WO2000001406A1 - Utilisation medicinale du cofacteur ii de l'heparine - Google Patents

Utilisation medicinale du cofacteur ii de l'heparine Download PDF

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Publication number
WO2000001406A1
WO2000001406A1 PCT/JP1999/003646 JP9903646W WO0001406A1 WO 2000001406 A1 WO2000001406 A1 WO 2000001406A1 JP 9903646 W JP9903646 W JP 9903646W WO 0001406 A1 WO0001406 A1 WO 0001406A1
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Prior art keywords
disease
agent
preventing
treating
macrophages
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PCT/JP1999/003646
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English (en)
Japanese (ja)
Inventor
Minoru Tsukada
Takashi Gotoh
Teruaki Imada
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Welfide Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Welfide Corporation filed Critical Welfide Corporation
Priority to AU43975/99A priority Critical patent/AU4397599A/en
Publication of WO2000001406A1 publication Critical patent/WO2000001406A1/fr

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    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel medicinal use of heparin cofactor II (hereinafter abbreviated as HCII). More particularly, the present invention relates to the use of HC II for the prevention and treatment of diseases involving macrophages, lung epithelial cells and / or synovial cells. The present invention also relates to the above-mentioned agent for local administration, which comprises HCII as an active ingredient.
  • HCII heparin cofactor II
  • HCII is a plasma glycoprotein that has a blood coagulation inhibitory effect, and is known to inhibit proteases such as thrombin mainly in vitro (i /? Vitro) in the presence of dermatan sulfate and a large amount of heparin (Tollefsen et al., J.
  • HCII is different from antithrombin III (hereinafter abbreviated as A)), which exhibits an antithrombin action in the presence of heparan sulfate, and is specific at a site where a large amount of dermatan sulfate is present in vivo. It is thought that HCII alone may be administered in vivo (in vivo), and that HCII exhibits anticoagulant effects in specific organs, tissues or cells. It has been clarified that systemic administration is effective in the prevention and treatment of various diseases such as sepsis, diseases causing abnormal blood flow, and organ disorders such as liver, lung, kidney, and brain (EP-7815) No. 58).
  • A antithrombin III
  • HCII is expected to be able to act specifically in vivo when administered alone, systemic administration requires large doses to achieve an effective therapeutic effect. May not be obtained.
  • an object of the present invention is to search for a further pharmaceutical use of HCII, that is, a novel therapeutic effect of HCII for a disease, and to clarify the mechanism of the therapeutic effect.
  • Another object of the present invention is to provide an HCII preparation which provides a selective therapeutic effect at a site to be treated by local administration of a low dose of HCII, thereby treating said disease.
  • HCII has a remarkable prophylactic and therapeutic effect on joint diseases such as rheumatoid arthritis and osteoarthritis, and that the prophylactic and therapeutic effect can be obtained by combination use of ⁇ and Z or pelinastatin Has been found to be further enhanced.
  • HCII is a macrophage present in the joint capsule (a connective tissue membrane present around the joint) and a cell of synovial cells or macrophages. It has been found that it suppresses the function, that is, the abnormal increase of serine protease producing action and cytokine producing action, and suppresses the proliferation of these cells.
  • the present inventors have considered, among other diseases for which the therapeutic effect of HCII is known, a disease caused by abnormal dysfunction of cells performing the same cell function as macrophage synovial cells, specifically, Pulmonary epithelial cells present in the alveoli, macrophages in the abdominal cavity, macrophages appearing around the site of vascular injury, are caused by abnormal enhancement of thrombin and other serine proteinase-producing, blood clotting, and cytokine-producing effects Similarly, the mechanism of HCII treatment for pulmonary diseases and diseases associated with vascular disorders Investigated Nism. As a result, it was also found that HCII exerts a therapeutic effect on these diseases by similarly suppressing the abnormal enhancement of the above-mentioned cell functions of the lung epithelial cells ⁇ Macular phage.
  • the present inventors have investigated the administration of the above-mentioned joint disease, pulmonary disease and vascular disease to the joint cavity in which synovial cells are present and the alveoli in which pulmonary epithelial cells are present.
  • Local administration of HCII in the respiratory tract and around the site of vascular injury where migratory macrophages are present the present invention succeeded in obtaining at least the same preventive and therapeutic effects as systemic administration of HCII. It was completed.
