min was calculated as an index of diastolic function.
  • the weight of the myocardial necrosis was measured by ligating the coronary artery again 120 minutes after reperfusion, and using the EVANS blue solution ( After administering 2 mL of bolus (20 mg / mL) from the right femoral vein, the heart was excised and the weight of the left ventricle was measured. The necrotic part was stained with the solution (37 minutes, 20 minutes), and the weight of the unstained necrotic part was measured, and the weight of the necrotic part was calculated from these values.
  • HC II has an excellent effect of preventing or treating ischemic injury or ischemia-reperfusion injury.
  • the freeze-dried product was dissolved in 20 mL of distilled water for injection at the time of use to prepare an intravenous formulation.
  • the heparin cofactor II of the present invention has a cardioprotective effect in a canine myocardial ischemia-reperfusion model, a myocardial protective effect in a rat myocardial ischemia-reperfusion model, and ischemic injury or ischemia-reperfusion injury from other pharmacological experiments.
  • This application is based on U.S. Patent Application No. 248031 filed in Japan, the contents of which are incorporated in full herein.

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  • Urology & Nephrology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention concerne de nouveaux médicaments pour prévenir ou traiter des lésions ischémiques ou des lésions de reperfusion ischémique, lesquels contiennent le cofacteur d'héparine II. Ces médicaments de prévention ou de traitement ont un effet protecteur sur le myocarde de modèles canins présentant une reperfusion ischémique du myocarde, un effet protecteur myocardique chez des modèles murins présentant une reperfusion ischémique myocardique, etc., ce qui montre que ces médicaments peuvent être utilisés pour prévenir ou traiter des lésions ischémiques ou des lésions de reperfusion ischémique, en particulier une lésion ischémique ou une lésion de reperfusion ischémique associée à des maladies cardiaques ischémiques.
PCT/JP2000/005974 1999-09-01 2000-09-01 Medicaments pour la prevention ou le traitement de lesions ischemiques ou de lesions de reperfusion ischemique Ceased WO2001015723A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68691/00A AU6869100A (en) 1999-09-01 2000-09-01 Preventives or remedies for ischemic injury or ischemic reperfusion injury

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP24803199 1999-09-01
JP11/248031 1999-09-01

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019789A1 (fr) * 1994-01-21 1995-07-27 The Green Cross Corporation Agent de prevention ou de traitement des troubles moteurs
JPH09110718A (ja) * 1995-10-16 1997-04-28 Green Cross Corp:The 虚血再灌流肝障害治療剤
EP0781558A2 (fr) * 1995-12-27 1997-07-02 Minoru Tsukada Utilisation pharmaceutique du cofacteur II de l'héparine
JP2000290196A (ja) * 1999-03-31 2000-10-17 Welfide Corp 血圧低下抑制剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019789A1 (fr) * 1994-01-21 1995-07-27 The Green Cross Corporation Agent de prevention ou de traitement des troubles moteurs
JPH09110718A (ja) * 1995-10-16 1997-04-28 Green Cross Corp:The 虚血再灌流肝障害治療剤
EP0781558A2 (fr) * 1995-12-27 1997-07-02 Minoru Tsukada Utilisation pharmaceutique du cofacteur II de l'héparine
JP2000290196A (ja) * 1999-03-31 2000-10-17 Welfide Corp 血圧低下抑制剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YASUO YAMAGUCHI: "Kyoketsu saikanryu shougai ni okeru kouchukyu to kekkan naihi saibou no inter-action", NIPPON GEKA GAKKAI ZASSHI, vol. 100, no. 5, May 1999 (1999-05-01), pages 319 - 324, XP002934778 *

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