  • the present invention is as follows.
  • Macrophages, pulmonary epithelial cells or synovial cells containing pharmaceutically effective amount of HCII and pharmaceutically acceptable carrier, especially serine protease producing action, blood clotting activity activating action A preventive and therapeutic agent for a disease caused by abnormally high activity of at least one of and cytokine production.
  • An agent for preventing and treating joint diseases comprising a pharmaceutically effective amount of HCII and a pharmaceutically acceptable carrier.
  • the agent for preventing or treating a disease according to any one of the above (1) to (4) which is in a form for local administration, particularly for administration to a joint, an airway or a site around a vascular disorder.
  • Macrophages, pulmonary epithelial cells or synovial cells have cell functions, especially serine protease generation, blood coagulation activation and cytokine production.
  • H C II Use of H C II for prevention and treatment of a disease caused by abnormally increased production of serine protease in macrophages, pulmonary epithelial cells or synovial cells in vivo.
  • HCII for the manufacture of a prophylactic and therapeutic agent for a disease caused by abnormally increased production of serine protease in macrophages, pulmonary epithelial cells or synovial cells in vivo.
  • the disease preventive and therapeutic agent further contains AT 111 and / / or ⁇ Rinasutachin pharmaceutically effective amount.
  • Therapeutic agent is used for the treatment of diseases caused by abnormally enhanced macrophages, lung epithelial cells or synovial cells, in particular, the production of serine protease, at least one of blood coagulation activation and cytokine production.
  • the agent for preventing or treating a disease of the above 2 or 6, and the agent for preventing and treating the disease are capable of abnormally increasing the production of serine protease in macrophages, lung epithelial cells or synovial cells in vivo.
  • (21) Includes the agent for preventing or treating the disease of 4 or 6 above, and the package insert stating that the agent for preventing or treating the disease can or should be used for the prevention and treatment of joint disease Commercial package.
  • HC II has a prophylactic and therapeutic effect on diseases caused by abnormally enhanced cell functions of macrophages, lung epithelial cells or synovial cells.
  • Tissue factor is expressed on the cell surface in the presence of cytokines released or released from these cells as macrophages, lung epithelial cells or synovial cells, and promotes blood coagulation. Stimulation of thrombin and other serine proteases to produce cytokines, and lung epithelial cells and synovial cells stimulate their own cell growth by stimulation of thrombin and the like, but are not limited thereto. .
  • the disease caused by abnormally enhanced cell functions of macrophages, lung epithelial cells or synovial cells includes at least one of serine protease generation, blood coagulation activation and cytokine production.
  • diseases caused by abnormal enhancement of one of the actions for example, abnormal functioning of synovial cells and synovium-derived macrophages present in the joint cavity, such as rheumatoid arthritis and osteoarthritis.
  • ARDS acute respiratory distress syndrome
  • IRDS idiopathic respiratory distress syndrome
  • pulmonary disease caused by abnormal dysfunction of lung epithelial cells present in the alveoli, postoperative disorders (Eg, restenosis after PTCA), atheroma, and the like, which are caused by abnormal dysfunction of macrophages existing around the site of vascular injury.
  • the HCII used in the present invention is not particularly limited as long as it is derived from mammals such as humans, monkeys, pests, pomas, dogs, puppies, mice, and rats. Are preferably used. Moreover, as long as it is purified to the extent that it can be used as a medicine, it may be natural or artificial. Natural products can be purified from known whole blood of mammals such as humans, whole plasma, plasma fraction, serum or serum squeezed from coagulated blood using known means. A method for purifying HCII from human plasma is described in, for example, Blinder et al. (Biol. Chem., 264: 5128-5133, 1989), Japanese Patent Application Laid-Open No. 9-186697, and the like.
  • the agent for preventing and treating diseases of the present invention is obtained by appropriately mixing HCII with necessary components such as pharmaceutically acceptable carriers (eg, excipients, diluents, etc.), and injecting, injecting, tablets, capsules, and tablets. It can be formulated into any commonly used dosage form such as a preparation and can be administered orally or parenterally.
  • pharmaceutically acceptable carriers eg, excipients, diluents, etc.
  • the agent for preventing and treating diseases of the present invention is preferably formulated into a dosage form generally used for topical administration.
  • HCII is formulated into a liquid formulation together with a pharmaceutically acceptable carrier, or is prepared as a solid formulation such as powders, granules, tablets, etc. Sterile purified water, physiological food Salt water).
  • a pharmaceutically acceptable carrier as a lyophilized sample, and dilute it at the point of use with distilled water for injection, for example, so that the HC ⁇ concentration will be approximately 0.01-10000 units1. It is preferable to use them.
  • compositions for preventing and treating diseases of the present invention include, for example, buffers (which are not particularly limited as long as they maintain a physiologically preferable pH value), and the like.
  • buffers which are not particularly limited as long as they maintain a physiologically preferable pH value
  • examples include tonicity agents (these are not particularly limited as long as they maintain a physiologically isotonic salt concentration), and stabilizers (eg, saccharides such as mannitol and sorbitol), but are not particularly limited thereto.
  • the agent for preventing and treating diseases of the present invention can be locally administered to a site to be treated, for example, a joint, a respiratory tract, or a vascular disorder site.
  • the dose of HCII varies depending on the degree of disease progression, the severity of the patient (patient), tolerance to drugs, the species of animal, etc., but it is usually 5 to 100 000 units (0.1 2002000 units (in terms of Z kg), preferably about 50-25000 units (in terms of 1-500 units in terms of Z kg), and this amount can be administered once or in several divided doses.
  • the agent for preventing and treating diseases of the present invention can be administered using an administration route such as oral, intravenous or intravenous, in addition to local administration.
  • the dose of HCII varies depending on the degree of disease progression, the severity of the patient (patient), tolerance to drugs, body weight, animal species, etc., but usually 1 to 10,000 units / day for an adult. It is about kg body weight, preferably about 10 to 2000 units Zkg body weight, and this amount can be administered once or in several divided doses (In the present invention, the titer of HCII is in the presence of heparin.
  • the antithrombin activity of HCII was measured by the synthetic substrate method, and a calibration curve was prepared using ⁇ with a known titer, and one unit of ⁇ was regarded as one unit of HCII ⁇ One unit was 1 m 1 of normal human plasma Equivalent to the amount contained in).
  • the agent for preventing and treating diseases of the present invention is more preferably used in combination with ⁇ and Z or pelinastatin.
  • ⁇ and / or pelinastatin It may be formulated into an HCII formulation and formulated, or may be formulated individually and administered sequentially or simultaneously.
  • ⁇ and ⁇ linastatin can be used together with necessary components such as pharmaceutically acceptable carriers (eg, excipients, diluents, etc.), as well as injections, tablets, capsules, syrups, etc. Can be formulated into any of the commonly used dosage forms and can be administered orally or parenterally. If HCII is administered topically, ⁇ and pelinastatin can also be formulated in a form for topical administration.
  • ATIII or pelinastatin may be prepared as a liquid formulation together with pharmaceutically acceptable excipients, or prepared as a solid formulation such as powders, granules, tablets, etc. Water, sterile purified water, physiological saline, etc.).
  • ⁇ or pelinastatin is prepared and stored as a lyophilized sample together with a pharmaceutically acceptable carrier, and when used, for example, the AT III concentration is adjusted to about 0.01 to 10,000 units / m1 with distilled water for injection.
  • the concentration of pelinastatin is about 10 to 50,000 units / m1 (the titer of pelinastatin was applied to trypsin 2 / ig, and the amount that inhibited the enzyme activity of 1 ⁇ g of trypsin was defined as 1 unit of pelinastatin). It is preferable to use it after diluting it.
  • the pharmaceutically acceptable carrier include the same carriers as in the above HCII preparation.
  • HCII When HCII is used in combination with ATIII and / or pelinastatin, the dosage of each component varies depending on the route of administration, disease progression, patient (patient) severity, drug tolerance, body weight, animal species, etc.
  • systemic administration such as oral, intravenous, and intraarterial administration
  • HCII per adult day is usually: ⁇ 10000 units / kg body weight, ATIII and pelinastatin, respectively, 1-10000 units Zkg body weight and 10-20000 units / kg body weight, preferably HC II 10-2000 units Z kg body weight, AT III And pelinastatin are 10-2000 units Zkg body weight and 10-10000 units Zkg body weight, respectively.
  • HCII is usually about 5 to 100,000 units
  • Nastatin is about 5 to 100,000 units and about 500 to 100,000 units, respectively
  • HCII is about 50 to 25,000 units
  • ⁇ and perinastatin are about 50 to 25,000 units and about 5000 to 100,000 units, respectively.
  • a heron (Japanese white, male, 3 to 4 months old) was administered lml of 1% lagedin-added saline twice every 7 days into the knee joint cavity of the left hind limb.
  • the knee joint diameter in the horizontal direction was measured with a vernier caliper before and after the second dose of force-lagenin, and the ratio (%) of the joint diameter after the second dose to the joint diameter before the force-lagenin was calculated to swell.
  • Degree Choose a heron with the same degree of swelling and divide it into 7 groups of 9 birds per group.
  • the left knee joint diameter was measured, and the swelling (%) was calculated as the swelling degree based on the joint diameter before the administration of tyrageenin.
  • the patella pad was cut, lml of cold saline was injected into the joint cavity, and the joint cavity was sufficiently spread.Then, 0.5 ml of the joint fluid 0.5 ml was injected using a syringe. Collected.
  • the acid phosphatase activity in the synovial fluid was measured using an acid phosphatase activity measurement kit (manufactured by Sigma) according to the attached protocol. Further, the degree of thrombus formation, the degree of synovial cell proliferation, and the degree of bone destruction were measured by conventional methods. Table 1 shows the results.
  • Macrophages were collected intraperitoneally or from atherogenic vessels. Synovial cells were obtained from synovium obtained by synovectomy from rheumatic patients. Pulmonary epithelial cells were isolated from rat lungs by conventional methods. Some macrophages, synovial cells and lung epithelial cells were cultured to obtain cultures (free and released).
  • thrombin receptor 1 day later and the number of cells 4 days later were measured. Receptor expression and cell proliferation were compared between those with and without the addition of HC 11 during thrombin stimulation. Table 4 shows the results.
  • Thrombin (1 nmo 1 ZL for macrophage stimulation, 100 nm for others) o1 / L) was added to peritoneal macrophages, macrophages collected from the plaque-forming blood vessels, lung epithelial cells or synovial cells, and cultured at 37 ° C. TNF, IL-16, GM—CSF was examined. The expression of each of the above cytokines was compared between the case where HCII was added during thrombin stimulation and the case where HCII was not added. Table 5 shows the results.
  • Cytokine produced by each cell at the time of thrombin stimulation Percentage of each cytokine produced by each cell at the time of addition of HCII Cytokine production was increased by thrombin stimulation at all cells, but the addition of HCII was not This was suppressed.
  • HCII exhibits an antithrombin activity (anticoagulant activity) in the presence of macrophages, lung epithelial cells or synovial cells, and also has an inhibitory effect on the proliferation of these cells and an inhibitory effect on the production of site force. Therefore, it is useful for prevention and treatment of diseases involving macrophages, lung epithelial cells or synovial cells.
  • the agent for preventing and treating diseases of the present invention is extremely useful because topical administration can provide excellent preventive and therapeutic effects with low doses of HCII.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne l'utilisation du cofacteur II de l'héparine dans la prévention et le traitement de maladies provoquées par l'accélération anormale des fonctions de macrophages, des cellules épithéliales pulmonaires et/ou des cellules synoviales, notamment un effet favorisant la coagulation sanguine et un effet producteur de cytokine (par exemple, des maladies articulaires, des maladies pulmonaires, des maladies associées à l'insuffisance vasculaire); ainsi que l'utilisation du cofacteur II de l'héparine dans la production de préventifs/remèdes pour les maladies précitées. Les préventifs/remèdes contenant le cofacteur II de l'héparine peuvent être administrés localement à une articulation, aux voies respiratoires, en liaison avec une insuffisance vasculaire, etc. et obtiennent un effet thérapeutique sur le site ciblé en une dose de HCII faible.
PCT/JP1999/003646 1998-07-07 1999-07-05 Utilisation medicinale du cofacteur ii de l'heparine WO2000001406A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43975/99A AU4397599A (en) 1998-07-07 1999-07-05 Medicinal utilization of heparin cofactor ii

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JP10/191977 1998-07-07
JP19197798 1998-07-07

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WO2000001406A1 true WO2000001406A1 (fr) 2000-01-13

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019701A2 (fr) * 1995-11-30 1997-06-05 Hamilton Civic Hospitals Research Development, Inc. Conjugues de glycosaminoglycanes-antithrombine iii/co-facteur ii de l'heparine
JPH09176040A (ja) * 1995-12-27 1997-07-08 Green Cross Corp:The ヘパリンコファクターｉｉの医薬用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019701A2 (fr) * 1995-11-30 1997-06-05 Hamilton Civic Hospitals Research Development, Inc. Conjugues de glycosaminoglycanes-antithrombine iii/co-facteur ii de l'heparine
JPH09176040A (ja) * 1995-12-27 1997-07-08 Green Cross Corp:The ヘパリンコファクターｉｉの医薬用途

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